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Title: Hormones, Receptors, and Signal Transduction MCB 720 March 2, 2010


1
Hormones, Receptors, and Signal TransductionMCB
720March 2, 2010
  • John J. Kopchick, Ph.D.

2
Hormone -Receptor Interactions
  • Hormone stems from a Greek term meaning to spur
    on.

3
General principles
  • Higher organisms, from the fruit fly to humans,
    are comprised of 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 long distances.

4
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.

5
General characteristicsof 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 located
    on, or in, target tissue.

6
Hormone/Receptor InteractionSecondary Signals
7
Mediator Protein
Hormone
Receptor
Effectors
H1
R1
G1
E1
Range of possible pathways
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.

8
Cellular genes
Proteins or peptides
Regulatory Proteins
Enzymes
Amino acid analogues
Neurotransmitters
Steroids
Hormones
Eicosanoids
Oncogenes
Oncogene products
Paracrine and/or autocrine factors
Vitamins
Diet
9
The four primary arenas of hormone action
Growth Development
Reproduction
Hormones
Maintenance of internal environment
Energy production, utilization storage
10
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 specific action.

11
Endocrine
Blood vessel
Hormone secretion into blood by endocrine gland
Distant target cells
Paracrine
Secretory cell
Adjacent target cell
Autocrine
Receptor
Hormone or other extra cellular signal
Target sites on same cell
12
Actions of hormones neurotransmitters their
interrelationships
(H,hormone R, receptor N,neurotransmitter.)
13
Examples of Hormones and glands that produce them
14
Selected hormones their functions
  • Insulin Pancreas Controls blood-sugar level
    and storage of glycogen.
  • Glucagon Pancreas Stimulates conversion of
    glycogen to glucose raises

  • blood sugar level.
  • Oxytocin Pituitary gland Stimulates
    contraction of the uterine 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 Stimulates
    growth.
  • Adrenocorticotrophic Pituitary gland Stimulates
    the adrenal cortex, which,in turn,releases
  • hormone (ACTH)
    several steroid hormones.
  • Prolactin Pituitary gland Stimulates milk
    production by the mammary glands

  • after birth of baby.

15
Selected hormones their functions cont...
  • 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.
  • Estrogen Ovaries Stimulates
    development and maintenance of female
    sexual characteristics.
  • Progesterone Ovaries Stimulates
    female sexual characteristics and maintains
    pregnancy.
  • Testosterone Testes Stimulates
    development and maintenance of male

  • sexual characteristics.

16
GenericHormone/Receptor Interactions
17
Regulation of transcription by hormones that act
on the cell surface.
18
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)

19
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 101 ratio.
  • Helps in the metabolism of sugars.
  • The half life of T4 is 7 days and that of T3 is 1
    day.

20
Tyroxine Tetra-iodothyronine (T4)
I
I
NH3
O
CH2
COO -
CH
HO
Thyroid Hormones
I
I
Tri-iodothyronine (T3)
Increase of oxidation of sugars by most body
cells induction of some enzymes
I
I
NH3
O
CH2
COO -
HO
CH
I
21
T3
T4
T3
T3
T4
T3
T3
Regulation of transcription by thyroid hormones.
T3 and T4 are tri-iodotyronine and tyroxine,
respectively.
22
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
    described.

23
Cholesterol Metabolism
24
Steroid Hormones
25
Regulation of transcription by steroid hormones
26
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!
27
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.
  • The half-life is a few seconds.

Several COX inhibitors!! - Problems
28
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29
Hormone Antagonists
30
Examples of hormone antagonists used in therapy
  • Antagonist to Use
  • Growth Hormone Acromegaly, Diabetes
  • Progesterone Contraceptive, abortion
  • Glucocorticoid Spontaneous Cushings Syndrome
  • Mineralo-corticoid Primary and secondary
    mineralocorticoid excess
  • Androgen Prostate cancer
  • Estrogen Breast cancer
  • GnRH Prostate cancer
  • -Adrenrgic Hypertension, hyperthyroidism
  • Prostaglandin Acute and chronic inflammatory
    disease

31
Hormone ReceptorsandSignal Transduction
32
Hormone Receptors
Nuclear receptors estrogens
Cytoplasmic receptors Most steroid and thyroid
hormones
Cell surface membrane receptors Polypeptide
hormones and catecholamines
33
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
differentiation.
34
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35
(No Transcript)
36
Receptors that span the membrane Seven times
37
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38
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39
cAMP
cAMP synthesis and degradation
40
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41
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
Result in activation or inactivation of the
recipient protein !
42
Amino acids that can be phosphorylated
43
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44
Peptide hormone receptors
45
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46
Huising, et.al. J. Endo. 2006. 1891-25
47
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48
General View of Metabolism
49
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
50
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51
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52
Glucose Tolerance Test
53
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54
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

55
Glucose Transporter Intracellular Trafficking
56
Insulin Receptor
Tyrosine kinase
57
Insulin-mediated glucose transport signaling
pathway
Insulin-mediated glucose transport signaling
pathway
Insulin
IR
a
a
b
b
Cell membrane
P
IRS
PI3K
Akt
P
Xiao Chen, 2006
58
Insulin-mediated glucose transport signaling
pathway
Insulin-mediated glucose transport signaling
pathway
IR
a
glucose
a
b
b
Cell membrane
P
IRS
PI3K
Akt
Xiao Chen, 2006
59
USA Life Expectancy Low 73.6 High 80.0
Time, Nov, 2006
60
Obesity is a Global Pandemic Disease
61
USA Today Feb. 9, 2010
62
USA Today Feb. 9, 2010
63
USA Today Feb. 9, 2010
64
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65
USA Life Expectancy Low 73.6 High 80.0
Time, Nov, 2006
66
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67
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68
Insulin Signaling Pathways by C. Hooper
http//www.abcam.com/index.html?pageconfigresour
cerid10602pid7
69
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70
Cartoon of Intracellular Signaling System Used By
Many Peptide Hormones and Growth Factors
  • For example
  • Insulin
  • EGF

71
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 aggregate.
72
When the receptors aggregate, the tyrosine kinase
domains phosphorylate the C terminal tyrosine
residues.
73
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.
74
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 active.
75
Activated ras then causes the activation of a
cellular kinase called raf-1.
76
Raf-1 kinase then phosphorylates another cellular
kinase called MEK. This cause the activation of
MEK.
77
Activated MEK then phosphorylates another protein
kinase called MAPK causing its activation. This
series of phosphylating activations is called a
kinase cascade. It results in amplification of
the signal.
78
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 in gene transcription.
79
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80
Examples of therapeutics developed based on these
types of receptors and the associated tyrosine
kinase signaling systemErbitux Imclone
Iressa - AstraZeneca Gleevec Novartis
Herceptin - Genentech
81
EGF Receptor Signal Transduction Pathway
SIGMA-ALDRICH
Cell Proliferation
82
Epidermal Growth Factor Receptor



83
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).

84
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.

85
Epidermal Growth Factor Receptor in
NonSmall-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.

86
 Influence of histological type, smoking history
and chemotherapy on survival after first-line
therapy in patients with advanced non-small cell
lung cancerItaya , Yamaoto, Ando, Ebisawa,
Nakamura, Murakami, Asai, Endo and Takahashi
Cancer ScienceVolume 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 lt 0.0001

87
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.

88
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 (EGFR-TK).
  • EGFR is expressed on the cell surface of many
    normal cells and cancer cells. No clinical
    studies have been performed that demonstrate a
    correlation between EGFR receptor expression and
    response to gefitinib.

89
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
90
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.

91
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)

92
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)

93
Gleevec (Novarits)
Mechanism of Action 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 chromosome positive chronic myeloid
leukemia. In colony formation assays using ex
vivo peripheral blood and bone marrow samples,
imatinib shows inhibition of Bcr-Abl positive
colonies from CML patients. In vivo, it inhibits
tumor growth of Bcr-Abl transfected murine
myeloid cells as well as Bcr-Abl positive
leukemia lines derived from CML patients in blast
crisis.
In vitro studies demonstrate imatinib is not
entirely selective it also inhibits the receptor
tyrosine kinases for platelet-derived growth
factor (PDGF) and stem cell factor (SCF), c-Kit,
and inhibits PDGF mediated cellular events
94
Monoclonal Antibody Therapy
95
Antibody to EGF R binds and blocks EGF from
binding



Erbitux, Imclone
Cell Membrane
Tyrosine Kinase Domain
Therefore, no tyrosine kinase activity and no
intracellular signaling
96
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
97
(No Transcript)
98
So two targets to inhibit EGF/EGFR signaling

EGF
1


Cell Membrane
Tyrosine Kinase Domain
2
Colored slide D-88
99
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).
100
Diabetes, cont.
  • 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 areinsulin resistant.

101
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.    
102
Diabetes, cont.
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.
103
        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.    
Types of diabetes mellitus (Diabetes 1996 Vital
Statistics, ADA)
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.
104
Types of diabetes, cont.
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 subsequent NIDDM is increased.  
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