Thesis of Manjusha Sudha Devi (05.03.2021)

Effect of Antioxidants and B-Group Vitamins on Risk of Infections
in Patients with Type 2 Diabetes Mellitus
TABLE OF CONTENTS
LIST OF TABLES II
LIST OF FIGURES III
LIST OF ABBREVIATIONS IV
ABSTRACT VI
CHAPTER 1: GENERAL INTRODUCTION 1-43
CHAPTER 2: LITERATURE REVIEW 44-110
CHAPTER 3: MATERIALS AND METHODS 111-121
CHAPTER 4: RESULTS 122-145
CHAPTER 5: DISCUSSION 146-162
CHAPTER 6: CONCLUSION 163-166
BIBLIOGRAPHY 167-172
Page I
LIST OF TABLES
Table No. Description Page
No.
Table 3.1: Vitamins and their concentration 116
Table 4.1: Patient's general characteristic (n = 100) 122
Table 4.2A: Baseline characteristics placebo and 124
supplement group
Table 4.2B: Baseline characteristics placebo and 126
supplement group
Table 4.2C: Baseline characteristics placebo and 127
supplement group
Table 4.2D: Baseline characteristics of responder and 129
non-responder of the study population
Table 4.2E: Responders baseline characteristics of 130
placebo and supplement group
Table 4.2F: Non-Responders baseline characteristics of 131
placebo and supplement group
Table 4.3A: Baseline and three months plasma 133
antioxidants and inflammatory markers in
the intervention group compared with the
placebo group (mean SD).
Table 4.3B: Baseline and three months plasma 134
placebo group
Table 4.3C: Baseline and three months plasma 135
Supplement group
Table 4.4A: Frequencies of infections over three months 137
in diabetic subjects of treatment and placebo
groups (n %).
Page II
Table 4.4B: Frequencies of infections over 12 months in 138

diabetic subjects of treatment and placebo
groups (n %).
Table 4.5: Food diary in diabetic subjects on treatment 139
and placebo (mean SD)
Table 4.6A: Exercise diary in diabetic subjects on 142
treatments and placebo at three months
Table 4.6B: Exercise diary in diabetic subjects on 143
supplements and placebo at 12 months
LIST OF FIGURES
Figure No. Description Page No.
Figure 3.1: Enrolment, treatment and follow up of study 113
patients.
Figure 4.1: Baseline and three months plasma 134
the intervention group compared with the
placebo group
placebo group
Supplement group
Figure 4.4: Frequencies of infections over three months 137
in diabetic subjects of treatment and
placebo groups
Figure 4.5: Frequencies of infections over 12 months in 138
diabetic subjects of treatment and placebo
groups
Page III
LIST OF ABBREVIATIONS
DM Diabetes Mellitus
IDDM Insulin-Dependent Diabetes Mellitus
NIDDM Non-Insulin-Dependent Diabetes Mellitus
T1DM Type 1 Diabetes Mellitus
T2DM Type 2 Diabetes Mellitus
GDM Gestational Diabetes Mellitus
DR Diabetic Retinopathy
CAD Coronary Artery Disease
PAD Peripheral Arterial Disease
CVD Cardiovascular Disease
MDA Malondialdehyde
OxLDL Oxidized Low Density Lipoprotein
OS Oxidative Stress
PUFA Polyunsaturated Fatty Acids
NADH Nicotinamide Adenine Dinucleotide
NADPH Nicotinamide Adenine Dinucleotide Phosphate
ALA Alpha-Lipoic Acid
SOD Superoxide Dismutase
GPx Glutathione Peroxidase
H2O2 Hydrogen Peroxide
WHO World Health Organization
RBP Retinol Binding Protein
Page IV
NAFLD Non-Alcoholic Fatty Liver Disease
PH Potentiometric Hydrogen ion concentration
TB Tuberculosis
mL Milliliter
IU International unit
nmol/ L Millimole per liter
H bAlc Hemoglobin Alc
mg Milligram
cm Centimeter
BMI Body Mass Index
Kg/m2 Kilogram per square meter
HPLC High-performance liquid chromatography
mol/L Micromoles per Liter
pg/ml Pico grams per Milliliter
ng/ml Nano grams per Milliliter
Mg/dl Milli grams per Deciliter
Page V
ABSTRACT
Background: The prevalence of type 2 diabetes mellitus is rising

exponentially both globally and locally. Infections and associated
morbidity are more common in diabetic patients. Many factors may
play a role, including the population's poor nutritional status. Due to
a lack of evidence in this area, we decided to investigate the
connection between dietary supplements and infection risk in
patients.
Aim and Objective: The aim of this study was to measure the effect of
dietary supplements on risk of infection in patients with type 2
diabetes mellitus.
Material and Methods: All patients with type 2 diabetes mellitus who
visit the Kerala Institute of Medical Sciences and Hospital's diabetes
center for daily diabetes follow-up will be considered for the study.
The chosen hospital is one of the city's four major hospitals, serving a
population of 7.88 lakhs. Patients with type 2 diabetes, aged 18 and
up, will be approached and encouraged to participate in the research.
Individuals with serious chronic health or mental illness, those who
are enrolled in other intervention trials, those who are taking dietary
supplements, and those who are unable to provide informed written
consent will be disqualified. In addition, the scholar is seeking
approval from a local research ethics committee. Eligible patients had
a fasting 10 mL of blood taken at baseline for measurements of
antioxidants, B group vitamins, and related nutritional and
biochemical variables, following the details required in written consent
and their recruitment to the study. Patients are then randomly
allocated to obtain an equivalent placebo or a capsule containing
Page VI
antioxidant vitamins (221 mg of α-tocopherol and 167 mg of vitamin

C) and B-group vitamins (1.67 mg folic acid, 1.67 mg vitamin B-2, 20
mg vitamin B-6, 0.134 mg vitamin B-12) regular for 90 days. Patients
are otherwise cared for in accordance with normal procedures. At
baseline, a clinical review of diabetes management, as well as related
risk factors and complications, is performed, and it is replicated three
months later. Fruit and vegetable consumption, physical activity, and
infection rates were measured three and twelve months after
randomization. Medical factors and self-reported infections were
included in the evaluation. It also contained details about infection-
related factors including physical activity and food consumption. A
fasting 10-ml blood sample was also taken to assess serum vitamin
levels and other biochemical variables.
Results: One hundred patients with type 2 diabetes were given either
an oral dose of daily B-group vitamins and antioxidant vitamins (n =
50) or an equivalent placebo (n = 50) daily for 90 days. Nutritional
status, fruits and vegetable consumption, physical activity, and self-
reported infections were assessed at baseline, three months, and
twelve months. In the intervention population, antioxidants and B-
group vitamins significantly increased vitamin E and folate plasma
concentrations while lowering homocysteine levels (p-values were
0.006, 0.001 and 0.657, respectively). After three months of
supplementation, the number of infections identified by the treatment
group was lower than that of the placebo group, 9 (27%) vs. 15 (36%)
(p = 0.623). At 12 months, the corresponding numbers of infections
were 25 (67.5%) and 27 (56.3%), respectively (p = 0.488). With a
sedentary lifestyle, up to 90% of diabetic patients were overweight or
obese, and their body weight rose even more during the three-month
follow-up period. Multivitamin supplements increased vitamin blood
concentrations, but did not reduce the number of infections in
diabetic patients, according to the report.
Page VII
Conclusion: Multivitamin supplements increased vitamin blood

concentrations and reduced the amount of infectious ions in diabetic
patients, according to the study. Larger studies are needed to assess
the daily vitamin dose and supplement period in diabetic and non-
diabetic patients who are at higher risk of infection.
Page VIII
CHAPTER 1: GENERAL INTRODUCTION
1.1 Introduction
Type 2 diabetes mellitus is a multifactorial disorder that is usually

related to energy metabolism, primarily carbohydrate and fat control
in the organism; however, most micronutrients are often involved in
some way, either as a cause or as an effect of this chronic pathology.
An imbalance between the production of free radicals and their
regulation by natural antioxidants causes the effects and
complications of diabetes. As a consequence, antioxidant-functioning
micronutrients are crucial in the development of the disease and its
complications, whereas non-antioxidant vitamins have also shown a
connection.
Over the last 40 years, India's population has undergone rapid

structural and social shifts as a result of urbanization. As a result of
the resulting improvements in diet and lifestyle, an epidemic of
overweight/obesity, type 2 diabetes, and other cardiovascular diseases
is on the rise (CVD). As a result, India has the world's second highest
diabetes mellitus prevalence. Diabetes patients are believed to be more
vulnerable to diseases than people who do not have diabetes. Short-
or long-term hyperglycemia has been shown to impair the host's
immune functions in animal and in vitro tests, including neutrophil
bactericidal activity, cellular immunity and complement activation.
Diabetic patients are more vulnerable to a range of serious or invasive
infections, including pyogenic bacterial infections, necrotizing
infections, Candida infections, and other fungi infections, due to
immune system deficiencies and vascular insufficiency. While specific
General Introduction Page 1

defects in innate and adaptive immune function have been identified

in diabetic patients in a number of studies, the significance of these
findings in relation to the increased risk of infections in diabetic
patients remains uncertain. Furthermore, a defect in immunity may
be one of the causes of the elevated infection rate. A number of
studies have documented changes in micronutrient status, especially
ascorbic acid and B vitamins, and deficiency of certain micronutrients
has been related to the presence of diabetic complications, including
infections, in some of these studies.
There's also a lot of evidence that the immune system and nutrient
status are related. Nutritional deficiency increases infection
vulnerability, and infection has a negative impact on nutritional
status. To our knowledge, no researches on the impact of dietary
supplements on the risk of infection in patients with type 2 diabetes
mellitus have been performed in India. The aim of this research was to
see how antioxidants and B-group vitamins influenced infection risk
in a group of type 2 diabetes patients who were living independently.
B vitamins include Thiamine, Riboflavin, Niacin, Panthotenic acid,

Pyridoxine, Biotin, Cobalamin, and Folic acid, and while most of them
have been related to type 2 diabetes, Riboflavin and Panthotenic acid
have received little publicity. Despite the fact that vitamins have
important effects on diabetes mellitus risk, progression, and
complications, there isn't enough evidence to recommend individual or
multivitamin supplementation in the general diabetic population in
most cases. To maintain adequate nutritional status, the best
recommendation is to eat adequate quantities of those foods that
contain vitamins in appropriate amounts. In this regard, dietary tests
are required in order to recognize particular intake deficiencies and
make recommendations. When considering the whole diet,

supplement use carries the risk of excess or toxicity with respect to

certain vitamins; again, when considering the whole diet, these
negative effects are virtually non-existent. However, there is ample
clinical evidence to suggest vitamin B12 supplementation in patients
with type 2 diabetes mellitus who are taking metformin to reduce the
risk of neuropathy and its complications.
1.2 Diabetes definition and prevalence worldwide
Diabetes mellitus (DM) is a disorder characterized by persistently

elevated blood glucose levels. Hyperglycemia and glucosuria (high
blood and urine glucose levels, respectively), polyuria (abnormally
large urine output), polydipsia (excessive thirst), polyphagia (excessive
hunger), rapid weight loss, and excessive blood and urinary ketones
(ketonemia and ketonuria, respectively) are the main symptoms of
diabetes mellitus [1]. Type 1 diabetes mellitus (T1DM), formerly known
as insulin dependent diabetes mellitus (IDDM), and Type 2 diabetes
mellitus (T2DM), formerly known as non-insulin dependent diabetes
mellitus, are the two primary types of diabetes mellitus (NIDDM).
T1DM is a form of diabetes that affects people under the age of 20. It
accounts for five to ten percent of all diagnosed cases of diabetes.
T1DM is caused by a lack of insulin secretion as a result of the
autoimmune destruction of pancreatic beta cells. Insulin injections
are necessary to maintain normal glucose metabolism during
treatment. Ketoacidosis is particularly common in people with T1DM
[2]. T2DM is closely related to obesity and insulin resistance, and it is
the leading cause of morbidity and mortality due to micro and
macrovascular complications worldwide. Retinopathy, nephropathy,
and neuropathy are examples of micro-vascular complications that
are unique to diabetes. Macrovascular complications occur due to

atherosclerosis and include coronary artery disease (CAD), stroke and

peripheral arterial disease (PAD) [3].
T2DM is the most common form of diabetes in India, and it has

become a major global public health concern. T2DM was projected to
impact 382 million adults aged 20 to 70 years in 2013, with 80
percent of those affected residing in low and middle income countries.
T2DM has been reported to be on the rise at an alarming pace [4].
T2DM is associated with oxidative stress and inflammation. Oxidative

stress destroys lipids, proteins, and DNA, resulting in the development
of oxidation products such as malondialdehyde (MDA), F2
isoprostanes, oxidized low density lipoprotein (OxLDL), protein
carbonyls, and glycated end product, all of which are oxidative stress
indicators [5]. Obesity, metabolic syndrome, and oxidative stress (OS),
as well as innate immune system imbalances and insulin resistance,
all lead to chronic low-grade inflammation, which is a crucial stage in
the development and progression of T2DM [6]. Endothelial
dysfunction, which raises the risk of cardiovascular disease (CVD) and
other T2DM-related complications, may be caused by oxidative stress
and inflammation. Dietary supplementation with anti-inflammatory
and antioxidant nutritional factors, such as vitamins, may be a novel
strategy for population-level prevention and regulation of T2DM [7].
1.3 The Immune system and risk of infection
The immune system, which comprises both innate and acquired

immunity, provides protective barriers against any microbial invasion.
The innate immune system is the body's first line of protection against
foreign invaders. Innate immunity is instantaneous, but non-specific
immunity does not require prior exposure. The skin and mucous

membranes, for example, are structural barriers that prevent

pathogens from entering the system; the skin, for example, can inhibit
most bacterial growth due to its low PH. Some proteins in saliva and
mucus, on the other hand, have the ability to destroy pathogens.
Physiological defenses such as temperature, pH, and oxygen levels are
another form of innate immunity. The stomach's low PH, for example,
helps in infection prevention [8].
Throughout an outbreak, the innate response activates adaptive

immunity in order to enhance pathogen identification. These cells and
processes, which are made up of highly specialized systemic cells and
processes, remove or avoid pathogenic risks. As a consequence of
prior interaction and memory, it begins to work; the adaptive immune
response is antigen-based, involving the identification of specific "non-
self" antigens during a phase known as antigen presentation. Antigen
specificity lead to production of responses that are adapted to specific
pathogens or pathogen-infected cell [9]
1.4 Immunity and risk of infection in diabetic patient
In diabetic patients, certain forms of immunity are impaired. All

stages of polymorphonuclear neutrophil output were altered in
diabetic patients [10]. The function of polymorphonuclear leukocytes
is reduced, particularly when acidosis is present. It's possible to affect
leukocyte adherence, chemo taxis, and phagocytosis [11,12]. It has
also been discovered that antioxidant coordination is compromised,
which plays a role in bactericidal activity [13].
It is commonly known that type 2 diabetic patients have a higher

mortality rate than non-diabetic patients. Many factors may lead to
this, but the most common causes are macrovascular and

microvascular complications. A prospective study of 471 Brazilian

type 2 diabetic outpatients found that infection-related mortality
among type 2 diabetic patients is six times higher than the general
population, with macrovascular and microvascular complications
responsible for the majority of the increase in mortality [14].
For many years, there has been a correlation between diabetes and
bacterial infection [15, 16]. Short- or long-term hyperglycemia has
been shown to impair the host's immune functions in animal and in
vitro studies, including neutrophil bactericidal activity [17], cellular
immunity [8], and complement activation [19]. Diabetic patients are
more vulnerable to a range of serious or invasive infections, including
pyogenic bacterial infections, necrotizing infections, Candida
infections, and other fungi infections, due to immune system
deficiencies and vascular insufficiency [20].
Diabetes Mellitus has been linked to an increased risk of tuberculosis.

In another study, no direct correlation between Mycobacterium avium
subspecies paratuberculosis and the incidence of Type 2 DM in
Sardinian patients was discovered [21]. Postoperative hyperglycemia
increased the risk of postoperative infection and duration of stay in
the hospital [22].
Diabetes is considered to increase the risk of morbidity and mortality,

as well as the incidence of wound infections and nosocomial chest
infections [23,24]. Diabetic patients have an increased risk of bacterial
infection, according to some reports [25]. Insulin-DM has a high
predictive rate in patients with infective endocarditis (I E) older than
15 years, according to a 16-month study conducted in six French
regions [26]. Despite some clinical evidence to the contrary, it has

been proposed that good blood glucose regulation will reduce the risk
of infection in diabetic patients [27].
1.5 Diabetes, Nutrition and Immunity
The relationship between diet and infection is one of the fields that
have gotten a lot of attention over the last 40 years. In 1968, the
World Health Organization (WHO) published the first monograph on
"Interactions between Diet and Infection," which claimed that
particular nutritional deficiencies increased the prevalence and
severity of many infections. Malnourished people have been shown to
have a greater susceptibility to infection. As a result, malnutrition and
infection are likely to have a synergistic relationship [28]. Some
studies looked at the correlation between nutrients and personal
defenses against infection, as well as the influence of infection on
nutritional status.
Malnutrition is related to immunodeficiency all over the world.

Nutritional deficiency harmed the clinical course and outcomes of
certain diseases, including bacterial and viral diarrhea, measles, and
tuberculosis. In certain cases, nutritional status has a small effect.
Nutritional deficiency is now commonly recognized as being related to
a range of immune responses, including cell-mediated immunity,
phagocyte activity, cytokine production, antibody response, antibody
affinity, and the complement system [29].
Relevant nutrients have been shown to play a role in the immune

system in recent studies [30]. Micronutrients' function in infection,
immunity, and inflammation has recently been expanded to include
not only protein-energy supply, but also many vitamins and minerals.
Vitamin A deficiency decreased the size of the thymus and spleen in

laboratory animals, as well as the activity of natural killer cells, the

production of interferon, the efficiency of fat macrophage activity, and
the response of lymphocytes to nitrogen stimulation [31]. Malnutrition
has been shown to impair adaptive and innate immunity in several
studies [32].
Both Type I and Type II diabetes mellitus, it is commonly known, can

cause changes in some micronutrients [33]. In England in 2002-03,
83 percent of hospital consultant episodes for malnutrition-related
diabetes mellitus necessitated hospital admission, resulting in a 5.6-
day rise in length of stay for these patients [34].
1.6 Dietary Supplements and Infection in Diabetic patients
According to the evidence that supports the effects of dietary

supplements on wellbeing, the US Centers for Disease Control and
Prevention reports that 40 percent of U.S. adults take supplements on
a daily basis, costing between $1.3 and $1.7 billion per year. Around
half of the population [35] takes a multivitamin and mineral
supplement. In the United Kingdom, about 25% of the elderly use
dietary supplements [36]. The relationship between immune function
and vitamin or mineral supplementation has been studied in a variety
of studies. Some of these studies indicate that multinutrient
supplementation can improve immune function in people who are at
risk for infections, such as the elderly [37,38]. Other showed the
opposite effect on immunologic response mainly in those who used
more than the recommended amount of certain dietary supplements
[39,40].
In a randomized, placebo-controlled trial in Grampian, Scotland, 910

participants aged 65 were given a daily multivitamin and mineral

supplementation or a placebo for a year, and were monitored for

primary indicators such as infections, self-reported day of infection,
quality of life, and secondary indicators such as antibiotic
prescriptions, hospital admissions, and adverse events. This study
found that giving older people living at home daily multivitamin and
mineral supplements has no effect on self-reported infection-related
morbidity [41].
The role of micronutrient supplementation as a prophylactic to delay

the onset of diabetes mellitus in those at high risk of developing the
disease has yet to be identified. However, certain supplements have
been found to help diabetic patients maintain lower blood glucose
levels. Supplementing with vitamin E or vanadium, for example, has
been shown to boost insulin action [42]. Maintaining blood glucose
levels as close to normal as possible is thought to play a role in
avoiding chronic disease complications. Healthy food is widely
accepted as contributing to infection control; numerous studies have
documented the relationship of specific foods and nutrients to
inflammation; however, few studies have looked at the impact of
various dietary types on inflammatory indicators. A two-year Japanese
study involving 7802 subjects to investigate the relationship between
dietary styles and circulating high-sensitivity C-reactive protein (hs-
CRP) in Japanese people found that a healthy dietary style is linked to
inflammation inhibition [43].
The aim of an Iranian study was to see if there was a correlation

between major dietary patterns and markers of systemic inflammation
in Iranian women. Using factor study, the researchers discovered
three big dietary patterns: The first was a balanced dietary pattern
marked by lower energy and cholesterol consumption and higher
vitamin B-6, magnesium, and fiber intake. The western dietary

pattern, on the other hand, is distinguished by higher energy and

cholesterol intakes and lower intakes of vitamin 8-6, magnesium, and
fiber. The third was the conventional dietary pattern, which is
distinguished by marginally lower energy consumption than those in
the lowest group, but no major difference in nutrient intake (P > 0.05)
in most cases. The study suggested an independent association
between inﬂammatory markers and major dietary patter [44].
Barringer and colleagues recently reported that taking a multivitamin

and mineral supplement decreased self-reported infections in 1 30
healthy people aged 45 to 64, with the majority of the benefits seen in
undernourished diabetics. The study was a randomized double-blind,
placebo-controlled trial in which the treatment group received a daily
oral tablet containing calcium 120 mg, magnesium 100 mg, and
vitamin B2 3.4 mg, and the placebo group received a daily oral tablet
containing calcium 120 mg, magnesium 100 mg, and vitamin B2 3.4
mg. Both tablets would have the same appearance and odor as the
treatment tablet. According to the study, 73 percent of the placebo
group registered an infectious disease, compared to 43 percent of the
treatment group (p 0.001). The placebo group had 57 percent
infection-related absenteeism from work, compared to 21 percent for
the treatment group (p0.00 1). It also emerged that 93 percent of
people with type 2 diabetes in the placebo group registered infections,
while only 17 percent in the treatment group did (p 0.001).
1.7 Antioxidants and type 2 diabetes
Diabetes mellitus (DM) is a widespread condition involving a variety of

disorders that affects many people and induces hyperglycemia due to
a lack of insulin secretion or action. It's related to a higher risk of
retinopathy, kidney failure, nerve damage, circulatory disorders, heart

disease, and stroke, among other things. When the pancreas does not
produce enough or any of the hormone insulin, or when the insulin
produced does not function properly, diabetes mellitus arises. In
diabetes, this results in an abnormally high amount of glucose in the
blood.
Insulin-producing cells in the pancreas are killed in type 1 diabetes,

resulting in a serious shortage of insulin. This is believed to be the
result of the body assaulting and killing its own pancreatic cells, a
disease known as an allergic reaction. Although it is unclear why this
occurs, a variety of theories and potential causes have been
suggested. These include:
 infection with a specific virus or bacteria;
 exposure of food-borne chemical toxins; and
 exposure of a very young infant to cow’s milk, where in as yet
unidentified component triggers the autoimmune reaction in the
body.
These are, however, just theories and are not confirmed triggers. Type-
1 diabetes is characterized as diabetes that results in an insulin-
dependent condition and affects only around 5% to 10% of diabetics.
Juvenile-onset diabetes is named for the fact that it typically strikes
during childhood or adolescence, but it can strike at any age.
Type 2 diabetes is believed to develop when:

 the receptors on cells in the body that normally respond to the
action of insulin fail to be stimulated by it- this is known as insulin
resistance. In response to this more insulin may be produced, and
this over-production exhausts the insulinmanufacturing cells in
the pancreas;
 these is simply insufficient insulin available and

 the insulin that is available may be abnormal and therefore doesn’t

work properly.
Type 2 diabetes is more likely to occur as people grow older, gain
weight, and become physically inactive. Certain medications,
pregnancy (gestational diabetes), and any infection or disease that
affects the pancreas and impairs its ability to produce insulin, such as
pancreatitis, are some of the rarer triggers. Type 2 diabetes is known
as mature-onset diabetes because it typically strikes people in their
forties or fifties, but it is increasingly affecting younger people,
including teenagers. This occurs in 90 percent to 95 percent of
diabetics, and it is most common in adults over 40 years old Type-2
diabetics typically have it for a long time before feeling the typical
signs of thirst, frequent urination, appetite, and weight loss. Although
the onset is less drastic than type 1 diabetes, the results can be just
as deadly over time [45]. A significant number of syndromes that
cause or are associated with secondary diabetes mellitus are other
forms of diabetes. Gestational diabetes is retained as a distinct
category, according to a recent definition proposed simultaneously by
the American Diabetes Association and the World Health
Organization, and includes any DM newly diagnosed during
pregnancy (as true gestational DM normally remits temporarily after
delivery). [46].
According to recent reports, up to ten percent of India's urban

population and two percent of the rural population over the age of 35
are diabetic. This number appears to be steadily growing, having
doubled in the last 20 years and threatening to reach epidemic
proportions. Genetic predisposition, lifestyle changes as a result of
rapid urbanization, and a high consumption of fast food without any
physical activity in an urban setting may all play a role in the high
prevalence. Because of a lack of health literacy and the current

socioeconomic climate, diagnosis is delayed. Diabetic treatment - A

study in Asia found that 40 percent of people with type 2 diabetes in
India's cities are obese. Glycemic regulation was also found to be
lacking. Even in tertiary care facilities, patients' self-monitoring is
ineffective. At a mean diabetes period of one year, over 55% of patients
develop late diabetic complications. In India, diabetes treatment needs
to be significantly improved, and every effort should be made in this
direction [47].
Type 2 diabetes is characterized by a complex interplay of various

metabolic disorders, including hyperglycemia, hyperinsulinemia, and
dyslipidemia, all of which signify carbohydrate, fat, and protein
metabolism disturbances. Hyperglycemia, a common diabetic
complication, depletes natural antioxidants and promotes the
development of reactive oxygen species (ROS), which can react with
lipids, proteins, carbohydrates, DNA, and other biological molecules to
trigger cytotoxicity in cellular components [48]. Thus, in diabetics,
enhanced ROS and impaired antioxidant defense contribute to the
onset and progression of micro and macrovascular complications
[49,50,51].
Increased activity of free radical-induced lipid peroxidation and

accumulation of lipid peroxidation products are related to certain
diabetes complications [52]. Lipid peroxidation is a free radical-related
mechanism that can be dangerous because it causes disruption of
membranes, lipids, and other cell components when it is uncontrolled
and self-enhancing. It's been related to a number of diseases,
including hypertension, atherosclerosis, and carcinogenesis [53]. It
also plays a part in oxidative stress, which is related to the
pathogenesis of diabetes and its complications [54]. Pancreatic beta
cells and vascular endothelium are especially vulnerable to oxidative

stress. This is because many biochemical pathways closely linked to

hyperglycemia (glucose autooxidation, polyol pathway, prostanoid
synthesis, and protein glycation) can increase free radical production.
When endothelial cells are exposed to high glucose levels, they develop
more superoxide radicals. Many of the effects of hyperglycemia on
endothelial functions, such as decreased endothelial dependent
relaxation and delayed cell replication, can be reversed with
antioxidants [55]. Antioxidant enzymes play an important role in
scavenging reactive oxygen species and thus help to regulate lipid
peroxidation.
The balance between the free radical load and the adequacy of
antioxidant defenses determines an organism's susceptibility to free
radical stress and peroxidative harm. High levels of lipid peroxidation
combined with a decline in antioxidant defense mechanisms may
result in oxidative stress and damage to cellular organelles. There are
several studies on oxidative stress and antioxidant status in type 2
diabetic patients [56,57,58]. Antioxidants are compounds that protect
biomolecules from oxidative damage by stopping, reducing, or
preventing it. Enzymatic, non-enzymatic, and metal chelators are
examples of these agents. Catalase, glutathione peroxidase, and
superoxide dismutase are examples of enzyme antioxidants.
Superoxide dismutase is a copper-zinc-manganese enzyme that

interacts with superoxide radical to create hydrogen peroxide, which is
then converted to water by glutathione peroxidase (a glutathione-
dependent selenoprotein) or catalase, a heme enzyme. Ascorbic acid,
alpha tocopherol, betacarotene, and polyphenols are non-enzymatic
antioxidants that help the body combat oxidative stress. Superoxide
and hydroxyl radicals are two radicals that ascorbic acid (vitamin C)
can react with. Peroxyl radicals react faster with alpha tocopherol

(vitamin E) than they do with other lipid molecules. Vitamin A, beta-

carotene, can also react with hydroxyl radicals to create less reactive
products. Ceruloplasmin, transferrin, and metallothionein are metal
chelators that prevent oxidation of polyunsaturated fatty acids (PUFA)
and LDL by chelating metal ions that serve as prooxidants when left
circulating [59].
Several studies have shown that people with type 2 diabetes have
lower levels of non-enzymatic and enzymatic antioxidants, leading to a
rise in free radicals. As a result, lipids, carbohydrates, proteins, and
nucleic acids are oxidized. This may contribute to the development of
atherosclerosis [60,61,62,63,64].) Increased lipid peroxidation (MDA)
often reduces membrane permeability and fluidity [65]. Dietary
supplementation of these antioxidants enhanced glycemic regulation
and decreased lipid peroxidation [66,67]. Other vitamin E and zinc
supplementation studies [68,69] found major changes in serum
glucose, total cholesterol, low density lipoproteins, and beta-cell
activity. (Insulin synthesis, transportation, secretion, and
conformational integrity all include zinc.) Low dietary zinc intake
tends to be linked to an increased risk of diabetes. Lower dietary zinc
intake was related to a higher prevalence of diabetes, glucose
resistance, and coronary artery disease in a crosssectional study of
3'575 Indian subjects [70].
Purine metabolism produces uric acid as a byproduct. During human

evolution, uric acid levels in the blood have risen. This may be due to
a gene mutation in which the ability to synthesize ascorbate
synthetase correlated with the ability to synthesize uricase, causing
uric acid levels to rise to compensate for some of ascorbic acid's
antioxidant functions [71]. Uric acid has antioxidant properties,
according to some reports, since it scavenges peroxyl and hydroxyl

radicals and binds metal ions that would otherwise catalyze free
radical reactions [72,73]. Bilirubin, bile pigment and hemoglobin
metabolite, also acts as an antioxidant, scavenging peroxyl radicals.
Bilirubin and albumin are two other markers of liver health. Inhibition
of oxidative modification of plasma proteins and formation of protein
carbonyl groups are two of bilirubin's defensive functions. The bulk of
bilirubin in circulation is bound to albumin [74]. The presence of
bilirubin on albumin prevents albumin from oxidation as well as the
peroxyl radical-induced oxidation of albumin-bound linoleic acid [75].
Albumin contains SH (sulphydral) groups that can react with
hydrogen peroxide and peroxyl radicals, making it a possible
antioxidant [76,77]. The patient's antioxidant status can influence
whether or not they develop microvascular or macrovascular
complications. Many medical researchers have discovered that a lack
of antioxidants in the body will increase the risk of diabetes
complications [78]. Rising serum antioxidant status has been
suggested as a preventive measure for cardiovascular disease growth.
Whole grains (wheat, oatmeal, and brown rice), oils from corn, olive,
soyabean, and safflower, dark orange, red, yellow, and green
vegetables, and fruits like prunes, raisins, berries, and grapes are rich
in antioxidants. By supplementing the diet with antioxidant-rich
components after regulating blood glucose levels in diabetic patients,
the lipid profile can be improved and lipid oxidation can be avoided,
and therefore more diabetic complications can be avoided. The
experiments were designed to look into the effects of antioxidants
such as superoxide dismutase, glutathione peroxidase, ascorbic acid,
uric acid, albumin, bilirubin, and the metal ion zinc in type 2 diabetic
patients.

1.8 Vitamin B Group and Diabetics
Normal cellular activity, replication, repair, metabolism, and energy

production are all dependent on B vitamins. B vitamins, in particular
B1, B6, and B12, are essential for normal nerve function and repair.
The water-soluble B vitamins may be lost more quickly in people with
diabetes than in people without diabetes, owing to increased urination
caused by the osmotic effects of high blood sugar, even though intake
is theoretically sufficient.
When reading supplement labels or written explanations of B vitamin

functions, it's easy to assume that taking large amounts of B vitamins
can help us "offset stress," "boost energy," "improve metabolism,"
"assist in normal adrenal function," and so on. Unfortunately, there is
very little clinical trial data to back up these arguments. There have
been few high-quality clinical trials on single B vitamins, let alone “B
complex” combinations, in diabetes. Homocysteine, a byproduct of
protein/amino acid synthesis that is affected by B vitamin intake, has
been linked to direct damage to the thin endothelial lining of the small
arteries, which is especially fragile in diabetics. Is it true that reducing
homocysteine reduces the risk of a heart attack or stroke? Is it still
important to test and measure homocysteine?
Thiamine/B1
Thiamine is a water-soluble vitamin essential for normal metabolism
of fat, glucose and protein as it is involved in key pathways of cellular
energy synthesis. Specifically, thiamine is a cofactor in the actions of
the enzymes:
 pyruvate dehydrogenase and alpha-ketoglutarate decarboxylase in
the breakdown of carbohydrates,

 branched chain alpha-keto acid dehydrogenase in the metabolism

of some amino acids,
 and transketolase which acts to breakdown more complex sugars
for energy production.
 Abnormalities of transketolase activity have been identified in
diabetes, and are partially responsible for the accumulation of
sorbitol contributing to cataract formation.
 In addition, classic thiamine deficiency has been long associated
with heavy alcohol consumption and is known to cause Wernicke’s
encephalopathy, a condition marked by nervous system symptoms
including numbness, tingling and muscle weakness.
Thiamine can be found in fortified wheat products, lentils, peas, pork,

brazil nuts, pecans, spinach, cantaloupe, pork, milk and eggs [79].
In recent research, it was discovered that 75% of diabetic patients had

lower thiamine levels and higher urinary thiamine excretion than
controls [80]. Low thiamine levels were linked to higher levels of
vascular adhesion molecules, which are recognized indicators of
vascular disease. Intravenous thiamine administration improved the
functioning of the inner, endothelial lining of small arteries in diabetic
patients during induced hyperglycemia in a clinical trial conducted by
Arora et al., confirming the involvement of thiamine in normal
vascular function [81]. Furthermore, in patients with diabetes, a
randomized, controlled trial of thiamine (25 mg/day) combined with
pyridoxine (B6) (50 mg/day) showed substantial changes in pain,
numbness, and paraesthesia (extra nerve sensations) [82].
Benfotiamine, a fat-soluble, synthetic form of thiamine, has recently

become available as a dietary supplement. Benfotiamine has been the
subject of some fascinating research, including studies that indicate it

protects the small and large arteries from damage caused by high
blood glucose and increased advanced glycosylation endproduct
intake in food [83]. Benfotiamine seems to be more readily absorbed
than normal water-soluble thiamine, but high-dose thiamine appears
to have a similar effect and can provide benefits. The jury is still out
on benfotiamine's safety, but there have been only minor safety issues
recorded in the literature so far.
Niacin/B3
Niacin, also known as nicotinic acid, is a common cofactor in the
production of cellular energy in humans. Niacin, in the form of
nicotinamide adenine dinucleotide (NADH), is used as an intermediate
in reactions in glycolysis and the Kreb's cycle, two of the most
essential energy production cycles in human biochemistry.
Niacin, in the form of nicotinamide adenine dinucleotide phosphate, is

also needed for fat metabolism and normal DNA synthesis and repair
(NADPH).Niacin is water soluble, much like thiamine. Pellagra is a
niacin deficiency that is very unusual in this country due to food
fortification. Animal foods, fortified wheat products, coffee, lima beans,
lentils, and peanuts are all strong sources of iron.
In medicine, niacin is best known as a treatment for

hypercholesterolemia, or elevated blood cholesterol. Niacin is used as
an over-the-counter supplement and as a prescription drug. B vitamin
supplement doses usually vary from 5 to 50 milligrams, while
cholesterol-lowering doses typically range from 500 to 2500
milligrams. Most cholesterol-lowering drugs affect just one risk factor;
nevertheless, niacin outperforms other cholesterol-lowering
medications because it lowers LDL cholesterol, increases HDL
cholesterol, lowers triglycerides, enhances LDL particle size, and

lowers lipoprotein a (Lpa), another cardiovascular disease risk factor

[84, 85].
Despite low blood glucose regulation, people with diabetes who took
niacin had less development of artherosclerosis than those who took a
placebo in other studies [86]. Niacin achieves these excellent results
by lowering HDL cholesterol clearance in the liver, resulting in more
HDL being in circulation and scavenging less stable LDL particles.
In diabetic patients with hypercholesterolemia, niacin is considered a

safe and effective medication, particularly at lower doses of 1000-1500
mg per day. Flushing is a common side effect of niacin therapy, and it
can be very painful for some. However, most people become used to
the flushing and the severity of it normally decreases. Niacin
treatment for high cholesterol (or low HDL cholesterol or high Lp(a))
can only be taken under the guidance of a doctor who can properly
titrate your dosage and test your cholesterol on a regular basis to
make sure it's working. Furthermore, higher doses of niacin can cause
an increase in liver enzymes, which is a sign of liver inflammation;
because liver enzymes are commonly elevated in people with diabetes
and the metabolic syndrome (due to fat deposition in the liver), liver
enzymes should be monitored by a physician on a regular basis.
Biotin/B8
If you haven’t already figured this out, many of the B vitamins work
together as co-factors in the function of many critical metabolic
enzymes. Biotin is no exception. Biotin, like thiamine and niacin, is
also required for normal function of:
 pyruvate decarboxylase (an enzyme involved in carbohydrate and
fat metabolism),
 propionyl-coA carboxylase (an enzyme involved in fat metabolism),

 and acetyl-coA carboxylase (also involved in carbohydrate and fat

metabolism).
 Biotin is known to bind to specific sites in these enzymes in order
to optimize function, and supplementation of biotin is known to
increase the activities of these enzymes in people with diabetes as
well as those without diabetes [87, 88].
Food sources of biotin include animal products, avocado, wheat bran,

baker’s yeast, raspberries, artichoke and cauliflower.
The majority of the literature on biotin in diabetes is focused on recent

studies funded by Nutrition 21, Inc., a company that manufactures
Diachrome®, a dietary supplement that incorporates chromium
picolinate and biotin. Recent studies have shown that combining
chromium picolinate and biotin resulted in a 0.54 percent reduction
in HbA1c, as well as substantial reductions in LDL and VLDL
cholesterol and triglycerides in people with diabetes [89,90,91].
Cobalamin/B12
Vitamin B12, also known as cobalamin, is necessary for normal
nervous system function and cell proliferation. The absorption of
vitamin B12 necessitates the presence of a special protein known as
intrinsic factor (pernicious anemia, an autoimmune anemia, results
when your body produces antibodies against intrinsic factor impeding
absorption).
Intrinsic factor is created by a particular cell type in the stomach

lining, which can atrophy or weaken as we get older. As a result of
this atrophy, abnormal B12 absorption can lead to deficiency, making
older adults especially susceptible to vitamin B12 deficiency.

A different type of anemia, known as macrocytic anemia, is caused by

a lack of vitamin B12; macrocytic anemias are characterized by large
red blood cells (macrocytes, or large cells).
Vitamin B12 is also essential for normal homocysteine metabolism,

which will be addressed in greater depth in Part 2 of this article,
which will be published next month.
Seafood, beef, pork, chicken, dairy products, and eggs are all healthy
sources of vitamin B12. There are very few vegan (non-animal) sources
of B12. According to some sources, spirulina is a good source of B12,
although this may be due to contamination from small sea animals.
Vitamin B12 has mainly been researched in the sense of diabetes as a

treatment for neuropathies. Vitamin B12 was found to be an effective
treatment for diabetic peripheral neuropathy in a recent systematic
study, with pain and paraesthesias benefiting the most from
treatment [92].
Metformin, the first-line prescription drug for treating high blood

sugar in diabetics, has been shown to induce vitamin B12 deficiency
and increase homocysteine levels [93].
1.9 The Role of Supplements in Diabetes Management
In the United States, diabetes is the seventh leading cause of death,

and patients often expect complications [94,95]. In the United States,
more than 30 million people have diabetes, and 84 million more have
prediabetes. 1 Diabetes patients are more likely than non-diabetic
patients to use dietary supplements [96]. Regular use of dietary

supplements was documented by more than half of patients at an

outpatient diabetes clinic, with use being twice as frequent in type 2
diabetes as in type 1 diabetes [97]. The A1C level was found to be
lower in patients who reported taking supplements, though the
supplements used were not specified. In other trials, dietary
supplement use in diabetic patients ranged from 22 percent to 67
percent [98].
Dietary supplements are items that are taken by mouth and contain a
dietary component to complement the diet. Vitamins, plants, minerals,
amino acids, and other substances such as enzymes, metabolites, and
organ tissues can all be contained in these [99]. Tablets, softgels,
tablets, liquids, powders, and bars are all popular types of dietary
supplements. It's important for pharmacists to note that since dietary
supplements are labeled as foods, they're not subject to the same FDA
regulations and supervision as prescription drugs [100].
Manufacturers must only provide proof of safety and effectiveness to

the FDA before selling a new dietary ingredient, and the FDA cannot
take the product off the market until it is proved unsafe.
Patients should be mindful of the lack of regulation and how to

disclose adverse effects associated with dietary supplement use,
according to pharmacists. Between 2007 and 2012, the FDA received
over 6,300 reports of significant adverse effects involving dietary
supplements, including emergency department visits, hospitalizations,
and 115 deaths [101].
There are a number of reasons why patients are interested in using

dietary supplements to treat their diabetes. These may include a
desire to prevent the side effects of conventional drugs, the high cost
of medications, the perception that supplements are "normal" and

risk-free, strong messages from family and friends, and the

seriousness and length of diabetes.
Dietary Supplements for Diabetes Management

To control diabetes and its complications, a number of dietary
supplements have been used. Dietary supplements are widely used for
a number of purposes, including reducing blood glucose, blood
pressure, cholesterol, insulin resistance, neuropathy, and the
prevention of other diabetes-related complications. Dietary
supplement use was found to be relatively widespread among a subset
of diabetic patients, with slightly more than half reporting use [102].
The majority of patients who took dietary supplements said they took
two or three, and they were usually unaware of the potential for
dietary supplement and prescription drug interactions. Magnesium
and herbs were the most frequently mentioned supplements in a small
community of 150 diabetic patients. Antioxidant vitamins, B-group
vitamins, and omega-3 fatty acids were also common supplements.
Dietary intake also reported calcium, magnesium, and potassium
deficits, which were compounded if the patient did not supplement the
diet.
Alpha-Lipoic Acid: Alpha-lipoic acid, or ALA, is an antioxidant that

aids the body's conversion of energy into food. ALA, unlike most
diabetes dietary supplements, is mainly used for peripheral
neuropathy rather than blood glucose or A1C monitoring. ALA does
not cure neuropathy, but it does help with the symptoms that come
with it. It is unclear if it delays progression at this point. Although
ALA isn't widely used to lower blood sugar, it can help, particularly in
patients who are taking a drug that has hypoglycemia as a side effect.

This is due to the fact that ALA increases insulin sensitivity by 18% to
20% in patients with type 2 diabetes [103].
Chromium: Diabetic patients may be lacking in chromium, a trace

element. Increased insulin sensitivity and increased glucose tolerance
are theorized benefits in type 2 diabetes, though Brownley et al argue
that, based on mixed clinical-trial evidence, the assumption that
chromium aids glucose control is generally unjustified [104].
Chromium has also been linked to carbohydrate and lipid metabolism
[105]. The most popular type of chromium is chromium picolinate.
Patients want to use chromium for weight loss, which is regulated by
dopaminergic and serotonergic pathways.
Despite the fact that individual studies have shown benefits for A1C,
glucose, and insulin levels, Althius et al found no effect on A1C,
glucose, or insulin in patients with and without diabetes in a meta-
analysis [106]. There is inconclusive data on the benefits of chromium
supplementation in diabetes, according to the American Diabetes
Association [107]. Before beginning chromium for diabetes
management, patients should be thoroughly tested since it interacts
with a variety of medications. Antacids, beta-blockers, corticosteroids,
H2 receptor antagonists, nicotinic acid, and nonsteroidal anti-
inflammatory medications all interact with chromium.
Cinnamon: Patients with diabetes and hyperlipidemia commonly use

cinnamon. Cassia cinnamon is the same type of cinnamon used in
cooking and baking that is used in cinnamon supplements. According
to a meta-analysis, cassia cinnamon dosages of 1 to 6 g per day
resulted in lower fasting blood glucose and lipids, but not lower A1C
[108]. However, for 1 g per day, a real-world analysis observed a 0.83
percent reduction in A1C over 3 months [109]. Another research

found only a 0.36 percent reduction in A1C with 2g per day, and a
Cochrane review found inadequate evidence [110,111].
Although A1C does not appear to improve dramatically with cinnamon

use, dosages of 1 to 6 g daily for 40 days resulted in blood glucose
reductions of 18 to 29 percent. One gram (roughly 1/2 teaspoon)
increased blood glucose levels for up to 20 days after it was stopped.
Cinnamon's active ingredient is hydroxychalcone, which is thought to
improve insulin activity. When taken orally, cinnamon is usually
healthy, but high doses can cause liver damage due to high coumarin
levels [112].
Fenugreek: This dietary supplement smells like maple syrup and is

widely used in cooking. Fenugreek has been shown in small studies to
help lower blood glucose levels, most likely by inducing insulin
release. Fenugreek also includes fiber, which helps to minimize
carbohydrate digestion and absorption by slowing gastric emptying.
Probiotics: The effects of probiotics in type 2 diabetes have recently

been studied in meta-analyses. Although the findings have been
mixed, Yao et al's meta-analysis and Sun and Buys' separate meta-
analysis both found that probiotic supplementation helped reduce
A1C and insulin resistance [113,114]. Sun and Buys discovered
substantial decreases in fasting blood glucose levels, but Yao et al. did
not. Yao et al looked for benefits in lipid metabolism as well, but found
none. Probiotics have strain-specific effects, so pharmacists can
suggest a probiotic species and strain that has been shown to have
clinical benefit in the past.
Bifidobacterium breve, B longum, Lactobacillus acidophilus, L

bulgaricus, L casei, L rhamnosus, and L sporogenes have all shown to

be effective in multiple trials. A probiotic mixture increased fasting

blood glucose and insulin resistance, as well as weight gain, in a small
sample of pregnant women with gestational diabetes [115].
Improvements were not seen until after 6 weeks of continual use, and
results need to be verified in larger clinical studies.
B Vitamins: Thiamine (B1), pyridoxine (B6), biotin, folic acid (B9), and
cobalamin are all B vitamins that are widely used in type 2 diabetes
(B12). Since many people with neuropathy have a thiamine deficiency,
thiamine is commonly used to treat neuropathy associated with
diabetes. Since thiamine is poorly absorbed, high doses are needed.
Thiamine levels have been shown to be lower in type 2 diabetes
patients. Despite its widespread use for neuropathy, thiamine has
been shown to lower glucose and lipid levels in diabetic patients [116].
Diabetes patients have been discovered to have lower levels of the
active form of pyridoxine. A clinical trial found no correlation between
folic acid, pyridoxine, or cobalamin and type 2 diabetes productions. A
pyridoxine deficiency, on the other hand, can delay the progression of
diabetes-related complications. Biotin research in diabetes is limited,
and the majority of evidence is in conjunction with chromium.
Cobalamin malabsorption is caused by long-term use of metformin,

and it normally shows up after 12 months. Cobalamin deficiency has
been related to diminish cognitive function in diabetic patients, and it
is used to treat the deficiency rather than the disorder itself. Glycemic
regulation and insulin resistance have been shown to benefit from
folic acid. Metformin may also be related to a lack of folic acid.
Vitamin D: Liese et al found a connection between geographical

latitude and the incidence of type 1 and type 2 diabetes, as well as a
seasonal variation in disease-state regulation. This indicates a

negative association between sunlight and the occurrence of diabetes

[117]. Vitamin D receptors are located in pancreatic beta cells, and it
is believed that vitamin D decreases insulin resistance and improves
insulin secretion. Vitamin D deficiency has been related to type 2
diabetes, most likely due to vitamin D deposition in fat, where it
becomes less bioavailable.
Insulin sensitivity is diminished when vitamin D levels are low.

Vitamin D supplementation was found to reduce the risk of type 2
diabetes in clinical trials of calcium and vitamin D supplementation.
Vitamin D can improve insulin secretion and glucose tolerance in
patients with impaired glucose tolerance and type 2 diabetes,
resulting in lower A1C levels. While clinical trials on vitamin D as a
type 2 diabetes risk modifier are small, a meta-analysis published in
2007 indicated that vitamin D, when combined with calcium, can
improve beta-cell function and insulin sensitivity [118].
Counseling on Dietary Supplements

Dietary supplement consumers with diabetes are often unaware of the
potential for them to interfere with prescription drugs. Furthermore,
only 16% of patients sought medical advice on the use of dietary
supplements with their prescription drugs, and only 8% of those
patients consulted a pharmacist. Almost every patient who sought
medical assistance did so through their doctor. Dietary supplements
should be used with caution in people with diabetes because dietary
deficiencies may cause carbohydrate metabolism problems, and
supplementation may increase the risk of hypoglycemia. Patients
should be told about the risks and benefits of dietary supplements
they choose to use for diabetes control, including whether there is any
evidence to support the product's benefit in diabetes and whether
there are any ADA statements or similar recommendations for use.

They should be told about possible side effects and encouraged to

keep an eye out for them and report them if they occur.
It's important to make sure that patients don't use dietary

supplements instead of evidence-based prescription medications to
treat their diabetes and complications. Dietary supplements can only
be used in combination with FDA-approved prescription medications.
Patients should be advised to alert the FDA if they experience any
significant health-related reactions or illnesses as a result of taking
dietary supplements. Patients should also be advised to avoid using
the medication right away. If the side effect is severe or life-
threatening, the patient should be encouraged to seek medical
attention right away.
Patients with diabetes often seek dietary supplements to help them

control their disease. While most supplements lack sufficient clinical
evidence to support their use in type 2 diabetes, the risks of side
effects are small. When patients seek dietary supplements for diabetes
control, they should be aware of the clinical evidence, or lack thereof,
and any possible medication interactions with current therapy should
be assessed. Furthermore, patients should be told that dietary
supplements should only be used as an alternative to drug therapy for
diabetes treatment, not as a substitute for it.
1.10 Rational for the Study
The prevalence of diabetes mellitus in India is the second highest in

the world. Obese or overweight individuals are more likely to develop
Type 2 diabetes. Diabetes is becoming more widespread as a result of
changes in lifestyle, such as a decline in physical activity caused by
climate change and an increasing dependence on technology, as well

as increased consumption of high-fat, high-energy foods. In diabetic

patients, infections are a big concern.
Diabetes makes people more vulnerable to infection. When infections

occur in diabetic patients, the incidence and symptoms of such
infections increase. Diabetic adults have been shown to have a higher
risk of infection-related mortality in research. Many immune function
factors, such as reduced antioxidant vitamin activities involved in
bacteriocidal activity, can contribute to this increased danger. In other
parts of the world, multivitamin and mineral supplements to type 2
diabetic patients have shown some effect in reducing infections such
as respiratory infections, flu, and gastrointestinal infections, but
evidence is limited. This may be attributed to the supplement's effect
on the patients' existing nutritional shortages, which could be linked
to poorly regulated diabetes. Multivitamins are also thought to
support people who are overweight, diabetic, have insufficient
nutrition, or have underlying diseases.
To our knowledge, no researches on the impact of dietary supplements

on the risk of infection in patients with type 2 diabetes mellitus have
been performed in India. The aim of this study was to see how
antioxidant and B-group vitamins affected infection risk in type 2
diabetes mellitus patients living in the community. The findings of this
study could provide useful information to health-care providers about
the antioxidant and B-vitamin nutritional status of patients with type
2 diabetes, as well as help to minimize morbidity and improve
outcomes in this vulnerable category of patients by lowering the risk
of infection.

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CHAPTER 2: LITERATURE REVIEW
2.1 Effect of Diet on Type 2 Diabetes Mellitus
The ancient Egyptians and Indians first identified diabetes mellitus

(DM) as a disease about 3000 years ago, showing certain clinical
characteristics that are very close to what we now know as diabetes
[1]. DM is made up of two words: "diabetes," a Greek word derivative
that means "to siphon," or "to move through," and "mellitus," a Latin
word that means "honeyed" or "sweet." Excess sugar in the blood and
urine was first identified in Great Britain in 1776 [2,3]. With the
passing of time, a comprehensive understanding of diabetes, as well
as thorough etiology and pathogenesis, has emerged. “A metabolic
disorder characterized by hyperglycemia arising from either a defect in
insulin secretion or the action of insulin,” according to the concept of
DM. Poorly managed diabetes can damage a variety of organs,
including the eyes, kidneys, nerves, and cardiovascular system [4].
Based on the etiology and clinical characteristics, DM can be classified
into three groups. Type 1 diabetes mellitus (T1DM), type 2 diabetes
mellitus (T2DM), and gestational diabetes mellitus (GDM) are the three
types of diabetes mellitus (GDM). The death of cells in the pancreas by
a cellular mediated autoimmune mechanism induces total insulin
deficiency in T1DM. Insulin resistance and relative insulin deficiency
are both present in T2DM. GDM refers to any form of glucose
intolerance that occurs during pregnancy. Other diseases or drugs
may cause DM, including genetic syndromes, surgery, malnutrition,
infections, and corticosteroid use [5-7]. Age, genetics, race, and
Literature Review Page 44

ethnicity are immutable T2DM factors, while diet, physical activity,

and smoking are modifiable [8,9].
Epidemiology
T2DM is actually one of the most common diseases in the world, and
its prevalence is gradually growing. In 2011, it was estimated that 366
million people worldwide, or 8.3% of the population aged 20 to 79, had
T2DM. By 2030, this number is projected to grow to 552 million
(9.9%) [10]. This condition is related to significant complications that
have a detrimental effect on the patient's health, productivity, and
quality of life. Diabetes is the leading cause of end-stage renal disease
(ESRD), which necessitates dialysis or kidney transplantation in more
than half of people with the disease (primarily heart disease and
stroke). Diabetic retinopathy, also known as diabetic retinopathy, is a
significant cause of blindness in adults due to retinal harm (DR).
People with T2DM have a 25-fold higher chance of lower limb
amputation than those who do not have the disease. In 2011, this
disease took the lives of approximately 4.6 million people aged 20 to
79 [11].
Physical Activity and Lifestyle

A important correlation between physical inactivity and T2DM has
been found in numerous cross-sectional, prospective, and
retrospective studies [12]. A prospective research was performed on
over a thousand nondiabetic individuals from the Pima Indians' high-
risk population. It was discovered that the diabetes incidence rate
remained higher in less active men and women from all BMI classes
after a 6-year follow-up period [13]. The evidence indicates a variety of
biological mechanisms for physical activity's protective effect against
the production of T2DM. For instance, it has been proposed that
physical activity enhances insulin sensitivity. Physical exercise greatly

increased abnormal glucose tolerance when caused by insulin

resistance rather than insufficient levels of circulating insulin,
according to a comprehensive study released by the US Department of
Health and Human Services in 2015 [14]. Second, physical exercise is
more likely to help prevent the development of T2DM in the early
stages, before insulin therapy is required. Physical exercise tends to
have a synergistic effect with insulin as a defensive mechanism.
Contracting skeletal muscle increases glucose absorption into cells
during a single extended bout of physical activity. This effect enhances
muscle blood flow and improves glucose transfer into muscle cells
[15]. Finally, physical exercise has been shown to minimize intra-
abdominal fat, a recognized risk factor for insulin resistance. Physical
exercise has been shown to be inversely linked to intra-abdominal fat
distribution and to minimize body fat stores in other studies [16]. The
key causes of the extreme rise in the incidence of T2DM have been
described as lifestyle and environmental factors [17].
Patient’s Knowledge Regarding DM

Diabetes awareness and treatment continue to be significant obstacles
for stakeholders around the world. Many researches from developed
countries [18] have found a lack of diabetes awareness. According to
some reports, diabetes is more prevalent in some ethnic groups than
others [19]. To achieve better compliance with medical therapy,
awareness is needed [20]. Patients' awareness and self-care
management of DM is inadequate, according to a study conducted by
Mohammadi [21]. Diabetes results are affected by a lack of
information about diabetes. The findings showed that receiving
diabetes education improved patients' understanding of the disease
substantially (p 0.001). The study also showed that having a basic
understanding of diabetes would greatly enhance a patient's quality of
life while also reducing the stress on their families. In India, Dussa

[23] conducted a cross-sectional analysis on diabetes awareness.

According to the results, diabetes awareness among patients and the
general public is limited. According to a study conducted in India by
Shah [24], 63 percent of T2DM patients have no idea what diabetes is,
and the rest are unaware of its complications. According to a study
conducted in Saudi Arabia by Bani [25], the majority of patients (97.3
percent males and 93.1 percent females) were unaware of the value of
diabetes control, with no substantial gender disparity. Type 2
diabetics in Qatar were also studied for their diabetes awareness,
attitude, and practice. The patients' knowledge of diabetes was
extremely limited, as was their understanding of the effects of diabetes
on the feet [26]. According to the results of a study conducted in
Najran, Saudi Arabia [27], approximately half of the patients did not
have sufficient knowledge of diabetes disease. Male patients in this
study learned more about diabetes than female patients. In Al-Khobar,
Saudi Arabia, diabetes awareness among self-reported diabetic female
teachers was investigated [28]. The study showed that diabetic female
teachers had very little knowledge of the disease. It was also suggested
that diabetic awareness and education be provided to the sample
patients as soon as possible. Diabetes awareness includes information
on eating habits, exercise, weight monitoring, blood glucose levels,
drug usage, eye treatment, foot care, and diabetes complications
control [29].
Relation between Diet and Type 2 DM

As previously mentioned, Indians suggested the role of diet in the
etiology of T2DM, observing that the disease was almost exclusively
confined to rich people who consumed excessive quantities of oil,
flour, and sugar [30]. Food shortages and famines in the countries
concerned, such as Germany and other European countries caused a
decrease in diabetes mortality during the First and Second World

Wars. The mortality rate for diabetes in Berlin dropped from

23.1/100,000 in 1914 to 10.9 in 1919. In comparison, diabetes
mortality rates in other countries with no food shortages over the
same time span, such as Japan and North American countries
remained unchanged [31]. Few studies have found a clear correlation
between T2DM and a high carbohydrate and fat intake. A number of
studies have found a correlation between a high sugar intake and the
production of T2DM [32]. Ludwig [33] performed a 19-month study of
over 500 ethnically diverse schoolchildren. After optimizing for
nutritional, socioeconomic, anthropometric, and lifestyle variables,
researchers discovered that the prevalence of obesity increased with
each additional serving of carbonated drinks consumed. A research
was carried out that included diabetic patients with different levels of
glycemic control. The mean daily plasma glucose levels and diurnal
glucose profiles did not vary. The relation between dietary fats and
T2DM was also inconclusive [34], as it was with carbohydrates. Many
prospective studies have discovered links between fat consumption
and the risk of developing T2DM.
More than a thousand participants without a previous diagnosis of

diabetes were prospectively investigated for four years in a diabetes
study performed at San Louis Valley. The researchers discovered a
correlation between fat intake, T2DM, and impaired glucose tolerance
in that study [35,36]. Another study looked at the correlation between
various diet components, such as fat, fiber, and sucrose, and the risk
of T2DM in two groups of women. After adjusting for other factors, no
connection was found between fat, sucrose, carbohydrate, or fber
intake and diabetes risk in either community [37].
Evidence recently indicated a correlation between soft drink

consumption and obesity and diabetes, owing to the large quantities

of high fructose corn syrup used in soft drink processing, which

increases blood glucose levels and BMI to dangerous levels [38]. Diet
soft drinks, according to Assy [39], contain glycated chemicals that
significantly increase insulin resistance. Obesity has been closely
related to food consumption, not just in terms of volume but also in
terms of diet composition and consistency [40]. Increased
consumption of red meat, candy, and fried foods raises the risk of
insulin resistance and T2DM [41]. Vegetable consumption, on the
other hand, was found to have an inverse relationship with T2DM.
Fruits and vegetables, which are high in nutrients, fiber, and
antioxidants that act as a protective barrier against diseases, can help
to prevent the development of T2DM [42]. Recently, in Japanese
women, a report revealed that elevated intake of white rice was
associated with an increased risk of T2DM [43]. This demands an
urgent need for changing lifestyle among general population and
further increase the awareness of healthy diet patterns in all groups.
Dietary Knowledge of Type 2 Diabetics

Self-dietary management is described by the American Diabetes
Association as a key step in providing diabetics with awareness and
ability in relation to care, nutritional aspects, medications, and
complications. According to a report, the targeted group of people who
were at high risk of developing T2DM had low dietary awareness.
Males were found to consume more red meat and fried foods than
females. The daily rice intake ratio of males to females was
substantially higher [44].
Food preferences, portion sizes, and sedentary lifestyles have all risen
significantly in Saudi Arabia in recent years, resulting in a high risk of
obesity. Unfortunately, due to the convenience of fast food, many
Saudis are becoming obese, contributing to the troubling diabetes

figures [45]. Saudis, on the other hand, eat many too many high-sugar
beverages. Furthermore, according to Backman [46], dietary
awareness is a significant factor that affects dietary behavior. Patients'
food preferences and dietary habits can be affected by their good
awareness of diabetic diet guidelines, according to a study conducted
by Savoca and Miller [47]. An important positive association was
found between diabetic diet awareness and calorie requirements (r =
0.27, p = 0.05) [48]. The study concluded that understanding diabetic
diet is important and essential for better eating habits. According to
the results of a study conducted in Saudi Arabia, more than half of
diabetic patients denied changing their eating patterns, losing weight,
or exercising.
According to the National Center for Health Statistics, socioeconomic

status plays a major role in the development of T2DM, which was
historically regarded as a disease of the affluent [49]. T2DM, on the
other hand, was found to be more common in people with lower
incomes and less education, according to the same source. It's likely
that the variations are due to the type of food eaten. Nutritionists
claim that not just the type of food, but also the amount of food eaten,
has an effect on blood sugar levels. Meals should be eaten at regular
intervals and should contain low fat, high fiber, and a small amount of
carbohydrates. It was observed that daily consumption of protein, fat
and energy intake by Saudi residents were higher than what is
recommended by the International Nutritional Organization [50].
Attitude of Type 2 Diabetics toward Food

Improvements in a patient's nutritional awareness, behaviors, and
activities will help them regulate their diabetes. These elements are
regarded as critical components of comprehensive diabetes treatment
[51]. Despite the high prevalence of diabetes in Gulf countries,

patients still have a poor understanding of the role of diet in diabetes

control [52]. According to research, evaluating a patient's dietary
attitude will help with medication compliance and reduce the rate of
complications. According to a study conducted in Egypt, patients'
attitudes toward food, medication enforcement, food management with
and without drug use, and foot care were all insufficient. According to
another study, one-third of diabetic patients understand the value of
diet preparation and limiting cholesterol intake to avoid CVD. Several
studies have shown that T2DM patients have a higher incidence of
eating disorders and eating disorder symptoms. The majority of these
studies have concentrated on binge eating disorder, which has a clear
link to obesity, which is related to T2DM [53]. In addition, a study
found that weight gain among diabetic patients was related to an
eating disorder as a result of psychological distress [54]. Another
research [55] looked at eating disorder-related symptoms in T2DM
patients and found that the dietingbingeing sequence could be
extended to diabetics, especially obese diabetics. Diabetes is mainly
caused by unhealthy dietary habits and a lack of physical activity.
Failure to adhere to a strict diet and exercise schedule, as well as
taking prescribed medicine, is the leading causes of complications in
T2DM patients [56]. Previous research [57] in Saudi Arabia find that
diabetic patients do not follow their doctors' advice on meal
preparation, diet adjustment, and exercise on a daily basis.
Dietary Practices of Type 2 Diabetics

The dietary patterns of diabetics are largely affected by their cultural
backgrounds. There were important positive relationships between
diabetic diet awareness and dietary practices in each of the
dimensions of dietary practices. Controlling dietary habits required a
large amount of expertise. Furthermore, patients' understanding of a
recommended diet reflects their comprehension of dietary

recommendations, which affected their food choices and eating habits.

In previous studies, the relation between dietary awareness and
dietary practices among T2DM patients was inconclusive. According to
another study, there is no correlation between dietary awareness and
adherence to dietary practices [58]. On the other hand, the same
study discovered that having a high dietary awareness score was
related to following dietary guidelines and that knowledgeable patients
were better at self-management. Dietary awareness has a huge effect
on dietary habits. A research in Indonesia was conducted to evaluate
dietary habits among diabetic patients, and it revealed that
Indonesians tend to eat high-fat foods, which raises the risk of CVD
[59].
Breakfast skipping has become increasingly common among

teenagers, adolescents, and adults over the last decade [60,61].
There's more and more evidence that skipping breakfast is linked to
obesity and other health problems. 62 Furthermore, excessive eating
or snacking can boost body weight and increase the risk of metabolic
diseases [63,64]. Rimm [65] distinguished between western and
cautious eating habits. Increased consumption of fish, poultry,
various vegetables and fruits was associated with the prudent dietary
pattern, while increased consumption of processed and red meat,
chips, dairy products, refined grains, and sweets and desserts was
associated with the western dietary pattern. These trends had
previously been related to a higher risk of T2DM. The glycemic index
is a measurement of the postprandial blood glucose response to food
per gram of carbohydrate when compared to a control food like white
bread or glucose. As a consequence, the glycemic load is an indicator
of the quality and quantity of carbohydrates ingested [66-69].

Another research conducted in Lebanon found a direct connection

between refned grains and sweets, as well as fast food habits, and
T2DM in Lebanese adults [70]. However, the conventional food pattern
was found to have an inverse correlation with T2DM in the same
study.
Type 2 Diabetes Complications

DM is the fourth leading cause of complications-related deaths
worldwide. Diabetes and its complications claim the lives of more than
three million people per year. This disease has a global impact on
health systems as well as patients and their families, who are exposed
to excessive financial, social, and emotional stress. Complications
such as stroke, myocardial infarction, and coronary artery disease are
more common in diabetic patients. Complications including
retinopathy, nephropathy, and neuropathy, on the other hand, may
have a crippling effect on a patient's quality of life as well as a
substantial increase in financial strain. The prevalence of T2DM
complications identified in studies conducted around the world
showed varying rates. Cataracts were observed in 26-62 percent of
people, retinopathy in 17-50 percent of people, blindness in 3% of
people, nephropathy in 17-28 percent of people, cardiovascular
complications in 10-22.5 percent of people, stroke in 6-12 percent of
people, neuropathy in 19-42 percent of people, and foot disorders in
5-23 percent of people. The overall mortality rate was estimated to be
between 14 and 40 percent [71]. Researchers discovered that
developed countries have a 15.8% prevalence of DR, according to a
report. In Saudi Arabia, Sri Lanka, and Brazil, the prevalence of DR
was 30 percent, 31.3 percent, and 35.4 percent, respectively; in
Kashmir, it was 27 percent, and in South Africa, it was 40 percent. In
a study of 3000 diabetic patients from Pakistan, the prevalence of DR
was found to be 26.1 percent, which was significantly higher than the

rates recorded in India (18 percent) and Malaysia (14.9 percent ) pp.
72-76 In Saudi Arabia, there are few and minimal research on
diabetes complications. In a 1992 study from Saudi Arabia, cataracts
were observed in 42.7 percent of T2DM patients, neuropathy in
35.9%, retinopathy in 31.5 percent, hypertension in 25%,
nephropathy in 17.8%, ischemic heart disease in 41.3 percent, stroke
in 9.4 percent, and foot infections in 10.4 percent. This research, on
the other hand, found complications in both forms of diabetes [77].
Relation between Dietary Practices and Diabetes Complications

Interventional studies have shown that high carbohydrate and high
monounsaturated fat diets boost insulin sensitivity, while glucose
disposal dietary interventions are the first line of protection for
diabetic patients with dyslipidemia [78]. Nutrition therapy and lifestyle
improvements is prescribed as the first line of treatment for
dyslipidemia in several dietary interventional studies [79,80]. In the
treatment of diabetes and its complications, metabolic regulation is
the foundation. Obtaining a HbA1c target lowers the risk of
microvascular complications and may also protect against CVD,
particularly in newly diagnosed patients [81]. In people with diabetes,
carbohydrate consumption has a direct impact on postprandial
glucose levels and is the most troubling macronutrient in glycemic
control [82]. Furthermore, a person's food preferences and energy
balance have a significant influence on body weight, blood pressure,
and lipid levels. Healthcare practitioners can assist their patients in
achieving their health goals by personalizing diet interventions and
providing ongoing support for improvements [83-85]. According to one
study, consuming a Mediterranean-style diet rich in virgin olive oil can
help delay the progression of T2DM retinopathy [86]. Person dietary
patterns are important components of cardiovascular and metabolic
risk [87]. Over the past few decades, several health benefits have been

related to the Mediterranean diet, which requires a high consumption

of fruits and vegetables. The beneficial effects of fsh and olive oil have
been related to enhanced glucose metabolism and a lower risk of
T2DM, obesity, and cardiovascular disease [88].
Conclusion
According to a review of numerous studies, T2DM patients need
reinforcement of DM education, including dietary management, from
stakeholders (health-care providers, health-care facilities, etc.) to
enable them to better understand disease management, resulting in
better self-care and a higher quality of life. The ultimate aim of T2DM
therapy is to avoid early end-organ complications, which can be done
by careful dietary management. Dietary management performance
necessitates that health practitioners have a basic understanding of
the patients' cultural values, emotions, family, and social networks.
Since diabetes is a chronic condition, healthcare professionals should
have adequate therapy strategies, with a particular focus on nutrition,
in order to control the disease, minimize symptoms, and prevent
complications from emerging. Patients should also have a clear
understanding of the illness and diet; as a result, health-care
professionals should encourage patients to change their dietary habits
and food preparations. Diabetes and its complications can be avoided
with successful and efficient nutritional education.
2.2 Antioxidants in Type 2 Diabetes
Many medical researchers have discovered that a lack of antioxidants

in the body will increase the risk of complications from the most
common form of diabetes [89]. Diabetes results in the development of
oxygen free radicals, which trigger membrane damage due to lipid
peroxidation and protein glycation [90]. Antioxidants are highly

reactive compounds that neutralize oxygen free radicals, which are

potentially harmful byproducts of the body's energy conversion
method. Normally, the body develops enough antioxidants to protect
itself from the harmful effects of reactive oxygen. The researches
determined antioxidant levels by a new chemical assay and to obtain
more global picture of the body’s total antioxidant capacity.
Antioxidants which are the defense mechanism are of 3 types:
1. Primary antioxidants: They prevent formation of new free radical
species by preventing their formation from other molecules or by
converting existing radicals to harmless substances.
(a) Superoxide dismutase: Since it is present in almost all aerobic
species, SOD is the most important enzyme. Cu/Zn SOD, which is
located in the cytosol, MnSOD, which is found in the mitochondria,
and ecSOD, which is found in the extracellular spaces between
endothelial and vascular smooth muscle cells [91], are the three
isoforms of superoxide dismutase (SOD). SOD is the main scavenger
of O2.- in endothelial cells, resulting in H2O2 and (O2) from the
reduction of two O2.- molecules [92,93].
(b) Glutathione peroxidase (GPx): is thought to play a significant role
in the oxidant balance in vascular cells. It converts hydrogen peroxide
(H2O2) and lipid peroxidase to harmless molecules before they form
free radicals [94].
(c) Catalase: is localized in intracellular peroxisomes and in the
cytosol, where it reduces H2O2 to H 2O and O2. Catalase is thought to
be important in severe oxidative stress by reducing intracellular
H2O2, which is the by-product of O2.- self-interaction and SOD [95].
Metal binding proteins such as ferritin and cerulo-plasmin, which
limit the availability of Fe2+ necessary for the formation of the
hydroxyl radical.

2. Secondary antioxidants: They trap free radicals and prevent chain

reactions. These include the action of vitamin E (alpha tocopherol),
vitamin C (ascorbate), betacarotene, uric acid, albumin and bilirubin.
3. Tertiary antioxidants: They repair biomolecules damaged by free

radicals. These include DNA repair enzymes and methionine
sulphoxide reductase [96].
Changes in serum antioxidant status have been linked to increased

oxidative stress as a cause of diabetes, according to Nakazawa S.
(1993). A recent finding indicates that a low antioxidant activity in
diabetic serum leads to increased oxidative stress in the disease.
Increased oxidative stress is aggravated in type 2 diabetes by the
formation of free radicals during hyperglycemia, hyperinsulinemia,
and insulin resistance. Hyperglycemia-induced oxidative stress
induces a decline in the amount of glucose transporters, impaired
insulin signaling, and decreased pancreatic beta-cell insulin secretion
[97]. Low levels of alphatocopherol and vitamin C in the blood, as well
as decreased glutathione and increased serum malonaldehyde, have
been found in type 2 diabetics. Membrane permeability and fluidity
are also harmed by increased lipid peroxidation [98].
According to Mahboob M et al. (2005), an increase in MDA, a lipid

peroxidation product, and a decline in glutathione-dependent
antioxidant defenses may appear early in type 2 diabetes, before
secondary complications develop [99]. Due to excessive oxidative
stress, Tho L L et al (1988) and other researchers discovered
decreased superoxide dismutase (SOD) activity in diabetic patients
[100,101,102].

SOD activity has produced mixed results. For example, MCRury S.M.
et al (1993) recorded that diabetic SOD activity was not statistically
different [103.104]. Increased autooxidative glycosylation haemoglobin
may have contributed to increased generation of free radicals like the
superoxide anion, causing SOD depletion [105].
Tare R.S et al (1999) found a negative association between erythrocyte

SOD activity and glycosylated haemoglobin. Some antioxidant systems
are either micronutrients or depend on them for their work. Vitamin E
and carotenoids improve cellular and humoral immunity, while
vitamin C protects against free radicals. Type 2 diabetic patients had
lower concentrations of ascorbic acid and alpha tocopherol, which
function in the anti-oxidant protection mechanism, and increased
MDA concentrations as a result of lipid oxidation, according to Nur K
et al (1999).
Vitamin C metabolism is altered in diabetics, according to Idris Akkus

et al (1995). Hyperglycemia reduced the active transport of ascorbic
acid. When compared to healthy controls, the patients' lipid
peroxidation was slightly higher and their vitamin C levels were lower.
Susan McLennan (1988) discovered that diabetes reduces the

concentration of ascorbic acid in the blood and tissues. The purpose
of this study was to find out what triggered this phenomenon and
what it meant. The mechanism underlying this decrease in ascorbic
acid levels in diabetics is unclear, as is its functional significance.
Nur K et al. (1999) found that treating type 2 diabetes patients with
vitamin C and vitamin E substantially improved oxidative stress,
blood pressure, and endothelial function.

However, Eriksson and Kohvakka (1995) discovered that

supplementing with 2 g of vitamin C daily had beneficial effects. Other
vitamin E supplementation research observed major increases in
serum glucose, total cholesterol, and low density lipoproteins [107], as
well as better beta-cell function and higher plasma insulin [108].
Polidori M.C. et al. (2000) discovered that patients with type 2

diabetes who are very old have a low plasma level of vitamin A, E, and
carotenoids, which is negatively associated with age [109].) Bile
pigment formed by heme catabolism and transported bound to
albumin protects albumin bound fatty acids from peroxidation,
according to Halliwell and Gutteridge (1990). It's also a singlet O2
output sensitizer. Bilirubin is transported by albumin. Bilirubin
functions as an antioxidant and a lipid peroxidation inhibitor,
according to Stocker et al (1984). It's conceivable that it prevents
albumin-bound fatty acids from oxidation. Albumin's ability to protect
cells from copper ion-mediated damage is most likely a function of the
protein itself. Albumin is a potent scavenger of HOCl in plasma, and
bilirubin helps in this process.
Uric acid can act as an antioxidant, according to Ames et al. (1981),

by binding iron and copper ions in ways that do not accelerate free
radical reactions, as well as scavenging oxidizing species like singlet
O2, HOCl, and peroxyl radicals.
Kittridge et al. (1984) and Aruoma et al (1989) demonstrated that the

reaction of uric acid with oxidizing species such as OH or peroxyl
radicals can create uric acid radicals that can cause biological harm.
According to Bruce N. Ames (1981), uric acid is a strong antioxidant

and a scavenger of singlet oxygen and radicals, and urate decreases

the oxoheme oxidant produced by the peroxide reaction at

physiological concentrations. Urate is just as effective as ascorbate as
an antioxidant. Human plasma urate levels are much higher than
ascorbate levels, rendering it one of the most effective antioxidants. He
also stated that uric acid, a potent antioxidant and the end product of
purine metabolism, acts as a protective agent in human plasma [110].
Urate, as a scavenger of singlet oxygen, has been shown to be an

important inhibitor of lipid peroxidation by Foote (1976). Urate has
been proposed as a scavenger of hydroxyl radicals by W.A. Pryor
(1981). Urate can be useful as a hydroxyl radical scavenger due to its
high concentration. Urate scavenges hydroxyl radicals produced by
hydrogen peroxide plus either FeSO4 or UV light, according to Howell
et al (1966). Urate serves as an oxo-heme oxidant scavenger [111].
Diabetes decreases uric acid levels, according to Asayama (1994).
Stocker et al. (1987) proposed that, one beneficial function of bilirubin

may be, to act as an antioxidant because under low oxygen
concentration and when incorporated into liposomes, it scavenges
peroxyl radicals as efficiently as alpha tocopherol which is regarded as
the best antioxidant of lipid peroxidation [112].
According to Roland et al (1987), bilirubin protects albumin bound

linoleic acid from peroxyl radical mediated oxidation when bound to
human albumin and at concentrations found in normal human
plasma. They also reported that albumin bound bilirubin competes
effectively with uric acid for peroxyl radicals, but is less effective than
ascorbic acid in scavenging these radicals. The findings clearly
demonstrate that albumin bound bilirubin, at concentrations present
in healthy adult plasma, is an excellent peroxyl radical scavenger and
protects fatty acids ‘incorporated' on albumin from radical oxidation.

Low serum bilirubin levels are characterized by extreme diabetes,

according to Lars H. Breimer et al (1995).
2.3 Vitamins and Type 2 Diabetes Mellitus
Type 2 diabetes mellitus is a multifactorial disorder that is usually

related to energy metabolism, primarily carbohydrate and fat control
in the organism; however, most micronutrients are often involved in
some way, either as a cause or as an effect of this chronic pathology.
An imbalance between the production of free radicals and their
regulation by natural antioxidants causes the effects and
complications of diabetes [113]. As a consequence, antioxidant-
functioning micronutrients are crucial in the development of the
disease and its complications, whereas non-antioxidant vitamins have
also shown a connection.
Vitamin A or Retinol
The term vitamin A refers to a group of chemical compounds that are

structurally and functionally related. Retinol, which is found in
animal tissues and is esterified with long chain fatty acids, is the most
active form. Carotenes found in plant tissues are hydrolyzed
enzymatically to retinal, which is then converted to retinol in the
enterocyte. Some xanthines are converted to retinol as well. Vitamin A
participates in multiple metabolic processes such as genetic
expression, cellular differentiation and growth, playing a very
important role in the immune system, fetal development, sight, taste,
hearing, appetite and spermatogenesis. It has also been postulated
that retinoids may be involved in hepatic lipid metabolism,
adipogenesis as well as pancreatic β-cell activity. While retinol binding
protein (RBP), an adipokine that transports retinoids, has a significant

impact on insulin sensitivity. A mouse model missing the gene for

retinaldehyde dehydrogenase 1, which is involved in the development
of retinoic acid for use in lipid metabolism, has better lipid profiles
than mice with sufficient Raldh1a1 production [115]. Even though
more research is required to determine the specific mechanisms by
which retinoids and their pathways affect carbohydrate and lipid
metabolism in health and disease, it is clear that adequate vitamin A
intake, concentrations, and reserves should be maintained in the
average healthy person and particularly in those with chronic diseases
involving carbohydrates and lipids. Vitamin A and carotenoids plasma
concentrations are lower in very old type 2 diabetic patients [116].
Adult diabetic participants, on the other hand, had average serum
retinol concentrations, with lower carotene and higher RBP than
controls [117]. Before accounting for cardiovascular risk factors, a
nested case-control analysis found that elevated levels of plasma beta-
carotene are related to a lower risk of diabetes [118]. Retinol excretion
in the urine has also been shown to be higher in diabetic subjects
relative to controls, which has been related to the diagnosis of
nephropathy [119].
Retinol binding protein (RBP), especially RBP4, together with

transtyrethin (TTR) transports retinol from the liver to peripheral
tissues by binding to specific cell receptors and has been linked to
lipid metabolism and insulin sensitivity. RBP4 expression is affected
by retinol status, and their ratio is used as a retinol sufficiency
indicator [120]. RBP4 plasma concentrations have been shown to be
higher in diabetic subjects, and this has been related to plasma TTR
levels [121]. Increased concentrations of RBP4 have been shown to
lead to low glucose absorption by skeletal muscle and high glucose
liver output in mice, with a consequent increase in insulin resistance
[122]. Retinopathy, cardiovascular disease, nephropathy, and non-

alcoholic fatty liver are some of the complications of diabetes; some

studies have related RBP4 to these diseases, but the findings are still
controversial. RBP4, retinol, and TTR levels were compared in diabetic
and healthy BMI-matched subjects; they found no variations between
those with retinopathy or macrovascular disease, with lower values of
all three markers associated with micro and macro-albuminuria,
concluding that retinopathy and cardiovascular disease are unrelated
to RBP4 status.
Wu et al. [124] found increased levels of RBP4 in diabetic patients

with and without non-alcoholic fatty liver disease (NAFLD), especially
in males, suggesting a role in the disease's pathogenesis. The RBP4-
803A allele has been linked to an increased risk of type 2 diabetes in
the Dutch population, but the authors note that this is not specifically
related to retinoid status [125]. Aside from retinol blood
concentrations and urinary excretion, another significant retinol
metabolism indicator is the ratio of retinol binding protein (RBP)
concentrations to retinol blood concentrations. While this ratio is high
in diabetic patients, the cause is unknown.
Erikstrup et al. [126], for example, assessed RBP and retinol

concentrations in type 2 diabetic, mild, or disabled glucose tolerant
subjects with or without obesity; diabetic subjects had lower RBP and
retinol levels, as well as a higher RBP to retinol ratio. Retinol levels
and the retinol/RBP ratio have also been found to be higher in
diabetic patients than in control subjects, suggesting a retinol excess
in these patients [127]. Retinoic acid administration increased insulin
sensitivity in diabetic mice by lowering RBP4, decreasing the retinol to
RBP4 ratio, and decreasing RBP4 [128].

B Vitamins
B vitamins include Thiamine, Riboflavin, Niacin, Panthotenic acid,

Pyridoxine, Biotin, Cobalamin, and Folic acid, and while most of them
have been related to type 2 diabetes, Riboflavin and Panthotenic acid
have received little publicity.
Thiamine or B1
Thiamine is a coenzyme involved in the active transfer of aldehyde
groups and glycation, as well as neurotransmission and neuronal
conductivity, and it can affect the onset of diabetic complications
[129]. In diabetic patients with nephropathy, Polizzi et al. discovered
increased DNA-glycation in leukocytes, which was reduced after a 5-
month thiamine and pyridoxine supplement trial [130]. Both Type 1
and Type 2 diabetic patients have low thiamine levels and improved
renal clearance [131]. Thiamine levels were lower in diabetics in a
cross-sectional sample of normal controls, microalbuminuric DM
patients, and macroalbuminuric DM patients, with a gradual decrease
with albuminuria, more so in macroalbuminuria. In
microalbuminuria, there was a negative association between thiamin
and lipid profile [132].
Several studies on thiamine supplementation have yielded promising

results. For example, when diabetic patients were given thiamine for a
month, glucose and leptin levels were found to be lower than in
controls [133].
Rabbani et al. [134] conducted a double-blind placebo-controlled

study of diabetic patients with microalbuminuria with a consequent
reduction in urinary albumin excretion after a three-month
intervention.

Pyridoxine or B6
Pyridoxal, pyridoxine, and pyridoxamine, as well as their
phosphorilated forms, are all members of the vitamin B6 family.
Pyridoxal-5'-phospate is the active source of this vitamin (PLP). It's an
aminotransferase that also acts as a coenzyme for
glucosephosphorilase in the utilization of glucogen in the liver and
muscle, making it a crucial player in glucose metabolism [135]. When
compared to non-diabetic subjects, newly diagnosed diabetic patients
have lower PLP concentrations [136].
Despite the fact that a long-term placebo-controlled trial of combined

folic acid, pyridoxine, and B12 supplementation found no differences
in the risk of developing type 2 diabetes in women with a high risk of
CVD, homocysteine levels were lower in the supplemented group
[137], there were no differences in the risk of developing type 2
diabetes in women with a high risk of CVD. Even though vitamin B6
status is not specifically linked to the development of type 2 diabetes
mellitus there is evidence that its deficiency could be effecting
adversely the progression of some of its complications once the
disease is present. In this regard, pyridoxamine supplementation
reduced insulin concentration and sensitivity while having no effect on
blood glucose levels in an experimental model [138].
In diabetic patients' leukocytes, the combination of pyridoxine and

thiamine, but not alone, has been shown to minimize DNA glycation.
In diabetic patients with nonproliferative retinopathy, a six-month
supplementation study demonstrated a drop in retinal edema and an
improvement in light sensitivity [139].

Niacin or B3
Nicotinic acid is a component of NAD and NADH, both of which are
needed for cellular ATP production and energy efficiency [140].
Although there hasn't been much research done in relation to
diabetes, niacin supplementation has been shown to boost HDL
cholesterol, lower tryacilglycerides, and lower LDL cholesterol [141].
It's used as a lipid-lowering drug on its own or in conjunction with
other lipid-lowering drugs, but its effect on lowering cardiovascular
disease is still unclear [142]. These lipidmodifying effects may have a
function in diabetes-induced atherosclerosis; cell-adhesion molecules
(CAM), which mediate processes that result in atherogenesis, the
expression of CAM’s is increased in diabetes. Niacin supplementation
has been shown to minimize diabetic patients' monocyte adhesion to
endothelial cells [143]. However, there have been some negative effects
associated with niacin supplementation, such as the Coronary Drug
Project, which found a significantly increased risk of type 2 diabetes
mellitus in men with prior myocardial infarction and normoglycemia
or impaired fasting glucose (IFG) [144].
While Zhou et al. [145] suggest that nicotinamide excess from an

increase in niacin, thiamin and riboflavin population intake, through
food fortification, may be associated with oxidative stress and insulin
resistance, thus exerting a negative effect on the development of
complications related to type two diabetes mellitus.
Biotin
Biotin is a cofactor for carboxilases such as acetyl CoA carboxylase
that participates in biosynthesis and elongation of fatty acids,
pyruvate carboxylase involved in gluconeogenesis, metilcrotonil CoA
carboxylase necessary for the degradation of leucine and propyonil
CoA carboxylase. Although mammals do not produce biotin, its

deficiency is rare due to its presence in a wide variety of animal and

plant origin foods [146]. There hasn't been much research conducted
on type 2 diabetes mellitus. A study of biotin and chromium
piccolinate supplementation of type 2 diabetic rats resulted in anti-
diabetic effects, apparently preventing insulin resistance in skeletal
muscle by an increase in the expression of the glucose transporter
protein GLUT4 [147,148].
Cobalamin or B12
Vitamin B12 is a coenzyme involved in the synthesis of methionine,
pyrimidine, and purine bases in single-carbon metabolic pathways. Its
deficiency, which is caused by DNA damage or faulty repair, has been
linked to cancer, vascular disease, and certain birth defects, while
hyperhomocysteinemia, which is also linked to folic acid deficiency,
has been linked to hypertension and atherosclerosis [149]. The
Women's Antioxidant and Folic Acid Cardiovascular Research reported
no variations in the occurrence of type 2 diabetes mellitus in women
with or without cardiovascular disease risk factors who were treated
with folic acid, pyridoxine, and B12 or placebo for approximately 7
years. While Movva S, et al. recommend that people at risk of diabetes
be checked for the MTHFR C6771 mutation, as this polymorphism is
associated with an increased risk of diabetes, and vitamin B12, B6,
and folic acid supplementation may help reduce the risk in these
people [150].
In a systematic review of cohort studies, Rafnsson et al. [151]

concluded that there is no evidence that cobalamin deficiency is a risk
factor for mortality from cardiovascular diseases or diabetes, and that
supplementation is unnecessary. As a result, the use of prophylactic
vitamin B12 to minimize the risk of diabetes is still debatable. Type 2
diabetes mellitus, on the other hand, is an oxidative stress disease;

vitamin B12 and folic acid deficiencies in diabetic subjects have been
related to oxidative stress and hyperhomocysteinemia [152]. As a
result of this relation, vitamin B12 deficiency may theoretically be
considered a risk factor for diabetic complications. Peripheral
neuropathy is one of the most common complications of type 2
diabetes mellitus, and its development has been attributed to
hyperhomocisteinemia, which is more common in diabetic patients
[153-157].
In diabetic retinopathy, pyridoxine, folate, and B12 combined

supplementation has been found to enhance retinal edema and
improved light sensitivity, even in the presence of
hyperhomocysteinemia [158]. Type 2 diabetic Nigerians had higher
total homocysteine levels and lower vitamin B12 plasma
concentrations than healthy controls [159]. Atherosclerosis is another
common complication of diabetes, and Shargorodsky et al. [160]
discovered a correlation between high homocysteine levels and arterial
stiffness. Vitamin B12 deficiency is rare in the general population
because it is found in almost all animal foods, and it is particularly
common in strict vegetarians. However, long-term use of metformin,
the drug of choice for people with uncomplicated diabetes, induces
cobalamin malabsorption, increasing the risk of deficiency [161-166].
For example, a cross-sectional analysis discovered lower plasma levels
of vitamin B12 in type 2 diabetic patients taking metformin, and a
retrospective examination of medical records verified this [167, 168].
In elderly patients, short-term metformin treatment has been shown
to reduce cobalamin levels [169].
Vitamin B12 deficiency, on the other hand, has been identified in

diabetic patients who do not take metformin [170]. Diabetic subjects
who took metformin performed worse on cognitive tests than those

who did not take metformin or those who were not diabetic. Vitamin
B12 supplementation is recommended by the authors to enhance
cognitive efficiency [171]. Intracellular and extracellular markers of
vitamin B12 metabolism were calculated by Obeid et al. In type 2
diabetic subjects, they discovered normal extracellular but reduced
intracellular vitamin B12, with metformin treatment reversing the
effect [172]. In diabetic subjects, supplementation studies have shown
a rapid recovery from this deficiency and its consequences [173-176].
NHANES data also revealed a correlation between metformin therapy

and vitamin B12 deficiency in diabetics, leading to the
recommendation of supplementation with the amount contained in
general multivitamins; however, this is not always tracked or
practiced on a regular basis [177-179]. Supplementing with lipoic acid
and methylcobalamin increases nerve conduction velocity and diabetic
neuropathy, according to a meta-analysis of seventeen studies [180].
After reviewing the results, we can conclude that diabetic patients
taking metformin are at a higher risk of developing vitamin B12
deficiency and, as a consequence, hyperhomysteinemia, which can
lead to neuropathy and other complications; hence, cobalamin
supplementation appears to be a good idea in these patients.
Folate, Folic Acid or B9

The term folate refers to 150 members of the pteroilglutamate family
of amino acids that play a role in cell replication through enzymatic
activity in purine base synthesis for DNA and are an important co-
factor for transamination in the conversion of amino acids,
particularly homocysteine to methionine. Folate deficiency has been
related to megaloblastic anemia, neural tube defects, cardiovascular
disease, cancer, and senile dementia [181].

Folates can be found in animal tissue, leafy plants, legumes, and

nuts. The function of folic acid in the pathogenesis of type 2 diabetes
is related to vitamin B12 deficiency and hyperhomocysteinemia, and
despite the fact that deficiency is rare, supplementation trials in
diabetic patients have been performed. Low folate and B-12 intakes
were related to hyperhomocysteinemia in type 2 diabetic patients,
according to a case-control report. Folic acid supplementation can
reverse DNA damage as calculated by the presence of micronuclei,
reducing the impact of oxidative stress in diabetic patients [182].
Folate supplementation has also been shown to boost glycemic

regulation in type 2 diabetes patients by lowering glycosylated
hemoglobin fasting blood glucose, serum insulin and insulin
resistance, as well as homocysteinemia [183]. Supplementing with
pyridoxine, folate, and vitamin B12 has also been found to enhance
the signs and symptoms of diabetic retinopathy. Metformin, like
vitamin B12, can cause folate deficiency; a double-blind randomized
clinical trial of 8 weeks of folic acid supplementation in diabetic men
on metformin showed improvements in homocysteine levels, total
antioxidant ability, and malondialdehyde [184].
Vitamin C or Ascorbic Acid
Asorbic acid functions as a cofactor in a variety of reactions, including

collagen, neuropeptide, and carnitin synthesis, increasing iron
absorption, inhibiting histamine release, and stimulating the immune
system. The elevated levels of oxidative stress caused by
hyperglycemia are the key cause of increased vitamin C requirements
in type 2 diabetes mellitus [185]. The concentrations of vitamins C
and E, as well as antioxidants, were found to be lower in diabetic
patients compared to safe controls [186]. During the first two years of

the disease, newly diagnosed cases of type 2 diabetes mellitus were

found to have higher lipid peroxidation and lower antioxidant enzymes
as well as vitamins C and E [187].
Vitamin C levels in the blood have been shown to be inversely linked

to glycosylated hemoglobin, fasting and postprandial blood glucose,
and oxidative stress, but not to lipid profiles [188, 189]. Periodontal
disease has been linked to diabetes, and vitamin C supplementation
in combination with dental maneuvers has been shown to improve
chronic periodontitis in newly diagnosed type 2 diabetics [190].
Vitamin C has also been shown to reduce anxiety levels but not stress
and depression scores in diabetes [191]. Three month
supplementation of vitamins C and E decreased hypertension, blood
glucose while increasing superoxide dismutase and glutathione levels
[192].
Vitamin D
Vitamin D, also known as calciferol, is an unsaponifiable heterolipid of

the steroid community that comes in two specific forms: D2
(ergocalciferol), which is present in plants as a result of ultraviolet B
radiation on ergosterol; and D3, which starts out as
dehydrocholesterol and then becomes pre-vitamin D3. Vitamin D3 is
produced in the human epidermis and can also be obtained from fish
oil, egg yolk, fortified foods, and supplements [193]. The major
circulating metabolite of vitamin D is 25-hydroxivitamin D [25 (OH)D],
which is converted in the liver. The active type is 1,25-
dihydroxyvitamin D [1,25(OH)2D] or dihydroxycholecalciferol, which is
a hormone formed primarily in the kidney and regulated by
parathyroid hormone, calcium, and phosphorous concentrations
[194]. Most tissues have vitamin D receptors, including the

endothelium, vascular smooth muscle, and myocardium, which can

transform 25(OH)D to 1,25(OH)2D. 1,25(OH)2D regulates several
genes, including those involved in insulin production and the growth
of vascular smooth muscle cells, directly or indirectly, which is why it
is believed to be a major contributor to cardiovascular disease [195].
According to epidemiologic evidence, 9 out of 10 cases of T2DM can be

linked to modifiable lifestyles; however, long-term lifestyle changes are
difficult to achieve and sustain. Vitamin D can play an important role
in modifying the risk of diabetes, according to recent evidence in
humans and animal models [196, 197]. Vitamin D receptors can be
found in cells of the pancreas and the immune system. Vitamin D also
plays a role in calcium absorption regulation; it participates in the
activity of calcium-dependent -cell endopeptidases and can act in two
ways: by directly inducing- cells to secrete insulin through an increase
in intracellular calcium concentration through Ca channels, or by
mediating -cell calcium-dependent activation to facilitate converse.
The union of 1,25-dihydroxyvitamin D to its receptors in the beta cell
will mediate vitamin D's role in pancreatic cell function. Alternatively,
vitamin D may improve insulin sensitivity by stimulating insulin
receptor expression and activation of PPAR- (peroxisome proliferator
activated receptor delta), which has been linked to skeletal muscle
fatty acid metabolism regulation. [200-203].
Calbindin-D28K (vitamin D based on the union of proteins and

calcium) expression has been shown to protect beta cells from
cytokine-mediated cell death, thereby lowering the risk of T2DM.
Although there are few human studies linking vitamin D to T2DM
patients' chronic inflammatory status, evidence indicates that vitamin
D may boost insulin sensitivity and promote pancreatic-cell survival
by modulating the effects of cytokines and nuclear transcription

factors like NF-ĸB [204]. Vitamin D deficiency, on the other hand, has
been linked to obesity, and although the mechanism is still unknown,
it is thought that due to vitamin D accumulation in adipose tissue, an
increase in the percentage of body fat could reduce its bioavailability
[205]. Low vitamin D status has been linked to the risk of T2DM in
some cohort studies in multi-ethnic populations [206-211].
More research has discovered links between serum vitamin D levels,

insulin resistance, and -cell dysfunction. Despite the fact that this
association has only been observed in females, further research is
likely needed to create a connection between sex hormones, vitamin
D, adipose tissue, and -cell function [212-216]. There is no consensus
on vitamin D supplementation; clinical trials have looked into how
this vitamin affects T2DM patients and related indicators. These
studies lasted anywhere from two months to seven years, with vitamin
D doses ranging from 400 to 200,000 IU/day; some showed
improvements in clinical parameters like central glycemia [217],
insulin sensitivity, and even lipid profile, while others showed
improvements in risk factors for complications like endothelial
function [218].
However, some interventional trials have shown that vitamin D

supplementation can improve diabetic patients' inflammatory status
by adjusting adipokine concentrations and decreasing pro-
inflammatory cytokines like TNF-, as well as some other parameters
like natriuretic peptide concentrations and blood pressure, but it does
not improve metabolic parameters [219-221]. Other research [222-
230] found no impact on diabetes incidence reduction even after years
of follow-up. Vitamin D deficiency is linked to diabetes-related
cardiovascular disease [231-235]. Vitamin D deficiency, which is very
common in European countries [236], is linked to insufficient intake,

low sun exposure, and age-related changes in vitamin absorption,

synthesis, and metabolism in elderly patients with type 2 diabetes
[237]. In this community of patients, there is a connection between
25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and the
development of type 2 diabetes [238]. Although the deficiency is linked
to a higher risk of cardiovascular death, it also raises the risk of
autoimmune disorders, Alzheimer's disease, and even colorectal and
breast cancer [239].
Vitamin E
The vitamin E complex consists of tocopherols and tocotrienols;

however, only -tocopherol is found in human plasma, and the other
types are not interchangeable, so they are not considered for human
health. While other antioxidants can be substituted for vitamin E, it
plays an essential antioxidant function in the body. It also plays a role
in the development of microsomial enzymes and protein kinase C, as
well as the induction of apoptosis in tumoral cells, platelet aggregation
inhibition, immune system modulation, gene expression, cell-
membrane stability, and erythrocyte formation [240].
Vitamin E levels have been shown to be lower in type 2 diabetes

patients, among other vitamins. In the general population, high levels
of -tocopherol have been linked to a lower risk of diabetes, but not in
middle-aged smokers [241]. Vitamin E's impact on the risk of diabetes
and its complications is most likely due to its antioxidant properties; a
decrease in plasma tocopherol has been linked to lipid peroxidation
and cardiovascular complications in diabetic subjects with longer
disease period [242], as well as total cholesterol and central form
obesity [243]. Plasma tocopherol, on the other hand, was not linked to
mortality in diabetic patients with hemodyalisis [244]. Some vitamin E

and other vitamin supplementation studies in haptoglobin 2-2

genotype carriers, although not in haptoglobin 2-1 genotype carriers,
have shown beneficial effects on hypertension, blood glucose and
antioxidant status, and HDL function [245-248]. Other studies [249-
251] have found no effect on lipid profile or insulin sensitivity.
Vitamin K
The vitamin K complex is made up of phylloquinone and

menaquinone, which can be found in a variety of animal and vegetable
foods. Vitamin K is needed for seven coagulation proteins, as well as -
glutamilcarboxilase, - carboxyl-glutamate acid, and the protein in the
matrix of -glutamic acid, all of which are involved in bone metabolism
[252]. Vitamin K intake has been linked to insulin sensitivity, glucose
metabolism, and thus diabetes in several studies. For example, the
PREDIMED research in Spain looked at dietary vitamin K intake and
diabetes markers; baseline values showed no associations, but after a
year of follow-up, those with the highest intakes had lower plasma
concentrations of ghrelin, glucose-dependent insulinotropic peptide,
glucagon-like peptide-1, IL-6, leptin, TNF, and visfatin. Increased
vitamin K intakes were linked to a lower risk of diabetes mellitus in
the same study [253, 254]. After approximately 10 years of follow-up,
a retrospective Dutch database study of vitamin K intake and the
incidence of type 2 diabetes mellitus discovered that phylloquinone
and menaquinone intakes were inversely correlated with the risk of
developing diabetes [255].
In a systematic review of studies that examined associations of

vitamin K deficiency or intake with cardiovascular disease, type 2
diabetes mellitus, and the metabolic syndrome, Rees et al. [256]

concluded that phylloquinone has no effect on risk, but

menaquinones can.
Multivitamins
The majority of the studies we've looked at so far have focused on

individual vitamins; however, there has also been research on the use
of multivitamin supplements and their effect on type 2 diabetes
patients' outcomes. Because of the potential for nutrient interactions,
we conclude that this form of study should be examined separately.
The 2010 Dietary Guidelines Advisory Committee did not recommend
multivitamins for the general healthy population, but they did say that
supplementation may help with some particular diseases [257]. This is
the case for type 2 diabetes, and numerous studies have been
conducted to see how multivitamin and mineral supplementation
affects the condition. In diabetic patients, for example, the use of a
daily vitamin-B group and antioxidant vitamins resulted in a rise in
folic acid and -tocopherol concentrations, as well as a decrease in
homocysteine. When compared to the placebo community,
supplemented patients showed a non-significant reduction in the
number of infections [258].
A single-blind randomized study of diabetic patients supplemented

with zinc sulfate plus a multivitamin/mineral preparation, only
multivitamin/minerals or placebo during 4 months, showed a
significant reduction in blood glucose, glycosylated hemoglobin and
improvement of lipid profile [259]. Long-term use of dietary
supplements, such as multivitamin/mineral, B-complex, vitamin C,
carotenoids, vitamin E, calcium with vitamin D, omega-3 fatty acids,
flavonoids, lecithin, alfalfa, coenzyme Q10 with resveratrol,
glucosamine, and a herbal immune supplement, improved C-reactive

protein, HDL cholesterol, triacylglycerides, serum homocystein, blood

pressure and incidence of diabetes. Patients with diabetes who took
multivitamins for six months had lower C-reactive protein levels and a
negative relationship with vitamins B6 and C [260]. On the other
hand, several studies have shown contradictory findings. The National
Institutes of Health-American Association of Retired Persons Diet and
Health Study found no connection between multivitamin supplement
use and the risk of developing diabetes [261].
In type 2 diabetes patients with subclinical micronutrient deficiency, a

year of multivitamin and mineral supplementation decreased the
frequency of infections [262]. Martini et al. [263] concluded that the
use of vitamin B complex, antioxidants (vitamin A, C, E, and
carotenoids), calcium, vitamin D, vitamin K, magnesium, sodium, and
potassium is not strongly correlated with glucose metabolism, so
multivitamin or mineral supplementation beyond the usual guidelines
for these nutrients is not recommended. The use of high doses of
antioxidants for the prevention and treatment of diabetes and its
complications is not supported by existing evidence [264].
Conclusions
Despite the fact that vitamins have important effects on diabetes
mellitus risk, progression, and complications, there isn't enough
evidence to recommend individual or multivitamin supplementation in
the general diabetic population in most cases. To ensure adequate
nutritional status, the best recommendation is to eat adequate
quantities of those foods that contain vitamins in sufficient amounts.
In this regard, dietary reviews are needed in order to recognize
particular intake deficiencies and make recommendations. When
considering the whole diet, supplement use carries the risk of excess
or toxicity with respect to certain vitamins; however, these harmful

effects are virtually non-existent when considering the whole diet.

However, there is sufficient clinical evidence to suggest vitamin B12
supplementation in patients with type 2 diabetes mellitus who are
taking metformin to reduce the risk of neuropathy and its
complications.
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CHAPTER 3: MATERIALS AND METHODS
3.1 Research Methodology
The proposed study is an experimental scientific study focused on

primary and secondary data. The sample will be a human being who
will be tested in a medical laboratory. Scholars use online and offline
libraries, as well as other tools such as articles and journals, to collect
secondary data. The primary data scholar has experience with diabetic
patients and physicians who specialize in this condition.
Hypothesis
 There is reduced immunity and an increase in risk of infection in
patients with type 2 diabetes.
 Supplementary B-group vitamins with antioxidants will enhance
vitamin status and antioxidant capacity and reduce the risk of
infections.
Purpose of the investigation

The purpose of the study was to
 Determine the antioxidant and B-vitamins nutritional status of
patients with type 2 diabetes.
 Study the effect of B-group vitamins and antioxidants on risk of
infections in community free living patients with type 2 diabetes
mellitus.
 Design of the Study A randomized, double-blind placebo-controlled
trial
Materials and Methods Page 111

3.2 Study Population
All patients with type 2 diabetes mellitus who visit the Kerala Institute
of Medical Sciences and Hospital's diabetes center for daily diabetes
follow-up will be considered for the study. The chosen hospital is one
of the city's four major hospitals, serving a population of 7.88 lakhs.
Patients with type 2 diabetes, aged 18 and up, will be approached and
encouraged to participate in the research. Individuals with serious
chronic health or mental illness, those who are enrolled in other
intervention trials, those who are taking dietary supplements, and
those who are unable to provide informed written consent will be
disqualified. In addition, the scholar is seeking approval from a local
research ethics committee. Patients with type 2 diabetes who regularly
visit outpatient clinics at the Kerala Institute of Medical Sciences and
Hospital were approached and asked to participate in the research.
The Figure 3.1 details the recruitment and intervention process and 3-
and 12-month follow-up.

Randomised
(n = 100)
Allocated to Supplement Allocated to Placebo
(n = 50) (n = 50)
Follow up at 3 Months Follow up at 3 Months
Infection diary (n= 34) Infection diary (n= 42)

Food diary (n= 30) Food diary (n= 30)
Exercise diary (n= 32) Exercise diary (n= 43)
Follow up at 12 Months Follow up at 12 Months
Infection diary (n= 37) Infection diary (n= 48)

Food diary (n= 32) Food diary (n= 43)
Exercise diary (n= 31) Exercise diary (n= 31)
Figure 3.1: Enrolment, treatment and follow up of study patients.
3.3 Selection Criteria
Inclusion criteria
• Individual aged 18 year and over with type 2 diabetes.
Exclusion criteria
 Individual with severe chronic clinical or psychiatric disease.
 Participating in other intervention trials.

 Have any medical illness or treatment which is likely to influence

the immune response and risk of infection other than diabetes
mellitus.
 Unable to give an informed written consent.
The exclusion criteria were designed to eliminate individual who might

have difficulty complying with the intervention.
Consent
Informed written consent was obtained from all participants who
agreed to take part in the study. Local research ethical committee
approval has been granted.
3.4 Study Procedure
Eligible patients had a fasting 10 mL of blood taken at baseline for

measurements of antioxidants, B group vitamins, and related
nutritional and biochemical variables, following the details required in
written consent and their recruitment to the study.
Patients are then randomly allocated to obtain an equivalent placebo

or a capsule containing antioxidant vitamins (221 mg of -tocopherol
and 167 mg of vitamin C) and B-group vitamins (1.67 mg folic acid,
1.67 mg vitamin B-2, 20 mg vitamin B-6, 0.134 mg vitamin B-12)
regular for 90 days. Patients are otherwise cared for in accordance
with normal procedures. Clinical assessment that included control of
diabetes and associated risk factors and complications are also
performed at baseline and repeated at 3 months. Fruits and vegetable
intake, physical activity and rate of infections were assessed at 3 and
12 months post-randomization.

Supplements and Placebo

The Placebo tablet will identical to the active supplement vitamin
capsule. No doctor, investigator, nurse or patient could differentiate
between the active treatment capsule and the placebo capsule.
Compliance with Trial Medications

Compliance will assess counting the remaining supplement tablets
and analysis of blood vitamin levels collected immediately after the
end of the supplement period at the 3-month follow up visit.
3.5 Experimental Procedure
The study is a randomized controlled trial to see how antioxidant

vitamins (vitamins C and E) and B-group vitamins (Folic acid, Vitamin
B2, Vitamin B6, and Vitamin B 12) supplementation affects vitamin
status, antioxidant capability, and infection risk in type 2 diabetics.
100 patients with type 2 diabetes who visited the outpatient diabetic
clinic at the Kerala Institute of Medical Sciences and Hospital were
randomly assigned to one of two groups:
Antioxidant vitamins (vitamin C and E) and B-group vitamins

(Folate, B2, B6, B12) [n = 50]; or a placebo for 90 day [n = 50]
Safety and efficacy of the dosages

Vitamin C, E, B2, B6, B 12 and Folate.
The literature concerning the safety of these vitamins has been

reviewed in detail. This level of supplement has not been associated
with any adverse effect in human population. Furthermore double of
these doses have been used in previous studies with no side effect
being reported.

Table 3.1: Vitamins and their concentration
Ingredients in Input per Capsule Capusle

decreasing weight in mg
Order
Vitmin E Powder 221.000 Vitamin E
Natural
(Covitol l 210 EU)
Vitmin C- Ascorbic 167.000 Vitamin C
Acid
Capsule- size 0- 96.000 Capsule shell
HPMC- ( Hydroxypropylmethyl
white/white cellulose,
hydroxypropylcellulose,
propylene glycol as
stabilizer, color
Titanium dioxide)
MICR Crystalline 97.000 As filling agent
Cellulose
Pyri Doxine 20.580 Vitamin B6
Hydrochloride
Mgnesium Stearate 7.946 as flow and release
agent
Riboflavin 1.670 Vitamin B2
Folic Acid 1.670 Folic acid
Cyanocobalamin 0.134 Vitamin B 12

3.6 MEASUREMENTS
Anthropometric data, including body weight, height and body mass

index (BMI), will measure using the Tanita body composition analyzer.
Waist circumference will measure using a flexible plastic tape.
Measurement of Fruits and Vegetables Intake

The consumption of fruits and vegetables was assessed using an
abbreviated semi-quantitative food frequency questionnaire tailored
for self-administration after a brief verbal discussion. It specifies the
normal level of food intake over the previous 12 months and assesses
each individual's average weekly nutrient consumption. A 7-day
weighted dietary intake was used to construct and verify the complete
version of the questionnaire. It's also been compared to a variety of
other diets and used in various studies.
Measurement of Physical Activity

A questionnaire may also be used to measure physical activity related
to work and leisure. The frequency and length of regular or weekly
physical exercise sessions lasting at least 20 minutes and during
which subjects become breathless or sweated are recorded. The
amount of hours spent in bed would also be a factor in the questions
(this included time spent reading, watching television or sleeping).
Infection Diary
Data on infection occurrence will be gathered from symptom and
treatment checklist diaries held during 3-month face-to-face
interviews and 12-month telephone interviews. The research scholar
then assigned a particular diagnosis and length of illness based on the
infection occurrence diary record. Common adult infectious diseases
(upper respiratory tract infection, lower respiratory tract infection,

influenza-like illnesses, sore throat, sinusitis, skin infections, eye and

ear infections, gastrointestinal infections, and urinary tract infections)
will be diagnosed using standard guidelines.
Blood Samples
Fasting blood samples will be taken and placed in two vacutainer
tubes containing potassium EDTA as an anticoagulant. At room
temperature, the samples will be thoroughly mixed before being
transported to the laboratory. Both tubes were immediately
centrifuged at 4000 rotations per minute for 10 minutes. Plasma and
serum will be collected and processed at 80°C for vitamin analysis in
the future.
3.7 Reagents and Instruments
Folate is a good source of vitamin B12. We used a reagent kit from

BACKMA COULTER to perform KFTs, HbAlc, and blood sugar
analysis. Both of these samples are subjected to a thorough
examination (unicel DXI 800 access immunoassay system and unicel
OXC 880i synchrone access clinical system). HPLC was used to
analyze vitamins A, E, and C, and the study was carried out on a
Waters (Milford, MA) system gradient liquid chromatography (model
515) with auto injector (model 717).
Vitamin A (Retinol):
The calculation was based on the reference: MJ. Shearer's HPLC of
Small Molecules. 100 l of plasma with a known concentration of 0.5
g/ml trans-retinol acetate in ethanol (Internal Standard) is applied
and blended to 100 l of plasma with a known concentration of 0.5
g/ml trans-retinol acetate in ethanol. After that, 200 l of hexane
extraction solvent was added, mixed for 30 seconds, and then moved

to a shaker for 10 minutes. The upper hexane layer, which includes

both retinol and retinol acetate, was transferred to a new eppendorf
tube and dried at 40°C with a slow stream of nitrogen. The residue
was reconstituted in 100 l of ethanol and 20 l was injected onto a
HPLC system with column (00 406X250mm BECK MAN) and with
100% methanol as the mobile phase. UV detector set at 325 nm
carried out estimation of retinol.
Vitamin C (L-Ascorbic Acid):

Vitamin C was measured using an HPLC device with a fluorescent
detector. Deproteinized plasma was treated with acetate buffer and
ascorbate oxidase to convert L.ascorbic acid to dehydr L.ascorbic acid,
then derivatized with OPDA to improve fluorescence before being
injected into HPLC. This approach to estimating total ascorbic acid by
A.J peek et al Journal of Chromatography, 305 (1984) 53-60,
accounts for the oxidative loss of L.ascorbic acid during processing,
transport and other processes. A75 l volume wa injected onto a
reverse phase coloumn (CHROMPACK-C 18 100MM X 4.6 MM) and
eluted with a potassium di-hydrogen phosphate/methanol mobile
phase, flow rate 1 ml/minute. ﬂuorescent detector was used with
excitation 365 nm and emission 418 nm.
Vitamin E (a-Tocopherol):
The vitamin E estimation were performed with B.L.Lee, S.C .Chua et
al, Journal of chromatography 581 (1992) 41-47. Plasma tocopherol
was extracted using butanol-ethyl acetate mixture (1:1) v/v along with
the internal standard, tocopherol acetate. Subsequent to proper
mixing, incubation and centri ugation 100 l of the superatant was
injected onto a 3.9 X300mm C 18 reverse phase H PLC coloumn
(WATER) and eluted with methanol 89.5%, Butanol 5% and water
5.5% (v/v) Mixer. Detection was carried using a UV detector at 295

nm. Philips latex-free blood pressure cuffs was used to obtain the
blood pressure, and pulse. Body composition analyzer TANITA model
was used to obtain the anthropometric readings of the participants.
3.8 Statistics and Analysis
Randomization Strategy
The randomization sequence will generated using computer generated
tables, concealed in sequentially numbered sealed opaque envelopes
and kept in a clerical office.
Outcome measures
 Nutritional status including; Body weight, Body Mass Index (BMI),
and waist
 circumference
 Measures of fruits and vegetables intake.
 Exercise and physical activity.
 Blood pressure, lipid profile & vitamins markers.
 Risk of infection (number of infections and incidence of self-
reported infection)
Sample Size Calculation

A previous study has shown that supplementation of diet with 400 mg
of vitamin C increased plasma vitamin C by 45%. Therefore, a sample
size of 96 diabetic patients (48 treatment and 48 controls) would allow
the detection of a 30% difference between groups in total plasma
vitamin C concentrations with 80% power and a type 1 error
probability of ≤0.05.

Statistical Analysis
A repeated measures analysis of variance (ANOVA) test will use to test
within subject differences and a p-value < 0.05 was considered
significant. Differences in cumulative changes between groups will
adjust for age, BMI, duration and treatment of diabetes. The Mann—
Whitney U test will also use.
Quality Assurance
Two individuals conducted quality assurance by independently testing
the accuracy of data entry performed in order to improve the accuracy
of data collection, entry, and analysis. A random audit of 20 cases of
entered data against paper-based forms will be performed twice by two
separate operators, and it was discovered that over 96 percent of the
data entry process was correct.

CHAPTER 4: RESULTS
4.1 Baseline Characteristics
A total of 100 diabetic patients were enrolled in the study. 42 people

who received the placebo and 34 people who received the supplements
returned for a three-month follow-up and agreed to provide a blood
sample and complete an infection diary. For a 12-month follow-up, the
figures were 37 and 48, respectively. The failure to answer to the
infection diary questionnaire resulted in exclusions.
Table 4.1: Patient's general characteristic (n = 100)
Age mean (SD) 51.5 (11.5 )

Female 58 (58%)
Level of education [n (%)] ≤High school 79 (79%)
>High school 19 (19%)
Past medical history [n (%)] Hypertension 62 (62%)
Ischemic Heart Disease 15 (15%)
Cerebrovascular disease 1 (1%)
Peripheral vascular disease 3 (3%)
Atrial Fibrillation 3 (3%)
High cholesterol 74 (74%)
Smoker 8 (8%)
The participants' general characteristics are shown in (Table 4.1). The

participants' average age was 52.5 years, with 58 percent of them
being females and 42 percent being males. In terms of educational
Results Page 122

attainment, the study revealed that the majority of the participants

had not completed high school (79 percent). One-fifth of the patients
were college students or higher. In terms of co-morbidities, the
majority of the participants in the study had two or more, with
hypertension and high cholesterol being the most common.
4.2 Baseline Characteristics of placebo and supplement group
The participants were assigned to one of two groups: placebo (50) or

supplement (50). When comparing the general characteristics of the
two classes, a portion of the waist circumference of male patients was
found to be significantly different. The majority of the variables
revealed no substantial differences between the two groups, which is
less supplement group than the placebo group.
Table 4.2A,B,C shows baseline characteristics of the treatment and

placebo group. The 2 groups were comparable on entry into the study
with respect to age, adiposity, duration and treatment of diabetes and
other clinical and biomedical measures.
Results Page 123

Table 4.2A: Baseline characteristics placebo and supplement

group
Variable Placebo Supplement p-value
(n = 50) (n = 50)
N (%) N (%)
Gender female 32 (64%) 27 (54%) 0.416
Nationality India 39 (78%) 39 (78%) 1 .000
Others 11 (22%) 11 (22%)
Level of ≤High school 38 (76%) 41 (85.%) 0.309

education, n >High school 12 (24%) 7 (14%)
(%)
Smoking 2 (4% ) 6 (12.5%) 0.155
Duration of <5 years 17 (35.4%) 14 (28.6%) 0.29 1

diabetes 5- 10 years 14 (28%) 10 (20%)
> 10 years 17 (34%) 25 (50%)

Drug Insulin 12 (24%) 20 (40%) 0.085
Oral hypo 50 (100%) 47 (94%) 0.110
glycemics
Ca channel 1 (2%) 2 (4%) 0.546

blocker
diuretic 8 (16%) 6 (12.2%) 0.592
ACE 13 (26%) 12 (24.5%) 0.863

B Blockers 14 (28%) 16 (32.7%) 0.614
Nitrate 0 (0%) 1 (2%) 0.310
Aspirin 36 (72%) 40 (81.6%) 0.275
Others 38 (76%) 36 (73.5%) 0.772
Results Page 124

Total number of patients on 46 (92%) 47 (95.9%) 0.414

drugs
Past medical Hypertension 34 (68%) 28 (56%) 0.216
history Ischemic Heart 8 (16%) 7(14%) 0.779
Disease
Cerebrovascular 0(0%) 1 (2%) 0.3 1 5
disease
Peripheral 1 (2%) 2(4%) 0.558
vascular
disease
Atrial 1 (2%) 2(4%) 0.558
Fibrillation
High cholesterol 36(72%) 38(76%) 0.648
Othor 1 2(24%) 1 4(28%) 0.648
Total number of patients with 39 (78%) 39 (78%) 1 .000
past medical history
p≤0.05 significant
The female individual compared in Table 4.2A showed no statistical
significant difference between the Supplement and placebo groups two
group. The majority of the participants in the sample were Indian.
The participants' educational levels did not vary between the two
classes, with the majority of them being below the graduate level
(76%) and (85%) in the placebo and treatment groups, respectively. In
addition, there was no statistically significant difference in diabetes
length between the two classes. (Table 4.2A). In the study, 40 percent
of those who received the supplements were on insulin therapy alone
or a combination of oral hypoglycemic agents and insulin, compared
to just 24 percent of those who received the placebo. We didn't notice
a statistically significant difference between the two groups (p =
0.085). In addition, we discovered that 92 percent of those in the
placebo group take at least one drug other than diabetes drugs,
Results Page 125

compared to 96 percent of those in the treatment group (p = 0.414).

The study also discovered that 68 percent of diabetic patients in the
placebo group had hypertension, compared to 56 percent of diabetic
patients in the treatment group (p = 0.216). The prevalence of high
cholesterol was 72 percent in the placebo group and 76 percent in the
treatment group. Both groups revealed that 78 percent of participants
suffer from at least one or more co-morbidities (Table 4.2A).
Table 4.2B: Baseline characteristics placebo and supplement

group

(n = 50) (n = 50)
Previous hypertension (n) 34 28 0.219
Previous IHD (n) 8 7 0.781
High cholesterol (n) 36 38 0.650
Number of drugs/patient 2.2 2.3 0.849
Treatment of Diet 2 2 0.059 *
diabetes (n) Tablet 36 28
Metformin 22 16
Metformin + 12 8
glimepiride
Metformin + 2 3
rosiglitazone
Metformin + 0 1
gliclazide
Insulin 9 18
Both 3 2
(metformin
+ insulin)
Results Page 126

There was no significant difference between the two groups in terms of

the form and amount of drugs they used, and there was no significant
difference in terms of co-morbidities including hypertension and
cholesterol (Table 4.2B).
Table 4.2C: Baseline characteristics placebo and supplement

group

(n = 50) (n = 50)
Mean (SD) Mean (SD)
Age 51.2 (11.8) 51.8 (11.3) 0.798
Body weight Male 90.1 (18.8) 80.6 (15.3 ) 0.086
- kg Female 78.4 (15.9) 82 (21.2) 0.474
BMI (kg/m2) Male 31.4 (5.7) 28.5 (4.5 ) 0.093
Female 32.7(6.1) 3 3.5 (7.5) 0.637
Waist Male 110.4(12.8) 101.5(11.6) 0.024
circumference Female 103.1(13.2) 101.5 (13.2) 0.665
(cm)
Systolic BP (mm Hg) 133.6 (15.9) 137.5 (18.7 ) 0.28 1
Diastolic BP (mm Hg) 77.6 ( l0.5) 80.6 (10.2 ) 0.1 58
Urea – nmol/L 6.8(11.5 ) 6.1 (7.7 ) 0.750
Creatinine - nmol/L 58.7(25 ) 72.2 (40.6) 0.193
HbAlc (%) 8.1 (2.2 ) 8.0 (1.9) 0.802
Random blood sugar- 10.6 (3.7 ) 11.2 (4.2 ) 0.562
nmol/L
Total cholesterol (mmol/L) 4.7 (1.2) 4.4 (0.8) 0.081
Triglycerides (mmol/L) 1.44 (1.3) 1.49 (1.7) 0.851
Results Page 127

The treatment group's mean age is close to that of the placebo group
(51.8 years vs 51.2 years). The nutritional status markers showed that
there was no statistical significance between the two groups in terms
of body weight among the females, who made up 58 percent of the
total sample amount. BMI and waist circumference were correlated
with (p = 0.474), (p = 0.637), and (p = 0.665) respectively. The male
population, on the other hand, only reported statistically significant
differences in waist circumference (p = 0.024). Although there were
variations in body weight and BMI, they were not statistically
significant (p = 0.086), (p =0.093), respectively. Other clinical and
biochemical data measures, such as kidney function checks, HbAlc,
and fasting blood sugar, revealed no statistically significant
differences (Table 4.2C).
Results Page 128

Table 4.2D: Baseline characteristics of responder and non-

responder of the study population
Variable Respondents Non - p-value
(n-68) respondents
(n-32)
N (%) N (%)
Age mean (SD) 50 (l0) 54 (14) 0.194
Gender (male) 28 (41%) 13 (41%) 0.958

Smoking 4 (6%) 4 (12%) 0.485
Nationality India 53 (78%) 32 (78%) 0.292
Others 15 (22%) 0
Level of ≤High 55 (82%) 24 (77%) 0.387
education
school
>High 12 (18%) 7 (22%)
school
Body weight - male 83 (18) 79 (18) 0.296
kg
BMI (kg/m2) male 32 (6.6) 31 (5.5) 0.387
Waist male 104 (12) 102 (13.6) 0.567
circumference
(cm) mean (SD)
Urea – nmol/L mean (SD) 7.5 (11.3 ) 4.2 (1.3 ) 0.111
Creatinine - nmol/L mean 71 (46) 64 (14) 0.388
(SD)
HbAlc (%) mean (SD) 8.3 (2.2) 7.8 (1.8) 0.286
Random blood sugar- 10.7 (3.8 ) 11.5 (4) 0.457
nmol/L mean (SD)
Total number of patients 67 (98%) 32(100%) 0.338
on drugs
Total number of patients 52 (76%) 26 (81%) 1.000
with past medical history
p≤0.05 significant
Results Page 129

Table 4.2E: Responders baseline characteristics of placebo and

supplement group

(n-38) (n-30)
N (%) N (%)
Age mean (SD) 50 (11 ) 50 (9) 0.9 1 5
Gender (male) 15 (39%) 13 (43%) 0.748
Smoking 1 (3%) 3 (1%) 0. 174
Nationality India 28 (73%) 25 (83%) 0.229
Others 10 (22%) 5 (17%)
Level of ≤High 30 (79%) 25 (83%) 0.443
education
school
>High 8 (21%) 4 (13%)
school
Body weight male 83 (16.9) 84 (20) 0. 769
- kg
BMI (kg/m2) male 32 (6) 32 (7.5) 0.953
Waist male 105 (13) 1 03 (11) 0.656
circumference
(cm) mean
(SD)
Urea – nmol/L mean (SD) 8.7 (15) 6.9 (9.6 ) 0.682
Creatinine - nmol/L mean 57(29 ) 77 (50) 0.259
(SD)
HbAlc (%) mean (SD) 8.5 (2.5) 8 (1.9 ) 0.459
Random blood sugar- 10.2 (3.8) 11.1 (4) 0.418
nmol/L mean (SD)
Total number of patients 3 8 (100%) 29 (97%) 0.282
on drugs
Results Page 130

Table 4.2F: Non-Responders baseline characteristics of placebo

and supplement group

(n-12) (n-20)
N (%) N (%)
Age mean (SD) 54 (14) 54 (14) 0.912
Gender (male) 3 (25%) 1 0 (50%) 0.163
Smoking 1 (8%) 3 (15%) 0.581
Nationality India 11 (92%) 1 4 (70%) 0.335
Others 1 (8%) 6 (30%)
Level of ≤High 8 (66%) 16 (85%) 0.255
education
school
>High 4 (34%) 3 (15%)
school
Body weight male 82 (21) 77.5 (16) 0.472
- kg
BMI (kg/m2) male 32.6 (5.6) 30 (5.4) 0.210
Waist male 108 (15) 99 (12) 0.074
circumference
(cm) mean
(SD)
Urea – nmol/L mean (SD) 4 (1.5) 4.3 (1.3) 0.658
Creatinine - nmol/L mean 60.6 (19.7 ) 65.6 (1l.3 ) 0.454
(SD)
HbAlc (%) mean (SD) 7.7 (1.5 ) 7.8 (1.9) 0.909
Random blood sugar- 11. 7 (3.7 ) 1l.3 (4.8 ) 0.853
nmol/L mean (SD)
on drugs
Results Page 131

In Table 4.2D we contrasted the baseline characteristics of responders

and non-responder participants in terms of gender, ethnicity, level of
education, total drugs, medical diseases, smoking, body weight, BMI,
KFTs, HbAlc, and blood sugar in males. There were no statistically
significant differences between these two groups, according to the
report.
There were no statistically significant differences in the baseline

characteristics of the treatment and placebo groups among the
responder subjects, as shown in Table 4.2E. In the nonresponders,
there were no statistically significant discrepancies between the
treatment and placebo classes (Table 4.2F).
4.3 Effect of supplement on vitamin status
Vitamin supplementation significantly increased plasma vitamin E

and serum folate and reduced total plasma homocysteine levels and
some of the inflammatory markers in the intervention groups
compared with the placebo group (Table 4.3A) [1].
Results Page 132

Table 4.3A: Baseline and three months plasma antioxidants and

inflammatory markers in the intervention group compared with
the placebo group (mean SD).
Placebo Supplement p-value
(n = 50) (n = 50) *
Vitamin C (mg/L) Baseline 23.8 (16.8) 33.00 (20.1) 0.913
3 months 19.5 (12.1) 18.9 (12.8)
Vitamin E (mg/L) baseline 7.3 (4.5) 8.6 (3.2) 0.006
3 months 7.6 (4.6) 11.4 (4.5)
Folate (nmol/L) baseline 18.2 (8.9) 18.95 ((8.1) 0.001
3 months 18.7 (8.6) 32.4 (11.9)
B12 (pmol/L) Baseline 236 (103) 179 (93) 0.001
3 months 227 (99) 252 (191)
Homocysteine Baseline 10.3 (3.2) 12.7 (4.5) 0.657
(mmol/L) 3 months 10.7 (3.3) 11.5 (3.3)
IL6 (pg/mL) Baseline 3.42 (2.22) 2.49 (1.32) 0.023
3 months 5.40 (2.53) 3.35 (1.99)
TNFα (pg/mL) baseline 1.26 (1.63) 1.66 (2.24) 0.204
3 months 1.15 (0.8) 0.96 (0.21)
CRP (mg/L) Baseline 11.6 (8.9) 10.1 (8.6) 0.205
3 months 15.1 (15.9) 8.4 (3.4)
* Three months values were regressed on baseline values and
intervention (placebo 1/supplement 2).
Results Page 133

300
250
200
150
100 Placebo
Supplement
50
0
baseline
baseline
baseline
Baseline
Baseline
Baseline
Baseline
3 months
3 months
3 months
3 months
3 months
3 months
3 months
3 months
Baseline
Vit. C Vit. E Folate Vit. B12 Homo IL6 TNFα CRP
cysteine
Figure 4.1: Baseline and three months plasma antioxidants and

inflammatory markers in the intervention group compared with
the placebo group
Table 4.3B: Baseline and three months plasma antioxidants and

inflammatory markers in placebo group
Placebo (n = 50)
Baseline 3 months
Vitamin C (mg/L) 23.8 (16.8) 19.5 (12.1)
Vitamin E (mg/L) 7.3 (4.5) 7.6 (4.6)
Folate (nmol/L) 18.2 (8.9) 18.7 (8.6)
B12 (pmol/L) 236 (103) 227 (99)
Homocysteine (mmol/L) 10.3 (3.2) 10.7 (3.3)
IL6 (pg/mL) 3.42 (2.22) 5.40 (2.53)
TNFα (pg/mL) 1.26 (1.63) 1.15 (0.8)
CRP (mg/L) 11.6 (8.9) 15.1 (15.9)
Results Page 134

250
200
150
100
50
Baseline
0 3 months

inflammatory markers in placebo group
Table 4.3C: Baseline and three months plasma antioxidants and

inflammatory markers in Supplement group
Supplement (n = 50)
Baseline 3 months
Vitamin C (mg/L) 33.00 (20.1) 18.9 (12.8)
Vitamin E (mg/L) 8.6 (3.2) 11.4 (4.5)
Folate (nmol/L) 18.95 (8.1) 32.4 (11.9)
B12 (pmol/L) 179 (93) 252 (191)
Homocysteine (mmol/L) 12.7 (4.5) 11.5 (3.3)
IL6 (pg/mL) 2.49 (1.32) 3.35 (1.99)
TNFα (pg/mL) 1.66 (2.24) 0.96 (0.21)
CRP (mg/L) 10.1 (8.6) 8.4 (3.4)
Results Page 135

300
250
200
150
100
50 Baseline
0 3 months

inflammatory markers in Supplement group
4.4. Effect of Supplement on Infections
Tables 4.4A and 4.4B show the frequencies of infections in the

treatment group compared with the placebo group. The total number
of reported infections at three months of follow-up in the treatment
group was 9/34 subject (27%), compared with 15/42 (36%) in the
placebo group (p = 0.623) (Table 4.4A). At 12 months, the number of
reported infections in the treatment group was 25/37 (67.5%),
compared with 27/48 (56.3%) in the placebo group (p = 0.488) (Table
4.4B).
Results Page 136

Table 4.4A: Frequencies of infections over three months in

diabetic subjects of treatment and placebo groups (n %).
Type of infection Placebo Treatment p-value
(n = 42) (n = 34)
Cold 2 (4.7%) 0 0.623
Flu 2 (4.7%) 0
Sore throats 1 (2.4%) 1 (2.9%)
Bronchitis 0 1 (2.9%)
Urinary tract infection 0 1 (2.9%)
Gastro enteritis 1 (2.4%) 0
Ear infection 1 (2.4%) 1 (2.9%)
Other 8 (19%) 5 (14.7%)
Number of infections per subject 0.36 0.26
p ≤ 0.05 significant.
9
8
7
6
5
4
3
2
1
Placebo
0
Treatment
Figure 4.4: Frequencies of infections over three months in

diabetic subjects of treatment and placebo groups
Results Page 137

Table 4.4B: Frequencies of infections over 12 months in diabetic

subjects of treatment and placebo groups (n %).
Type of infection Placebo Treatment p-value
(n = 48) (n = 37)
Cold 3 (6.25%) 4 (10.8%) 0.488
Flu 4 (8.3%) 5 (13.5%)
Sore throats 4 (8.3%) 3 (8.1%)
Bronchitis 2 (4.2%) 1 (2.7%)
Urinary tract infection 3 (6.25%) 2 (5.4%)
Gastro enteritis 0 1 (2.7%)
Ear infection 2 (4.2%) 1 (2.7%)
Other 9 (18.8%) 8 (21.7%)
Number of infections per 0.56 0.67
subject
10
9
8
7
6
5
4
3
2
1
0 Placebo
Treatment
Figure 4.5: Frequencies of infections over 12 months in diabetic

subjects of treatment and placebo groups
Results Page 138

4.5 Food Intake
Table 4.5 indicates the sample population's fruit and vegetable

consumption after three and twelve months of follow-up. Except for
the tinned or dried fruits at three months (p = 0.000), there was no
substantial difference between the two classes, despite the fact that
consumption was relatively high at three months and increased
further at 12 months.
Table 4.5: Food diary in diabetic subjects on treatment and

placebo (mean SD)
Placebo Treatment p-value p-value

Variable n = 43 n = 32
number/week number/week
3 12 3 12 3 12
months months months months months months
Apples 3.2 (2.8) 5.5 (2) 2.8 (2.3) 5.5 (1.8) 0.500 0.900
and pears
Oranges 4 (2.6) 5.4 (1.9) 3.8 (2.4) 5.3 (1.6) 0.600 0.900
and
bananas
Tinned or 1.8 (2.4) 4.2 (2.4) 4 (2.6) 5.2 (2) 0.000 0.090
dried fruit,
fruit in
syrup or
juice
Fruit 3.1 (2.6) 3.9 (2.8) 3 (2.6) 3.5 (2.5) 0.800 0.600
(fresh or
from a
carton)
Results Page 139

Green 5.6 (2) 6 (0.9) 5.4 (2) 5 (2) 0.700 0.080

vegetables,
salad,
cabbage,
spinach
Potatoes, 1.9 (1.9) 3.9 (2.4) 1.6 (1.8) 3.6 (2.6) 0.500 0.700
mashed,
boiled,
baked,
chips
Vegetables 2.6 (2.3) 5 (2) 3.2 (2.3) 5 (1.8) 0.300 0.900
in soup,
stews,
ready
meals, etc.
Other 4.1 (2.6) 5 (1.4) 4.6 (2) 5.4 (0.9) 0.400 0.500
vegetables,
peas,
carrots,
onions,
tomatoes,
etc.
Average 3.8 5.6 2.1 4.7
number of
fruits and
vegetable
per day
Results Page 140

Table 4.5 indicates the food and dietary consumption of the

participants in the study, which was assessed at three and twelve
months during the analysis. Participants in both groups were asked to
answer questions about the amount of food items they eat each week
using a standard questionnaire. The placebo group had a higher
response rate (86%) than the treatment group (64%) respectively. The
analysis also revealed that there was some level of similarity between
the participants in the same group as well as between the two groups.
Except for tinned or dried fruit (p =0.000), there was no statistically
significant difference between the two groups.
4.6 Exercise and Physical Activity
Tables 4.6A and 4.6B reveal the three and 12 months physical activity
of the study population. During work and leisure time, the majority of
diabetic patients in this study registered very low levels of physical
activity. At three months, only two patients, for example, had a very
active career and two very active leisure periods. For the previous 12
months, the corresponding statistics were one patient with a very
active career and one patient who were active in his spare time. The
majority of patients responded less than once a week when asked how
much they are physically active for at least 20 minutes where they
become out of breath and sweat. This sedentary lifestyle was
accompanied by a high prevalence of overweight and obesity of up to
90% in the study population and a further increase in body weight—
mean body weight at baseline 82.2 kg increased to 86.9 at three
months of follow up.
Results Page 141

Table 4.6A: Exercise diary in diabetic subjects on treatments and

placebo at three months
Placebo Treatment p-value
Variable (n = 43) (n = 32)
Number (%) Number (%)
How not very 22 (51%) 12 (37.5%) 0.291
physically active
active moderately 18 (42%) 18 (56%)
is your active
occupation very active 2 (4.6%) 0
not working 1 (2.3%) 2 (6%)
How not very 16 (37%) 13 (40%) 0.517
physically active
active moderately 24 (55.8%) 19 (59%)
is your active
leisure time very active 2 (4.6%) 0
How many Mean 7 9 0.529
hours per SD (5.1) (10.6)
week do you
spend
doing
housework
How often are <1/week 26 (60%) 24 (75%) 0.402
you 1–2/week 8 (18.6%) 7 (22%)
physically 3–4/week 4 (9.3) 0
active for at 5–6/week 1 (2.3%) 0
least 20 min, 7–8/week 1 (2.3%) 0
where you >8/week 0 0
become out of
breath
Results Page 142

and sweat
How many <1 h 5 (11.6%) 3 (9%) 0.824
hours per 1–2 h 7 (16%) 5 (16%)
day do you 3–4 h 2 (4.6%) 0
usually 5–6 h 9 (21%) 8 (25%)
spend in bed 7–8 h 13 (30%) 13 (40%)
(this >8 h 5 (11.6%) 2 (6%)
includes time
spent
reading,
watching
television,
sleeping)
Table 4.6B: Exercise diary in diabetic subjects on supplements

and placebo at 12 months
Variable Placebo Supplements p-value
(n = 31) (n = 31)
Number (%) Number (%)
How not very 18 (58%) 21 (68%) 0.416
physically active
active is moderately 6 (19%) 6 (19%)
your active
occupation very active 0 1 (3%)
not working 7 (23%) 3 (10%)
How not very 24 (75%) 20 (65%) 0.372
physically active
active is moderately 7 (23%) 10 (32%)
your leisure active
Results Page 143

time very active 0 1 (3%)

How many Mean 15.6 12 0.126
hours per SD 7.9 7.1)
week do you
spend doing
housework
How often are <1/week 15 (48%) 16 (52%) 0.291
you 1–2/week 7 (23%) 5 (16%)
physically 3–4/week 1 (3%) 5 (16%)
active for at 5–6/week 1 (3%) 2 (6%)
least 20 min, 7–8/week 0 0
where you >8/week 7 (23%) 3 (10%)
become out
of breath and
sweat
How many <1 h 0 0 0.034
hours per 1–2 h 0 0
day 3–4 h 1 (3%) 1 (3%)
do you 5–6 h 3 (10%) 8 (26%)
usually 7–8 h 9 (29%) 16 (52%)
spend in bed >8 h 18 (58%) 6 (19%)
(this includes
times
spent
reading,
watching
television,
sleeping)
p ≤ 0.05 significant
Results Page 144

Table 4.6A reveals the 3 months physical activity of the participants in

both groups. The majority of diabetic patients who participated in the
study indicated low levels of physical activity; 51 percent of the
placebo group said their occupation is not very active, compared to
37.5 percent in the treatment group, and 42 percent of the placebo
group said their occupation is moderately active, compared to 56
percent in the treatment group. The difference between the two groups
was determined to be insignificant (p =0.291). In terms of leisure time,
37% of the placebo group said they didn't have much time, compared
to 40% in the treatment group, and 56% of the placebo group said
they did moderate exercise, compared to 59% in the treatment group,
with no statistical significance (p = 0.517). There was little difference
between the two groups in terms of low physical activity, which
resulted in breathlessness and sweating. Table 4.6B shows the 12
months follow up of both groups in term of the physical activities.
Physical behaviors at work were poor in both the placebo and
treatment groups (58 percent and 68 percent, respectively) (p = 0.418),
and leisure time was found to be inactive in 75 percent of the placebo
and 65 percent of the treatment (p = 0.372). There was no statistically
significant difference in the amount of hours spent doing housework
per week (p = 0.126), but 48 percent of placebo subjects registered
physical activity that resulted in breathlessness and sweating less
than once per week, compared to 52 percent of treatment subjects (p =
0.291).
4.7 References
1. Gariballa, S.; Afandi, B.; Abu Haltem, M.; Yassin, J.; Habib, H.;
Ibrahim, W. Oxidative damage and inflammation in obese diabetic
Emirati subjects supplemented with antioxidants and B-vitamins: A
randomized placebo-controlled trail. Nutr. Metab. 2013, in press
Results Page 145

CHAPTER 5: DISCUSSION
The purpose of this study was to assess the effect of 3 months

antioxidants and B-group vitamin supplement on rate of common
infections in type 2 diabetic patients in the community. The
participants were randomly assigned to one of two groups: one
received the treatment vitamins, while the other received a placebo.
The treatment allocation was kept a secret from both the patients and
the researchers. Throughout the study, all participants received the
same form of evaluation, inquiries, education, and interview process.
At the conclusion of the study, we discovered that there were no major

variations in general characteristics and measurements such as age,
level of education, BMI, and other baseline characteristics between the
placebo and treatment groups. The results of the study showed that
after three months of vitamin intake, the treatment group's serum
levels of Vitamin E, B12, and folate improved significantly. Vitamin A
and C levels fell in both the vitamin and placebo groups. This may be
due to a rise in oxidative damage, which results in a reduction in
antioxidant vitamin status.
The study also found that after three months of supplementation, the
number of infections identified by the treatment group was lower than
that of the placebo group (9 vs. 15), but this difference was not
statistically significant. After 12 months of follow-up, the gap in the
number of infections decreased (27 vs. 25). While the difference in the
number of infections recorded may be linked to vitamin
supplementation, the lack of statistical significance may be due to the
Discussion Page 146

low dose of vitamins used, the limited duration of supplementation, or

the impact of vitamins weaned during the 12-month follow-up.
5.1 Obesity
Diabetes is a major disease burden in India, and we have the world's

second-largest diabetes population. In India, over 72 million people
were diagnosed with diabetes in 2017 [1]. Obesity is clearly described
as a condition in which excess body fat has accumulated to the point
that health is jeopardized. Obesity is one of the most common and
also one of the most overlooked public health issues in both developed
and developing countries, according to the World Health Organization
(WHO) [2].
Other metabolic diseases, such as diabetes, hypertension,

dyslipidemia, cardiovascular disease, and even certain cancers, are
closely linked to obesity [3]. It's a big part of the type 2 diabetes
(T2DM) crisis, with almost 88 percent of people with T2DM being
overweight or obese. Just half of people with diabetes and other
chronic conditions receive diet and/or exercise therapy from their
primary care provider, despite the increased risk of poor health
outcomes and a detrimental effect on quality of life. [4] Obesity and
overweight have also been related to low blood pressure, cholesterol,
and blood glucose regulation in people with type 2 diabetes. [5] The
body mass index is often used to measure obese and overweight.
In our research it has been noticed that the rate of obesity among the
participants in our ample was high. 32% of subjects were overweight
(BMI between 25 kg/m2 and 30 kg/m2), and 58% of them were obese
(BMI greater than 30 kg m2). We also found that the majority of the
subjects involved in the study were centrally obese, which was
Discussion Page 147

determined by the absolute waist circumference (> 102 centimeters in

men and >88 centimeters in women) [6]. Male subjects had an average
waist circumference of 106 centimeters, while female subjects had an
average waist circumference of 102 centimeters. A number of studies
have been performed to assess the association between type 2
diabetes and central obesity, with central obesity being identified as a
risk factor for insulin resistance [7,8]. Obesity has long been
recognized as a risk factor for a variety of morbid conditions, but its
effect on infection has received less attention. Obese people are more
likely than average weight people to get infections in various body
systems, according to several studies [9].
5.2 Food and exercise assessment
In the last three decades, India's socioeconomic growth has influenced

all facets of life, including health and illnesses, as well as the
population's lifestyle, which has been influenced by improvements in
education and the adoption of new technologies. This has been
attributed to a reduction in physical activity and an increase in the
intake of high-calorie foods, which leads to obesity and high rates of
type 2 diabetes in the nation [10]. Physical activity of moderate
intensity and duration, as well as a higher degree of physical activity,
is linked to a lower risk of type 2 diabetes [11].
The US Department of Agriculture (USDA) created a food pyramid that

highlighted the value of fruits and vegetables as a rich source of
nutrients and good sources of vitamin A, vitamin C, and folate. Fiber-
rich fruits and vegetables are low in fat. 3 to 5 servings of vegetables a
day are recommended by the Food Pyramid. Fruit is a simple way to
fulfill the body's vitamin A and C requirements. Vitamins, minerals,
cellulose, and fiber are all found in abundance in vegetables. Vitamins
Discussion Page 148

A, C, E, K, and folic acid are abundant in green leafy vegetables.

Vitamin A can be found in abundance in carrots. Vitamin C can be
found in abundance in potatoes. Fruits and vegetables, especially raw
vegetables and fresh fruits, are high in vitamin content.
The participants' food intake, especially fruits and vegetables, was

taken into account, and it was tracked at three and twelve months to
compensate for their effect on vitamin levels. At 3 and 12 months, we
observed no major differences in fruit and vegetable consumption
between the two classes. During the report, we also kept track of our
physical activity with an exercise diary. The majority of participants in
both groups were not very active, and only a few were moderately
active, according to our findings. For example, consider the behavior
at work. At three months, we discovered that 51 percent of placebo
group participants were poorly active and 42 percent were moderately
active, compared to 38 percent in the treatment group who were
poorly active and 56 percent moderately active. The exercise
evaluation in the same area after 12 months of the study revealed that
58 percent of the placebo group subjects were poorly active and 19
percent were moderately active, while 68 percent of the treatment
group subjects were poorly active and 19 percent moderately active.
5.3 Diabetes Mellitus in India
Diabetes mellitus is very common in India, and the numbers are that
at an alarming pace. Diabetes is projected to rise from 40.6 million in
2006 to 79.4 million by 2030 in India alone. According to studies,
diabetes affects about 12.1 percent of urban Indian adults, with onset
occurring about a decade earlier than in western countries, and the
incidence of Type 2 diabetes is 4-6 times higher in cities than in rural
areas. Strong familial accumulation, central obesity, insulin
Discussion Page 149

resistance, and life style changes due to urbanization are all risk
factors for developing diabetes in Indians. Screening pregnant women
for gestational diabetes and reduced glucose tolerance allows for
primary prevention of the disease in both mothers and their infants.
Obesity and reduced glucose tolerance (IGT) (important predisposing
factors) are not only affecting adults, but children are being
increasingly affected as well. In comparison to other races and ethnic
groups, Indian diabetics have a higher rate of long-term macro and
microvascular complications. There is also a heavy familial clustering
of diabetic nephropathy among Indian Type 2 diabetics.
In urban Indians, clustering of cardiovascular risk factors such as

Syndrome X is normal. The rising prevalence of diabetes and its
complications would place a significant financial strain on our
country's health-care system. Not only for early detection, but also to
avoid progression to end stage have disease, timely successful
interventions/measures and screening tests for complications at the
time of diagnosis become critical. Screening pregnant women for
gestational diabetes will also aid in the disease's primary prevention.
Life style changes/interventions and drugs like rosiglitazone are the
current strategies that can prevent and/or delay the onset of diabetes.
Simple interventional strategies like "Eat less, Eat on time and Walk
more" can go a long way in preventing these chronic disorders among
present as well as in the future generations.
5.4 Effect of DM on immunity and risk of infection
Patients with diabetes mellitus are thought to be more susceptible to

infections than people that do not have the disease. In this group of
patients, infection progression is often more likely to be complicated
[12]. It has been proposed that a defect in immunity may be one of the
Discussion Page 150

causes of the increased infection rate. A longitudinal review of 101

293 adult inpatients showed that diabetic patients had a higher
incidence of bacteremia than non-diabetic patients; for every 1000
admissions, diabetic patients had 2/3 of the bacteremias, compared
to 113 for non-diabetic patients. (p<0.001) [13.] Diabetes can also play
a role in surgical wound infection. The wound infection rate in
patients who had complete hip replacement surgeries was 11 percent
in 42 diabetic patients, compared to 2 percent in 1,180 non-diabetics
patients of similar age [14].
Some research, on the other hand, found little difference in surgical

wound infection. In 354 subjects, the National Academy of Sciences-
National Research Council Cooperative study found that surgical
wound infection was higher in non-diabetic subjects (7.1%) than
diabetic subjects (7.2%) [15]. In clean orthopedic surgeries a study
conducted comparing the 203 diabetic and 3,414 non-diabetic
patients matched on age, sex, and length of surgery found that no
difference in the infection rates between the two groups(3.4% versus
3.6%) [16].
Several researches on the impact of dietary supplementation on

infection rates have been performed, with several of these studies
focusing on the importance of minerals and vitamin supplementation
in infection prevention. In a double-blind, randomized sample,
Chavannes and colleagues attempted to assess the effect of a
multivitamin supplement on infection prevention in stable elderly
subjects. Although they found no difference in rate of infect ion
between the two groups, they reported that, after 4 months of the
vitamin supplementation, the participant’s vitamin blood levels of
vitamins E, BL B2, B6 and folates were significantly higher in
treatment group than in placebo group (p < 0.001). Their study also
Discussion Page 151

reported that blood ascorbic acid concentration after 4 months of the

study was higher in treatment than in placebo group (p<0.05 ).
Vitamin A remained similar in the two groups [17]. Their research,
however, was not long enough to test long-term infections, but it was
close to ours in terms of vitamin supplementation duration. Our
research found that after three months of vitamin supplementation,
blood concentrations of Vitamin E, B12, and Folate had risen
significantly. Vitamin A levels fell from 0.9 to 0.8, and Vitamin C levels
fell from 30.1 to 18.8.
The mean number of days with an infection-related illness in the

placebo group was significantly higher than in the treatment group
(48 days vs. 23 days) in a 12-month double-blind randomized study
designed to examine the impact of vitamins and trace elements on the
incidence of infection-related illness in independently living, stable
elderly individuals [18]. A high quality healthy diet, combined with
adequate nutrient supplements, was found to boost immune
responses and minimize the rate of common respiratory illnesses [19],
as well as improve many immunological aspects [20]. Many other
studies suggested an effect of dietary supplements on the immunity
and reduce the risk of infection [21,22].
Vitamin C may have anti-oxidant properties that protect the immune

system from damage caused by free radicals released during the
inflammatory process [23]. It can aid in increasing the body's
interferon levels and reducing the severity and duration of diseases
[24]. In one study, vitamin E reduced the rate of infectious diseases
and decreased upper respiratory tract infections, mainly common
colds, while having no effect on lower respiratory tract infections or
seasonal [25]. Vitamin B6 with Folic Acid is involved in controlling
Discussion Page 152

homocysteine levels, which has been linked to immunity in the elderly

[26, 27].
Barringer and colleagues found that multivitamin and mineral

supplements were effective in a randomized double-blind, placebo-
controlled study (Multivitamins contains; Vitamin A, B-carotene, B14,
B3, B6, B12, C, D, E. K, Bioten, Pantothenic acid, and Folic acid and
mineral which includes manganese, copper, Iron, Zinc, Iodine,
selenium. and Chromium). In 130 stable people aged 45 to 64 years or
older, self-reported infections were significantly decreased, with the
majority of the beneficial impact seen in undernourished diabetics. In
addition, 73 percent of the placebo population, compared to 43
percent of the treatment group, indicated an infectious disease.
(p<0.001). The infection-related absenteeism from work for the placebo
was 57% in comparison with 21% for the treatment group (p <0.001).
The study showed that amongst the subjects with type 2 DM 93% of
placebo group reported infections while in treatment group it was 17%
(p <0.001). Although the baseline characteristics of the Barringer
study's sample population revealed that the treatment group was
more physically active and well-nourished than the placebo group,
there were no differences in baseline covariates. The majority of the
samples were female, with ages ranging from 45 to 64. About 10% of
the subjects had not completed high school. Two-thirds of the
participants were overweight or obese, and about a third of them had
type 2 diabetes [28]. Taking our observations and those of Barringer et
al. into account, we believe there is evidence that some vitamin
supplements can help diabetic patients improve their immunity and
avoid infection. Although the evidence is weak, broader studies are
needed to validate these results before they can be implemented by
health professionals caring for diabetic patients.
Discussion Page 153

5.5 Main Findings of This Study
Multivitamin supplements increased vitamin blood concentrations,

homocysteine, and certain inflammatory markers, according to the
study's results. After three months of supplementation, the treatment
group showed less infection per subject than the placebo group;
however, this difference was not statistically significant. When
compared to the placebo group, the treatment group had more
infections at 12 months. While the difference in the number of
infections reported after three months could be linked to vitamin
supplementation, the lack of statistical significance could be due to
the low dose of vitamins used, the short duration of supplementation,
or the high consumption of fruits and vegetables, or a combination of
all three factors. Our sample population also had very low levels of
physical activity. For several years, there has been a connection
between diabetes and bacterial infection [29,30].
Diabetic patients had a higher prevalence of bacteremia, primarily

urinary source, community-acquired, and attributed to E. coli, than
non-diabetics, according to a prospective study of adult inpatients
[31]. Diabetes can also play a role in surgical wound infection. In
another study, the rate of wound infection in diabetic patients who
had complete hip replacement surgeries was 11%, compared to 2% in
non-diabetic patients of similar age [32]. In diabetic subjects, not all
studies have found an increased risk of surgical wound infection
[33,34].
The mechanisms underlying the decline in innate and adaptive

immunity associated with diabetes are unknown, and there are
currently no successful strategies for preventing immune senescence
in diabetic patients. Improvements in nutritional status, on the other
Discussion Page 154

hand, have been shown to slow the decline in immune function in

other high-risk groups [35,36,37]. For example, randomized control
trials suggest that single-nutrient supplements of vitamin E [35],
vitamin A [38], zinc [39] and selenium [40] enhance aspects of
immune function in older people. Similarly, multi-nutrient
supplementation has been reported to improve immune status in
older adults [41]. Vitamin C can also act as an antioxidant, protecting
the immune system from damage caused by free radicals released
during inflammation [42]. B vitamins, including folic acid, play a role
in lowering homocysteine levels, which have been linked to immunity
in the elderly [43]. While not all diabetic patients are deficient in
micronutrients, a subgroup of patients has been reported as having
deficiencies. In diabetic patients, serum ascorbic acid and group B
vitamin concentrations, for example, may be poor [44].
Barringer and colleagues found that multivitamin and mineral

supplements decreased self-reported infections in 130 healthy people
aged 45 to 64 years or older, with the majority of the benefits seen in
undernourished diabetics [45]. While these studies show a link
between micronutrients and immune function, the majority of them
used micronutrient doses that were higher than recommended,
making the findings difficult to translate into dietary
recommendations. Few studies have attempted to modulate immune
status using foods or nutrient doses that are realistically achievable
by diet [46].
Such studies are significant because they show the effects of

individual diet components, but they do not recognize the benefits of a
mixed diet, and they are not intended to provide a method of long-
term dietary change that is acceptable to the majority of the target
population. Despite the fact that our study participants consumed a
Discussion Page 155

lot of fruits and vegetables, up to 90% of them were overweight or

obese, and their weight increased even more during the three months
of follow-up. A sedentary lifestyle is also linked to a high incidence of
overweight and obesity. These changes in lifestyle are almost certainly
leading to the growing epidemic of overweight/obesity, type 2 diabetes
and other related co-morbidities in the Indian society and other
similar population and are therefore in need of urgent public health
attention.
Although obesity as a risk factor for several morbid conditions is well

accepted, its contribution to infection has not been sufficiently
studied. Some studies have suggested that infections of several body
systems are more frequent in obese people than those of normal
weight [47].
5.6 Strengths and Weaknesses
If the vitamin doses had been higher, the supplement duration had
been longer, or the sample size had been greater, we would have seen
larger differences in the rate of infections between the supplement and
placebo groups. Despite the fact that the trial drugs were well-
tolerated and supplements substantially improved vitamin levels in
the blood, nearly a quarter of our subjects declined or were unable to
record infections at follow-up. The frequency of infections identified by
patients was used in this research. This may have resulted in a
margin of error in their true infection rate reporting. It's possible that
if we used a different method of gathering data, such as reviewing
patients' hospital records, tracking clinic records where the
participants had seen and received treatment, or simply having
patients call about every single episode of infection he or she
experienced, we might have gotten more accurate and reliable
Discussion Page 156

information on infection rate. Another significant flaw is that no

biological predictor of cellular or humeral immunity was measured.
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activity in elderly men is enhanced by beta-carotene
supplementation. Am. J. Clin. Nutr. 1996;64:772–777.
39. Bogden, J.D.; Oleske, J.M.; Lavenhar, M.A.; Munves, E.M.;
Kemp, F.W.; Bruening, K.S.; Holding, K.J.; Denny, T.N.;
Guarino, M.A.; Holland, B.K. Effects of one year of
supplementation with zinc and other micronutrients on cellular
immunity in the elderly. J. Am. Coll. Nutr. 1990;9:214–225.
40. Wood, S.M.; Beckham, C.; Yosioka, A.; Darban, H.; Watson,
R.R. Beta-Carotene and selenium supplementation enhances
immune response in aged humans. Integr. Med. 2000;2:85–92.
41. Bogden, J.D.; Bendich, A.; Kemp, F.W.; Bruening, K.S.;
Shurnick, J.H.; Denny, T.; Baker, H.; Louria, D.B. Daily
micronutrient supplements enhance delayed-hypersensitivity
skin test responses in older people. Am. J. Clin. Nutr. 1994;60:
437–447.
42. Sies, H.; Stahl, W. Vitamins E and C, betacarotene and other
carotenoids as antioxidants. Am. J. Clin. Nutr. 1995;62:1315S–
1321S.
Discussion Page 161

43. Francis, W.K.; Joanne, D.; Wenjie, L.; Kay, B.; Herman, B.;
Diane, R.; Adrianne, B.; John, D.B. Relationships between
immunity and dietary and serum antioxidants, trace metals, B
vitamins, and homocysteine in elderly men and women. Nutr.
Res. 2002;22:45–53
44. Mooradian, A.D.; Morley, J.E. Micronutrient status in diabetes
mellitus. Am. J. Clin. Nutr. 1987;45:877–895.
45. Barringer TA, Kirk JK, Santaniello AC, Foley KL, Michielutte R.
Effect of a multivitamin and mineral supplement on infection
and quality of life. A randomized, double-blind, placebo-
controlled trial. Ann Intern Med. 2003 Mar 4;138(5):365-71.
46. Hughes, D.A. Dietary carotenoids and human immune function.
Nutrition 2001, 17, 823–827.
47. Falagas, M.E.; Kompoti, M. Obesity and infection. Lancet Infect.
Dis. 2006, 6, 438–446.
Discussion Page 162

CHAPTER 6: CONCLUSION
6.1 Conclusion
In conclusion, we discovered that dietary supplements improved blood

vitamin levels over the course of three months, but that this
improvement did not translate into a low risk of infection over the
course of the 12-month follow-up period. A larger clinical trial is
required to see whether giving diabetic and non-diabetic patients at
higher risk of infection a higher daily vitamin dose and/or taking
supplements for a longer period of time results in a clinical benefit. If
vitamin supplements are found to reduce the rate of infections in
diabetics and other patients with similar conditions, this approach
may have far-reaching health and economic consequences for diabetic
patients in the India and elsewhere.
The aim of the research was to see how a dietary supplement affected
the risk of infection in type 2 diabetes patients living in the
community. Over the course of three months of supplementation, we
discovered that dietary supplements of the used multivitamins
substantially increased the concentration of the blood vitamin level of
the treatment group as compared to the placebo group. The study also
found that in type 2 diabetic patients, the number of self-reported
infections was lower in the treatment group than in the placebo group;
however, the difference was not statistically significant. A larger
clinical trial is needed to see if the results can be repeated not only in
diabetics, but also in other groups that are more susceptible to
infection, and particularly those who are concerned about nutrition. If
Conclusion Page 163

it is found that vitamin supplements can minimize the rate of infection

in diabetics and other patients with similar conditions. The
implementation of this policy on a larger scale in India and elsewhere
could have significant health and economic implications for diabetic
patients.
6.2 Strength, weakness and recommendation for future research
In our research, we discovered that three months of vitamin

supplementation increased the majority of vitamin blood levels in the
treatment group relative to the placebo group. This variation in
vitamin blood levels between the two groups was linked to a lower but
statistically insignificant difference in infection rates in the
supplement group versus the placebo group.
However, by 12 months, the gap had almost vanished, owing to the

fact that the supplement was topped up at the third month of the
study period. It's likely that if the vitamin dosage had been higher, the
supplement time had been longer, or the sample size had been larger,
we would have seen a greater difference in infection rates between the
supplement and placebo groups. Despite the fact that compliance with
the trial drugs was excellent and supplements greatly improved
vitamin levels in the blood, nearly a quarter of our subjects declined to
have blood drawn for vitamin analysis at three months. However, a
more detailed examination of baseline characteristics revealed no
substantial variations between those who agreed to have their
outcome data collected and those who did not.
In our research, we used the patient self-reporting methodology to

monitor infection rates. This may have resulted in a margin of error in
their true infection rate reporting. It's possible that we might have had
Conclusion Page 164

more accurate and reliable information on infection rates if we used a

different method of gathering data, such as reviewing patient hospital
records, tracking clinic records where the participants had seen and
received treatment, or just having patients call in about every single
episode of infection they had, or even doing moreresources and is very
time-consuming.
This study has many benefits, including the fact that the participants
were selected at random. The double-blind nature of intervention
therapy and assessment, as well as the placebo-controlled design. The
study was conducted prospectively, with participants in both groups
being tracked for a year and most of the related observable
confounding factors, such as food intake and level of activity, being
taken into account. Since the study was double-blind, neither the
participants nor the assessors knew which treatment group the
subjects were in until the end. The placebo treatment was the same as
the real thing. No one could tell the difference between the placebo
and the drug vitamins, including the subjects and the researchers.
Furthermore, the allocation sequence was created by someone who
was not involved in the study participant's recruitment or follow-up.
The patient was interviewed three times by a single observer using a

standard checklist, and the research was performed over a year to
restrict the impact of external influences on the study and to obtain
more accurate results, including seasonal variation. Future research
should concentrate on the mechanisms of the dietary supplement's
impact on the immune system and infection rate; it is highly
recommended that the sample size of the participant be increased to
eliminate the effect of withdrawal or failure to complete the analysis. A
larger clinical trial is needed to see if these findings can be extended
not only to diabetic patients, but also to anyone who has a high risk of
Conclusion Page 165

infection. Vitamin concentrations can also be increased to meet

regular requirements, providing more information about the required
vitamin dose. A similar study that lasts longer than three months can
also be beneficial. Although the food frequency questionnaires were
not validated in India, they were validated in a number of other
countries. When developing or using similar questionnaires in the
future, future studies should take the country's culture into account.
Daily and frequent interviews with participants will improve the

methodology of self-reporting infections, reducing reliance on
participant memory and preventing infections from being missed.
Tracking the patient's record for any ailments and changes in the
patient's condition during the study is recommended in order to
gather accurate information about the essence of the disease, the
outcomes of blood tests, and any other important details that can aid
in assessing and following the participant's medical health status.
Conclusion Page 166

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Effect of Antioxidants and B-Group Vitamins on Risk of Infections

in Patients with Type 2 Diabetes Mellitus

LIST OF FIGURES III

CHAPTER 1: GENERAL INTRODUCTION 1-43

CHAPTER 2: LITERATURE REVIEW 44-110

CHAPTER 3: MATERIALS AND METHODS 111-121

CHAPTER 4: RESULTS 122-145

CHAPTER 5: DISCUSSION 146-162

CHAPTER 6: CONCLUSION 163-166

Table 4.4B: Frequencies of infections over 12 months in 138

IDDM Insulin-Dependent Diabetes Mellitus

NIDDM Non-Insulin-Dependent Diabetes Mellitus

T1DM Type 1 Diabetes Mellitus

T2DM Type 2 Diabetes Mellitus

GDM Gestational Diabetes Mellitus

CAD Coronary Artery Disease

PAD Peripheral Arterial Disease

CVD Cardiovascular Disease

OxLDL Oxidized Low Density Lipoprotein

PUFA Polyunsaturated Fatty Acids

NADH Nicotinamide Adenine Dinucleotide

NADPH Nicotinamide Adenine Dinucleotide Phosphate

ALA Alpha-Lipoic Acid

SOD Superoxide Dismutase

GPx Glutathione Peroxidase

H2O2 Hydrogen Peroxide

WHO World Health Organization

RBP Retinol Binding Protein

NAFLD Non-Alcoholic Fatty Liver Disease

PH Potentiometric Hydrogen ion concentration

nmol/ L Millimole per liter

H bAlc Hemoglobin Alc

BMI Body Mass Index

Kg/m2 Kilogram per square meter

HPLC High-performance liquid chromatography

mol/L Micromoles per Liter

pg/ml Pico grams per Milliliter

ng/ml Nano grams per Milliliter

Mg/dl Milli grams per Deciliter

Background: The prevalence of type 2 diabetes mellitus is rising

antioxidant vitamins (221 mg of α-tocopherol and 167 mg of vitamin

Conclusion: Multivitamin supplements increased vitamin blood

CHAPTER 1: GENERAL INTRODUCTION

Type 2 diabetes mellitus is a multifactorial disorder that is usually

Over the last 40 years, India's population has undergone rapid

General Introduction Page 1

defects in innate and adaptive immune function have been identified

B vitamins include Thiamine, Riboflavin, Niacin, Panthotenic acid,

General Introduction Page 2

supplement use carries the risk of excess or toxicity with respect to

1.2 Diabetes definition and prevalence worldwide

Diabetes mellitus (DM) is a disorder characterized by persistently

General Introduction Page 3

atherosclerosis and include coronary artery disease (CAD), stroke and

T2DM is the most common form of diabetes in India, and it has

T2DM is associated with oxidative stress and inflammation. Oxidative

1.3 The Immune system and risk of infection

The immune system, which comprises both innate and acquired

General Introduction Page 4