Hormones, Receptors, and

Signal Transduction

MCB 720

March 2, 2010

John J. Kopchick, Ph.D.

Hormone -Receptor
Interactions

Hormone stems from a Greek

term meaning “to spur on.”
 General  Higher organisms, from the fruit fly to
humans, are comprised of
principles cells.
 The cells often unite to form tissue
which come together to form
organs which together make up
the organism.
 Cells of an organism do not live in
isolation.
 The communication between cells
ultimately controls growth,
differentiation, and metabolic
processes within the organism.
 Communication between cells is
often by direct cell to cell contact.
 Communication frequently occurs
between cells over short and
General principles cont...
 In cases of short and long distance
communication, a substance may be
released by one cell and recognized by a
different target cell.
 In the target cell, a specific response is
induced.
 Cells use an amazing number of signaling
chemicals.
 These signaling molecules are termed
“hormones.”
 The ability of a hormone to induce a
response in a target cell is usually
mediated by a hormone receptor on, or
in, the target cell.
 General characteristics
of hormones
 Hormones are molecules synthesized by
specific tissue. Classically these tissue
were called glands.
 Hormones are secreted directly into the
blood which carries them to their sites
of action.
 Hormones are present at very low levels in
the circulatory system.
 Hormones specifically affect or alter the
activities of the responsive tissue
(target tissue).
 Hormones act specifically via receptors
Hormone/Receptor Interaction
Secondary Signals
 Hormone Receptor Mediator Effectors
Protein

Range of H1 R1 G1 E1
possible
pathway
s
H2 R2 G2 E2

Possible pathways of transmission of hormonal signal.

Each hormone can work through one or more
receptors; each hormone-receptor complex can work
through one or more mediator proteins (either G
proteins or other signaling mechanism), and each
mediating protein or enzyme activated by hormone-
receptor complexes can affect one or more effectors
functions.
The four primary arenas
of hormone action
Reproductio Growth &
n Development

Hormones

Maintenance Energy
of internal production,
environment utilization &
storage
 Definitions
Endocrine - Refers to the internal secretion
of biologically active substances.
Exocrine - Refers to secretion outside the body, for
example, through sweat glands, mammary
glands, or ducts lead to the gastrointestinal.
Hormone - Substances released by an endocrine
gland and transported through the
bloodstream to another tissue where it acts
to regulate functions in the target tissue
(classic definition).
Paracrine - Hormones that act locally on cells that
did not produce them.
Autocrine - Hormones that act on cells that
produced them.
Receptors -Hormones bind to receptors molecules on
cells. A receptor must specifically recognize
the hormone from the numerous other
molecules in the blood and transmit the
hormone binding information into a cellular
 Endocrin Blood vessel
e
Hormone
secretion into Distant target
blood by cells
endocrine gland
Paracri
ne
Secretory Adjacent target cell
cell
Autocrin Receptor
e Hormone or other
extra cellular signal

Target sites on same cell

 Endocrine cell Neurotransmitter cell

H H H H R
H H
H
H H
H H
H N
R H R H Blood H N
Autocrine Autocrine vessel

Axon

Paracrine
H N
N
R H R H
N
H N
R R
Actions of hormones &
H R
neurotransmitters & their
interrelationships
Neurotransmitter &
(H,hormone; R, receptor; N,neurotransmitter.) hormone target cell
Examples of Hormones
and glands that
produce them
 Selected hormones & their functions

Hormone Sourc Principal

Insulin
e
Pancreas
functions
Controls blood-sugar level and st
of glycogen.

Glucagon Pancreas Stimulates conversion of glycoge

glucose; raises
blood sugar level.

Oxytocin Pituitary gland Stimulates contraction of the ute

muscles and
secretion of milk by the mammary glands

Vasopressin Pituitary gland Controls water excretion by the

kidneys; stimulates
contraction of the blood vessels.

Growth hormone Pituitary gland Stimula

growth.

Adrenocorticotrophic Pituitary gland Stimulates the adrenal cortex,

which,in turn,releases
hormone (ACTH) several steroid hormones.

Prolactin Pituitary gland Stimulates milk production by th

mammary glands
after birth of baby.
 Selected hormones & their functions cont...
Hormone Sourc Principal
e functions
Cortisone Adrenal glands Helps control carbohydrate
metabolism, salt
and water balance, formation and
storage of
glycogen.
Thyroxine & Thyroid gland Increases the metabolic rate of
carbohydrates
Triiodothyronine and proteins.

Calcitonin Thyroid gland Prevents the rise of calcium and phosphate

in the
body.
Parathyroid Parathyroid gland Regulates the metabolism of calcium and
phosphate in hormone in the
body.

Gastrin Stomach Stimulates secretion of gastric

juice.

Secretin Duodenum Stimulates secretion of pancreatic

juice.
 “Generic”
Hormone/Receptor
Interactions
Regulation of transcription by hormones that
act on the cell surface.

M odification
H H R 2nd
F
M essenger PP

Effector
Pre-mRNA

Response
Protein mRNA
 Types of Hormones
 Catecholamines and Thyroid
Hormones
Small and derived from amino acids (epinephrine,
thryoxine.)
 Steroid Hormones and Vitamin D
Relatively small and derived from cholesterol
 Prostaglandin's
Relatively small and derived from fatty acids
 Proteins or Polypeptides
relatively large and derived from translation of
hormone specific mRNA (growth hormone, insulin)
 Thyroid Hormones
 Synthesized solely in the thyroid gland ( T4;
3’,5’,3,5-L-tetra-iodothyronine).
 Majority of the active form, T3 (3’,3,5-L-tri-
iodothyronine), is produced in the peripheral tissues
through deiodination of T4.
 Thyroid gland cells concentrates iodine for thyroid
hormone synthesis.
 Iodine is attached to tyrosine residues on a
protein, termed thyroglobulin. Tyrosine residues
are then coupled together to yield thyronines.
 Proteolytic digestion of thyroglobulin then yields T4
and T3 in a 10:1 ratio.
 Helps in the metabolism of sugars.
 The half life of T4 is 7 days and that of T3 is 1 day.
 Tyroxine [Tetra-iodothyronine (T4)]

I I
NH3+

HO O CH2 C COO -
H
Thyroid
I I Hormon
es
Tri-iodothyronine (T3) Increase of
oxidation of sugars
I I by most body
NH3+ cells; induction of
some enzymes
HO O CH2 C COO -
H

I
 T3
T4
R T3
T3
F F R F PP
T4

PB T3
T3
Pre-mRNA

Response
Protein mRNA

Regulation of transcription by thyroid hormones.

T3 and T4 are tri-iodotyronine and tyroxine,
respectively.
 Steroid Hormones
 Produced in the adrenals, ovaries, testes, and
placenta.
 Derived from cholesterol.
 Enzymes in the various glands control the final
product. For example, cytochrome P450c11 which
is located in the adrencortical cells, is involved in
coritsol production. This enzyme is lacking in the
gonads, that do not produce cortisol or
aldosterone.
 Gonads, however, can produce
dihydroxytestosterone, estradiol, or
progesterone depending upon the enzymes
present in the gonadal tissue.
 Over 50 different steroid metabolites have been
Cholesterol Metabolism
Steroid Hormones
 S S
HSP S S
S R
S HSP F F R R PP

S HSP S S S S HSP
PB R R R R HSP
HSP

pre-mRNA
S R HSP
HSP

Response
Protein mRNA

Regulation of transcription by steroid

 Catecholamines
 Are synthesized in nervous tissues from which
the adrenal medulla is derived.
 Adrenal medulla is the major source for
circulating epinephrine.
 Synthesized from tyrosine which is converted to
dihydroxyphenylalanine (DOPA) by tyrosine
hydroxylases.
 Subsequent conversions to dopamine and then
to nor epinephrine which is released by most
catecholamine-producing cells of the body.
 In the adrenal medulla and a few other tissue, nor
epinephrine is converted to epinephrine.
 The half life is 1-2 minutes.
Flight, fright, or fight!
 Prostaglandins and
Leukotrienes
 They can be produced by most cells depending upon
lipid and enzyme content of the cells.
 Arachidonic acid, which is derived from lipid
metabolism, is the precursor compound.
 Depending upon the lipoxygenase present in the
cell, either, HETE, prostaglandin (G2) or leukotrienes
 Cyclooxygenase (involved in PGG2 synthesis) is
widely distributed throughout the body and is
inhibited by aspirin, indomethacin, and other
nonsteroidal and anti-inflammatory agents.
Several COX inhibitors!! - Problems
 The half-life is a few seconds.
Hormone Antagonists
Examples of hormone antagonists used in
therapy
Antagonist to Use
Growth Hormone Acromegaly, Diabetes
Progesterone Contraceptive, abortion
Glucocorticoid Spontaneous Cushing’s
Syndrome
Mineralo-corticoid Primary and secondary

mineralocorticoid excess
Androgen Prostate cancer Tamoxifin
Estrogen Breast cancer
GnRH Prostate cancer
-Adrenrgic Hypertension,
hyperthyroidism
 Hormone
Receptors
and

Signal
Transduction
 Hormone
Receptors
Nuclear receptors
estrogens

Cytoplasmic receptors
Most steroid and thyroid hormones

Cell surface membrane

receptors
Polypeptide hormones and
catecholamines
 Hormone Membrane
Plasma Effects
Membrane

Receptor
Effector
Cellular
Trafficking

Enzymes Secondary Messenger

or Secondary Signal

Activated Inhibited
Protein
Synthesis
DNA Synthesis
Nucleus RNA Synthesis

A general model for the action of peptide hormones, catecholamines,

and other membrane-active hormones. The hormone in the extra
cellular fluid binds to the receptor and activates associated
effector(s) systems, that may or may not be in the same molecule.
This activation results in generation of an intracellular signal or
second messenger that, through a variety of common and branched
pathways, produces the final effects of the hormone on metabolic
enzyme activity, protein synthesis, or cellular growth and
 Receptors that span
the membrane Seven
times
 cAMP: synthesis and degradation

cAMP
cAMP
 Amino acid Phosphorylation is
very important in intracellular
signal transduction

ATP
ATP

S Serine
Protein Kinases – transfer terminal Phosphate groups
from ATP to Serine, Threonine, or Tyrosine residues
in proteins
sult in activation or inactivation of the recipient protei
S Serine
Amino acids
that can be
phosphorylat
ed
Threonin
e

Y
Peptide hormone
receptors
Huising, et.al.
J. Endo. 2006. 189:1-25
General View
of
Metabolism
 Levels of blood sugar
glucose) regulate secretion
of hormones from
the pancreas

Pancreas secretes
insulin when glucose
levels are high

Insulin binds to
insulin receptors
on fat and muscle
and “promotes”
glucose uptake

Overall effect: blood

glucose
levels return to normal
Glucose Tolerance Test
 The Insulin Receptor

 Responsible for clearance of

glucose
 In addition to binding insulin, it
possesses a tyrosine kinase
activity
 It is involved in many cellular
activities
Glucose Transporter Intracellular Trafficking
 Insulin Receptor

Tyrosine
kinase
 Insulin-mediated
Insulin-mediatedglucose
glucosetransport
transportsignaling
signalingpathway
pathway
Insulin

IR
 
 
Cell membrane

P
IRS
PI3K

Glut4 Akt
P

Xiao Chen, 2006

Insulin-mediated glucose transport signaling pathway
Insulin-mediated glucose transport signaling pathway

IR Insulin
glucose  
  Cell membrane

P
IRS
PI3K

Akt
P

Xiao Chen, 2006

xpectancy; Low = 73.6; High =
Time, Nov, 2006
Obesity is a Global Pandemic Disease
 USA Today
Feb. 9, 2010
 USA Today
Feb. 9, 2010
 Reduce

USA Today
Feb. 9, 2010
41 grams
xpectancy; Low = 73.6; High =
Time, Nov, 2006
Insulin Signaling Pathways by C. Hooper http://www.abcam.com/index.html?
pageconfig=resource&rid=10602&pid=7
 Cartoon of Intracellular Signaling System
Used By Many Peptide Hormones and
Growth Factors

 For example
– Insulin
– EGF
Tyrosine kinase receptors are a family of receptors with a
similar structure. They each have a tyrosine kinase domain
(which phosphorylates proteins on tyrosine residues), a
hormone binding domain, and a carboxyl terminal segment
with multiple tyrosines for autophosphorylation. When
hormone binds to the extra cellular domain the receptors
When the receptors aggregate, the tyrosine kinase
domains phosphorylate the C terminal tyrosine
This phosphorylation produces binding sites for
proteins with SH2 domains. GRB2 is one of these
proteins. GRB2, with SOS bound to it, then binds to
the receptor complex. This causes the activation of
SOS is a guanyl nucleotide-release protein (GNRP). When
this is activated, it causes certain G proteins to release
GDP and exchange it for GTP. Ras is one of these
proteins. When ras has GTP bound to it, it becomes
Activated ras then causes the activation of a cellular
kinase called raf-1.
Raf-1 kinase then phosphorylates another cellular kinase
called MEK. This cause the activation of MEK.
Activated MEK then phosphorylates another protein kinase
called MAPK causing its activation. This series of
phosphylating activations is called a kinase cascade. It
 Adapted from: Dr. Donald F. Slish,
Biological Sciences Department,
Plattsburgh State University,
Plattsburgh, NY.

Among the final targets of the kinase cascade are transcriptions

factors (fos and jun showed here). Phosphorylation of these proteins
causes them to become active and bind to the DNA, causing changes
 Examples of therapeutics
developed based on these
types of receptors and the
associated tyrosine kinase
signaling system

Erbitux – Imclone
Iressa - AstraZeneca
Gleevec – Novartis
Herceptin - Genentech
EGF Receptor Signal Transduction
SIGMA-ALDRICH
Pathway
Tyrosine kinase

Cell Proliferation
 Epidermal Growth Factor Receptor

EGF

Cysteine
Receptor
Rich EGF
Domain Dimerization

Cell
Membrane

Tyrosine *
*
Kinase * *
Domain * *
P P
Signal
Transduction
 EGFR Family
 The epidermal
growth factor
(EGF) family of
receptor
tyrosine kinases
consists of four
receptors,
 ErbB1 (EGFR)
 ErbB2 (Her/Neu)
 ErbB3 (HER3)
 ErbB4 (HER4).
 Non-small cell lung cancer
 Non-small cell lung cancer comprises
over 75% of all lung cancers. In 2006,
more than 338,000 cases of the disease
are expected to be diagnosed in the
seven major pharmaceutical markets.
High unmet needs of therapy still
persist for this tumor type. The overall
survival of NSCLC patients remains
below 12 months.
 The EGfR is expressed on these
cells.
 Epidermal Growth Factor Receptor in Non–Small-Cell Lung
Carcinomas: Correlation Between Gene Copy Number and Protein
Expression and Impact on Prognosis
Fred R. Hirsch, Marileila Varella-Garcia, Paul A. Bunn, Jr, Michael V. Di Maria, Robert Veve,
Roy M. Bremnes, Anna E. Barón, Chan Zeng, Wilbur A. Franklin
Journal of Clinical Oncology, Vol 21, 2003: 3798-3807, 2003

• The percentage of EGFR

positive tumor cells per
slide (0% to 100%) was
multiplied by the dominant
intensity pattern of staining
(1, negative or trace; 2,
weak; 3, moderate; 4,
intense); therefore, the
overall score ranged from 0
to 400 (Fig 1). Specimens
with scores 0 to 200, 201
to 300, and 301 to 400
were respectively classified
as having negative or low,
intermediate, and high
levels of expression.
Influence of histological type, smoking history and chemotherapy
on survival after first-line therapy in patients with advanced non-
small cell lung cancer

Itaya , Yamaoto, Ando, Ebisawa, Nakamura, Murakami, Asai, Endo and Takahashi
Cancer Science
Volume 98, Page 226, 2007

• For overall survival,

smoking history and
histology were
significant
prognostic factors.
The 2-year overall
survival rates were
as follows: smokers,
17%; non-smokers,
52%, P < 0.0001;
 Iressa (gefitinib tablets)
AstraZeneca.

IRESSA is indicated as
monotherapy for the
continued treatment
of patients with locally
advanced or
metastatic non-small
cell lung cancer after
failure of both
platinum-based and
docetaxel
chemotherapies who
are benefiting or have
benefited from
IRESSA.
 Iressa (gefitinib tablets)
AstraZeneca.
• Mechanism of Action

• The mechanism of the clinical

antitumor action of gefitinib is not
fully characterized.

• Gefitinib inhibits the intracellular

phosphorylation of numerous
tyrosine kinases associated with
transmembrane cell surface
receptors, including the tyrosine
kinases associated with the
epidermal growth factor receptor Gefitinib is an
(EGFR-TK). anilinoquinazoline with the
chemical name 4-
• EGFR is expressed on the cell Quinazolinamine, N-(3-
surface of many normal cells and
cancer cells. No clinical studies chloro-4- fluorophenyl) -7-
have been performed that methoxy-6- [3-4-
demonstrate a correlation between
EGFR receptor expression and morpholin) propoxy]
response to gefitinib.
C22H24ClFN4O3
 Zactima
Tyrosine Kinase Inhibitor for Treatment
of Lung Cancer
• Zactima (ZD6474) is an orally available Tyrosine Kinase Inhibitor
(TKI) under development by AstraZeneca for the treatment of solid
tumours. Following promising results in early clinical trials,
Zactima has now progressed to phase III development in Non-
Small Cell Lung Cancer (NSCLC), its primary indication.
• If phase III trials prove successful, analysts believe Zactima could
be on the market by 2008 and help to fill the void left by recent
setbacks with Iressa (gefitinib), its first TKI for lung cancer.
• At the beginning of the year, AstraZeneca withdrew its marketing
application for Iressa in Europe. This followed the release of new
long-term data that showed it to be no better than placebo in
prolonging patients' lives.
• Meanwhile, in the US Iressa will soon be available only to existing
NSCLC patients who have already shown treatment benefit and
will not be prescribed to new patients. While Iressa has stalled in
Europe and the US, it is approved in more than 30 countries
elsewhere.

http://www.drugdevelopment-technology.com/projects/zactima/
AstraZeneca
 BCR - ABL
• The exact chromosomal defect in Philadelphia chromosome is translocation.
Parts of two chromosomes, 9 and 22, swap places. The result is that part of
the BCR ("breakpoint cluster region") gene from chromosome 22 (region
q11) is fused with part of the ABL gene on chromosome 9 (region q34). Abl
stands for "Abelson", the name of a leukemia virus which carries a similar
protein.
• The result of the translocation is a protein of p210 or sometimes p185
weight (p is a weight fraction of cellular proteins in kDa). The fused "bcr-abl"
gene is located on the resulting, shorter chromosome 22. Because abl
carries a domain that can add phosphate groups to tyrosine residues
(tyrosine kinase) the bcr-abl fusion gene is also a tyrosine kinase. (Although
the bcr region is also a serine/threonine kinase, the tyrosine kinase function
is very relevant for therapy, as will be shown.)
• The fused bcr-abl protein interacts with the interleukin 3beta(c) receptor
subunit. The bcr-abl transcript is constitutively active, i.e. it does not require
activation by other cellular messaging proteins. In turn, bcr-abl activates a
number of cell cycle-controlling proteins and enzymes, speeding up cell
division. Moreover, it inhibits DNA repair, causing genomic instability and
potentially causing the feared blast crisis in CML.
 BCR-ABL
• The exact chromosomal defect in Philadelphia chromosome is translocation. Parts of two
chromosomes, 9 and 22, swap places. The result is that part of the BCR ("breakpoint cluster
region") gene from chromosome 22 (region q11) is fused with part of the ABL gene on
chromosome 9 (region q34). Abl stands for "Abelson", the name of a leukemia virus which carries
a similar protein.
• The result of the translocation is a protein of p210 or sometimes p185 weight (p is a weight
fraction of cellular proteins in kDa). The fused "bcr-abl" gene is located on the resulting, shorter
chromosome 22. Because abl carries a domain that can add phosphate groups to tyrosine
residues (tyrosine kinase) the bcr-abl fusion gene is also a tyrosine kinase. (Although the bcr
region is also a serine/threonine kinase, the tyrosine kinase function is very relevant for therapy,
as will be shown.)
• The fused bcr-abl protein interacts with the interleukin 3beta(c) receptor subunit. The bcr-abl
transcript is constitutively active, i.e. it does not require activation by other cellular messaging
proteins. In turn, bcr-abl activates a number of cell cycle-controlling proteins and enzymes,
speeding up cell division. Moreover, it inhibits DNA repair, causing genomic instability and
potentially causing the feared blast crisis in CML. (Chronic myelogenous leukemia)
 Gleevec
(imatinib mesylate, aka STI-571)

FDA APPROVES GLEEVEC FOR LEUKEMIA TREATMENT

The Food and Drug Administration today announced the

approval of Gleevec (imatinib mesylate, also known as STI-
571), a promising new oral treatment for patients with
chronic myeloid leukemia (CML) -- a rare life-threatening
form of cancer. FDA reviewed the marketing application for
Gleevec in less than three months under its "accelerated
approval" regulations.

Novartis, May 10, 2001

Used in the treatment of Chronic Myeloid Leukemia (CML)

and Gastrointestinal Stromal Tumors (GIST)
Mechanism of Action Gleevec (Novarits)

Imatinib mesylate is a protein-

tyrosine kinase inhibitor that inhibits
the Bcr-Abl tyrosine kinase, the
constitutive abnormal tyrosine kinase
created by the Philadelphia
chromosome abnormality in chronic
myeloid leukemia (CML). It inhibits
proliferation and induces apoptosis in
Bcr-Abl positive cell lines as well as
fresh leukemic cells from Philadelphia In vitro studies
chromosome positive chronic myeloid demonstrate imatinib
leukemia. In colony formation assays is not entirely
using ex vivo peripheral blood and selective; it also
bone marrow samples, imatinib inhibits the receptor
shows inhibition of Bcr-Abl positive tyrosine kinases for
colonies from CML patients. In vivo, platelet-derived
it inhibits tumor growth of Bcr-Abl growth factor (PDGF)
transfected murine myeloid cells as and stem cell factor
well as Bcr-Abl positive leukemia lines (SCF), c-Kit, and
derived from CML patients in blast inhibits PDGF
crisis.
Monoclonal Antibody Therapy
 Antibody to EGF R binds and blocks EGF from
binding
EGF

Erbitux, Imclone

Cell
Membrane

Tyrosine
Kinase
Therefore, no tyrosine kinase
Domain
activity and
no intracellular signaling
 Herceptin

is the first humanized antibody approved for the

treatment of HER2-positive metastatic breast
cancer. Herceptin is designed to target and block
the function of HER2 protein over expression.
Genentech

HER 2 = Human Epidermal Growth

Factor Receptor 2
 Herceptin,
a monoclonal antibody,
binds to HER2
and ultimately results
in destruction of the cell
 So two targets to inhibit EGF/EGFR
signaling
EGF

1
Receptor
EGF
Dimerization

Cell
Membrane

Tyrosine
Kinase
Domain
P P
2
Signal
Transduction Colored slide: D-88
 Diabetes

Diabetes - from the Greek word, diabetes, meaning

“a crossing over or passing through”. Any of
several metabolic disorders marked by excessive
discharge of urine and persistent thirst. (The American
Heritage Dictionary).

Diabetes mellitus - a chronic disease of pancreatic origin,

characterized by insulin deficiency, subsequent inability to
utilize carbohydrates, excess sugar in the blood and urine,
excessive thirst, hunger, and urination, weakness,
emaciation, imperfect combustion of fats resulting in
acidosis, and, without injection of insulin, results in coma and
death. (The American Heritage Dictionary).
 Diabetes, con’t.
 Type I or Insulin Dependent
Diabetes Mellitus (IDDM) – Also called
juvenile diabetes - lack of insulin

 Type II or Non Insulin Dependent

Diabetes Mellitus (NIDDM) – Also
called adult onset diabetes - insulin
present but cells do not respond
that is they are“insulin resistant”.
 Facts: (Diabetes 1996 Vital Statistics, ADA)

16-20 million Americans have diabetes.

385,000 diabetes die each year.

625,000 new cases each year.

Every minute of every day, someone new is

diagnosed with diabetes.

127,000 children (younger that age 20) have

diabetes.

11% of the U.S. population, age 65-74, has diabetes.

 Diabetes, con’t.

Diabetic eye disease (retinopathy): by 15 years

after diagnosis of diabetes, retinopathy is present in
97% of insulin users and 80% of non-insulin
users.

About 20% of people with diabetes have kidney

disease (nephropathy).

40% of the deaths associated with diabetes are due

to heart disease.
 Types of diabetes mellitus
(Diabetes 1996 Vital Statistics, ADA)

Type I or insulin-dependent diabetes mellitus

(IDDM) - Low or absent levels of endogenous insulin. Dependent
on insulin therapy to prevent ketoacidosis and sustain life. Onset
predominantly before age 30 but can occur at any age. Onset is
usually abrupt and patients are usually thin. Cause appears to be a
combination of genetic and environmental determinants. Pancreatic
islet cells are destroyed.
Type II or non-insulin dependent diabetes mellitus
(NIDDM) - Normal to High insulin levels characterize most
patients, indicating insulin resistance in tissues. Often see
development of low insulin levels as the disease progresses.
Patients are not prone to ketoacidosis during normal circumstances.
Although not dependent on insulin therapy for survival, many
require it for adequate blood glucose control. Onset is
predominantly after age 40, particularly in whites, and often
asymptomatic; most patients are obese. Cause appears to be a
combination of genetic and environmental lifestyle determinants.
Drugs are available to promote insulin release from the pancreas or
to allow cells to be more sensitive to insulin action.
 Types of diabetes, con’t.
Gestational Diabetes Mellitus (GDM) - Glucose intolerance that
has its onset or recognition during pregnancy. Associated with older
age, obesity, and family history of diabetes. Risk for subsequent
NIDDM is increased. Newborn offspring often have macrosomia and
may also be at increased risk for developing NIDDM.

Diabetes insipidus - Caused by the total or partial lack of the

hormone vasopressin, also called antidiuretic hormone. Blood
glucose is normal, but increased urine output with accompanying
thirst.

Other types of diabetes - Diabetes secondary to other conditions

with hyperglycemia at a level diagnostic of diabetes.

Impaired Glucose Tolerance (IGT) - Blood glucose levels that are

higher than normal but not diagnostic for diabetes mellitus. Risk for