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Hormones of the Pancreas

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Title: Hormones of the Pancreas


1
  • Hormones of the Pancreas
  • bulk of the pancreas is an exocrine gland
    secreting
  • Endocrine pancreas
  • Scattered through the pancreas are several
    hundred thousand clusters of cells called
  • islets of Langerhans.
  • The islets are endocrine tissue containing 4
    types of cells.
  • In order of abundance, they are the
  • b cells-secrete insulin and amylin
  • a cells- secrete glucagon
  • d cells-secrete somatostatin
  • cells-secrete a polypeptide of unknown function.
  • (36 aa and plays a role in food intake)


2

The endocrine portion of the pancreas takes the
form of many small clusters of cells called
islets of Langerhans or, more simply, islets.
Humans have roughly one million islets. In
standard histological sections of the pancreas,
islets are seen as relatively pale-staining
groups of cells embedded in a sea of
darker-staining exocrine tissue. The image to the
right shows 3 islets in a horse pancreas.
3
Interestingly, the different cell types within an
islet are not randomly distributed beta cells
occupy the central portion of the islet and are
surrounded by a "rind" of a and d cells. Aside
from the insulin, glucagon and somatostatin, a
number of other "minor" hormones have been
identified as products of pancreatic islets
cells.

4
Islets are richly vascularized, allowing their
secreted hormones ready access to the
circulation. Although islets comprise only 1-2
of the mass of the pancreas, they receive about
10 to 15 of the pancreatic blood flow.
Additionally, they are innervated by
parasympathetic and sympathetic neurons, and
nervous signals clearly modulate secretion of
insulin and glucagon.

5

6
Insulin Synthesis and Secretion Structure of
Insulin Insulin is a rather small protein, with
a molecular weight of about 6000 Daltons.
composed of 2 chains held together by disulfide
bonds. The figure shows a molecular model of
bovine insulin, with the A chain colored blue and
the larger B chain green.

The amino acid sequence is highly conserved among
vertebrates, and insulin from one mammal almost
certainly is biologically active in another. For
years diabetic patients were treated with insulin
extracted from pig or cow pancreases.
7
Biosynthesis of Insulin Insulin is synthesized
in significant quantities only in b cells in the
pancreas. The insulin mRNA is translated as a
single chain precursor called preproinsulin, and
removal of its signal peptide during insertion
into the endoplasmic reticulum generates
proinsulin. Proinsulin consists of three
domains an amino-terminal B chain, a
carboxy-terminal A chain and a connecting peptide
in the middle known as the C peptide. Within the
endoplasmic reticulum, proinsulin is exposed to
several specific endopeptidases which excise the
C peptide, thereby generating the mature form of
insulin. Insulin and free C peptide are packaged
in the Golgi into secretory granules which
accumulate in the cytoplasm.

8
Since insulin was discovered in 1921, it has
become one of the most thoroughly
studied molecules in scientific history.
9

10

11
Control of Insulin Secretion Insulin is secreted
in primarily in response to elevated blood
concentrations of glucose. This makes sense
because insulin is "in charge" of facilitating
glucose entry into cells. Some neural stimuli
(e.g. site and taste of food) and increased blood
concentrations of other fuel molecules, including
amino acids and fatty acids, also WEAKLY promote
insulin secretion. Our understanding of the
mechanisms behind insulin secretion remain
somewhat fragmentary. Nonetheless, certain
features of this process have been clearly and
repeatedly demonstrated, yielding the following
model

12
Control of Insulin Secretion Glucose is
transported into the b cell by facilitated
diffusion through a glucose transporter elevated
concentrations of glucose in extracellular fluid
lead to elevated concentrations of glucose within
the b cell.Elevated concentrations of glucose
within the b cell ultimately leads to membrane
depolarization and an influx of extracellular
calcium. The resulting increase in intracellular
calcium is thought to be one of the primary
triggers for exocytosis of insulin-containing
secretory granules.

13
Control of Insulin Secretion The mechanisms by
which elevated glucose levels within the b cell
cause depolarization is not clearly established,
but seems to result from metabolism of glucose
and other fuel molecules within the cell, perhaps
sensed as an alteration of ATPADP ratio and
transduced into alterations in membrane
conductance. Increased levels of glucose within
b cells also appears to activate
calcium-independent pathways that participate in
insulin secretion.

14
Control of Insulin Secretion Stimulation of
insulin release is readily observed in whole
animals or people. The normal fasting blood
glucose concentration in humans and most mammals
is 80-90 mg per 100 ml, associated with very low
levels of insulin secretion.

15
Control of Insulin Secretion The figure depicts
the effects on insulin secretion when enough
glucose is infused to maintain blood levels 2-3
times the fasting level for an hour. Almost
immediately after the infusion begins, plasma
insulin levels increase dramatically. This
initial increase is due to secretion of preformed
insulin, which is soon significantly depleted.
The secondary rise in insulin reflects the
considerable amount of newly synthesized insulin
that is released immediately. Clearly, elevated
glucose not only simulates insulin secretion, but
also transcription of the insulin gene and
translation of its mRNA.

16

17
Physiologic Effects of Insulin Stand on a
streetcorner and ask people if they know what
insulin is, and many will reply, "Doesn't it have
something to do with blood sugar?" Indeed, that
is correct, but such a response is a bit like
saying "Mozart? Wasn't he some kind of a
musician?" Insulin is a key player in the
control of intermediary metabolism. It has
profound effects on both carbohydrate and lipid
metabolism, and significant influences on protein
and mineral metabolism. Consequently,
derangements in insulin signalling have
widespread and devastating effects on many organs
and tissues.

18
Physiologic Effects of Insulin The Insulin
Receptor (IR) and Mechanism of Action Like the
receptors for other protein hormones, the
receptor for insulin is embedded in the PM The
IR is composed of 2 alpha subunits and 2 beta
subunits linked by S-S bonds. The alpha chains
are entirely extracellular and house insulin
binding domains, while the linked beta chains
penetrate through the PM.

19

The IR is a tyrosine kinase. it functions as an
enzyme that transfers phosphate groups from ATP
to tyrosine residues on target proteins. Binding
of insulin to the alpha subunits causes the beta
subunits to phosphorylate themselves
(autophosphorylation), thus activating the
catalytic activity of the receptor. The activated
receptor then phosphorylates a number of
intracellular proteins, which in turn alters
their activity, thereby generating a biological
response.
20
Physiologic Effects of Insulin Several
intracellular proteins have been identified as
phosphorylation substrates for the insulin
receptor, the best-studied of which is Insulin
receptor substrate 1 or IRS-1. When IRS-1 is
activated by phosphorylation, a lot of things
happen. Among other things, IRS-1 serves as a
type of docking center for recruitment and
activation of other enzymes that ultimately
mediate insulin's effects.

21

22

Physiologic Effects of Insulin Insulin and
Carbohydrate Metabolism Glucose is liberated from
dietary carbohydrate such as starch or sucrose by
hydrolysis within the SI, and is then absorbed
into the blood. Elevated concentrations of
glucose in blood stimulate release of insulin,
and insulin acts on cells thoughout the body to
stimulate uptake, utilization and storage of
glucose.
23
Physiologic Effects of Insulin Two important
effects are Insulin facilitates entry of
glucose into muscle, adipose and several other
tissues. The only mechanism by which cells can
take up glucose is by facilitated diffusion
through a family of glucose transporters. LARGEL
Y FAT and SKELETAL MUSCLE

24
Physiologic Effects of Insulin Two important
effects are In many tissues - muscle being a
prime example - the major transporter used for
uptake of glucose (called GLUT4) is made
available in the plasma membrane through the
action of insulin.In the absense of insulin,
GLUT4 glucose transporters are present in
cytoplasmic vesicles, where they are useless for
transporting glucose. Binding of insulin to IR on
such cells leads rapidly to fusion of those
vesicles with the plasma membrane and insertion
of the glucose transporters, thereby giving the
cell an ability to efficiently take up glucose.
When blood levels of insulin decrease and
insulin receptors are no longer occupied, the
glucose transporters are recycled back into the
cytoplasm.

25
Family of Glucose transport proteins Uniporters-tr
ansfer one molecule at a time Facillitated
diffusion Energy indepednent GLUT1- found on PM
every single cell in your body for glucose
uptake GLUT2-liver transporter, also found in b
cells GLUT3- fetal transporter GLUT4- insulin
sensitive glucose transporter GLUT5- GLUT7 NOT
to be confused with Naglucose transporter in
lumen of SI which is a symporter, couple the
movement of glucose (against) with Na (with
gradient)

26
GLUT1-glucose transporter on the plasma membrane
of every cell in your body
27
Glucose
GLUT1
Glucose
Glucose
Glucose
Cytoplasm
Glucose
Nucleus
28
GLUT4-a tissue specific insulin sensitive glucose
transporter
29
Glucose
GLUT1
Glucose
GLUT4
Glucose
Glucose
Glucose
Glucose
Glucose
Fat and Skeletal Muscle Cells have GLUT4
Nucleus
30
GLUT1
Glucose
INSULIN
GLUT4
Glucose
Insulin binds its cell surface receptor
Glucose
GLUT4 vesicles travel to PM
Nucleus
31
GLUT1
Glucose
INSULIN
GLUT4
Glucose
Glucose
Glucose
Glucose
Glucose
Lots of glucose inside cell
Nucleus
32
What tissue uses the most glucose??

33
Very important that glucose is in cells and not
in blood Hyperglycemia-high blood glucose
34
What tissue uses the most glucose??

35
In the absense of insulin, GLUT4 glucose
transporters are present in cytoplasmic vesicles,
where they are useless for transporting glucose.
Binding of insulin to receptors on such cells
leads rapidly to fusion of those vesicles with
the plasma membrane and insertion of the glucose
transporters, thereby giving the cell an ability
to efficiently take up glucose. When blood levels
of insulin decrease and insulin receptors are no
longer occupied, the glucose transporters are
recycled back into the cytoplasm.

36

37

38

39

40

I- IR-IRS1-PI3K-AKT(PKB)-glut 4
41

42
INSULIN TALK TO LIVER TO SUPPRESS HGO Hepatic
glucose output GLUT2 is the liver
transporter Insulin stimulates the liver to
store glucose in the form of glycogen. Some
glucose absorbed from the SI is immediately
taken up by hepatocytes, which convert it into
the storage polymer glycogen.

43
Insulin has several effects in liver which
stimulate glycogen synthesis. First, it
activates the enzyme hexokinase, which
phosphorylates glucose, trapping it within the
cell. Coincidently, insulin acts to inhibit the
activity of glucose-6-phosphatase. Insulin also
activates several of the enzymes that are
directly involved in glycogen synthesis,
including phosphofructokinase and glycogen
synthase. The net effect is clear when the
supply of glucose is abundant, insulin "tells"
the liver to bank as much of it as possible for
use later.

44
well-known effect of insulin is to decrease the
concentration of glucose in blood Another
important consideration is that, as blood glucose
concentrations fall, insulin secretion ceases.
In the absense of insulin, a bulk of the cells
in the body become unable to take up glucose, and
begin a switch to using alternative fuels like
fatty acids for energy. Neurons, however, require
a constant supply of glucose, which in the short
term, is provided from glycogen reserves. In
the absense of insulin, glycogen synthesis in the
liver ceases and enzymes responsible for
breakdown of glycogen become active. Glycogen
breakdown is stimulated not only by the absense
of insulin but by the presence of glucagon which
is secreted when blood glucose levels fall below
the normal range.

45
Insulin and Lipid Metabolism The metabolic
pathways for utilization of fats and
carbohydrates are deeply and intricately
intertwined. Considering insulin's profound
effects on carbohydrate metabolism, it stands to
reason that insulin also has important effects on
lipid metabolism.

46
Insulin and Lipid Metabolism Notable effects of
insulin on lipid metabolism include the
following Insulin promotes synthesis of
fatty acids in the liver. As discussed above,
insulin is stimulatory to synthesis of glycogen
in the liver. However, as glycogen accumulates to
high levels (roughly 5 of liver mass), further
synthesis is strongly suppressed.When the liver
is saturated with glycogen, any additional
glucose taken up by hepatocytes is shunted into
pathways leading to synthesis of fatty acids,
which are exported from the liver as
lipoproteins. The lipoproteins are ripped apart
in the circulation, providing free fatty acids
for use in other tissues, including adipocytes,
which use them to synthesize triglyceride.

47
Insulin and Lipid Metabolism Insulin promotes
synthesis of fatty acids in the liver. When the
liver is saturated with glycogen, any additional
glucose taken up by hepatocytes is shunted into
pathways leading to synthesis of fatty acids,
which are exported from the liver as
lipoproteins. The lipoproteins are ripped apart
in the circulation, providing free fatty acids
for use in other tissues, including adipocytes,
which use them to synthesize triglyceride.

48
Insulin and Lipid Metabolism Insulin inhibits
breakdown of fat in adipose tissue by inhibiting
the intracellular lipase that hydrolyzes
triglycerides to release fatty acids.Insulin
facilitates entry of glucose into adipocytes, and
within those cells, glucose can be used to
synthesize glycerol. This glycerol, along with
the fatty acids delivered from the liver, are
used to synthesize triglyceride within the
adipocyte. By these mechanisms, insulin is
involved in further accumulation of triglyceride
in fat cells.

49
INSULIN IN AN ANABOLIC HORMONE From a whole body
perspective, insulin has a fat-sparing effect.
Not only does it drive most cells to
preferentially oxidize carbohydrates instead of
fatty acids for energy, insulin indirectly
stimulates accumulation of fat is adipose tissue.

50
Other Notable Effects of Insulin (I) In addition
to insulin's effect on entry of glucose into
cells, it also stimulates the uptake of amino
acids, again contributing to its overall anabolic
effect. When I levels are low, as in the fasting
state, the balance is pushed toward intracellular
protein degradation. Insulin also increases the
permiability of many cells to K, magnesium and
phosphate ions. The effect on K is clinically
important. Insulin activates Na K ATPases in
many cells, causing a flux of K into cells.
Under some circumstances, injection of insulin
can kill patients because of its ability to
acutely suppress plasma K

51

52

53
Review Insulin made in the beta cells Has
actions on fat and skeletal muscle to increase
glucose uptake and actions on liver to inhibit
HGO. MAINTAIN GLUCOSE HOMEOSTASIS

54
Action of other Endocrine Hormones Besides
Insulin Insulin-shuts down HGO When liver is
saturated with glyogen, used for fatty acid
synthesis in form of lipoproteins which are
secreted. Lipid from these lipoproteins get
stored in fat. Insulin also acts directly on fat
to increase glucose uptake and inhibit FA
breakdown

55
Glucagon Glucagon has a major role in
maintaining normal concentrations of glucose in
blood, and is often described as having the
opposite effect of insulin. So, it increases
blood glucose levels. Glucagon is a linear
peptide of 29 aa. Its primary sequence is almost
perfectly conserved among vertebrates, and it is
structurally related to the secretin family of
peptide hormones.

56
Glucagon Glucagon is synthesized as proglucagon
and proteolytically processed to yield glucagon
within alpha cells of the pancreatic islets.
Proglucagon is also expressed within the
intestinal tract, where it is processed not into
glucagon, but to a family of glucagon-like
peptides (enteroglucagon).

57
Physiologic Effects of Glucagon The major effect
of glucagon is to stimulate an increase in blood
concentration of glucose. The brain in
particular has an absolute dependence on glucose
as a fuel, because neurons cannot utilize
alternative energy sources like fatty acids to
any significant extent. When blood levels of
glucose begin to fall below the normal range, it
is imperative to find and pump additional glucose
into blood. Glucagon exerts control over two
pivotal metabolic pathways within the liver,
leading that organ to dispense glucose to the
rest of the body

58
Glucagon stimulates breakdown of glycogen stored
in the liver. When blood glucose levels are
high, glucose is taken up by the liver. Under the
influence of insulin, much of this glucose is
stored in the form of glycogen. Later, when blood
glucose levels begin to fall, glucagon is
secreted and acts on hepatocytes to activate the
enzymes that depolymerize glycogen and release
glucose.

59
Glucagon activates hepatic gluconeogenesis.
Gluconeogenesis is the pathway by which
non-hexose substrates such as amino acids are
converted to glucose. As such, it provides
another source of glucose for blood. HGO This
is especially important in animals like cats and
sheep that don't absorb much if any glucose from
the intestine - in these species, activation of
gluconeogenic enzymes is the chief mechanism by
which glucagon does its job.

60

Breakdown glycogen Increase gluconeogenesis
61
Glucagon also appears to have a minor effect of
enhancing lipolysis of triglyceride in adipose
tissue, which could be viewed as an addition
means of conserving blood glucose by providing
fatty acid fuel to most cells.

62
Control of Glucagon Secretion So glucagon's
major effect is to increase blood glucose
levels-it makes sense that glucagon is secreted
in response to hypoglycemia or low blood
concentrations of glucose.

63

64
Disease States Diseases associated with
excessively high or low secretion of glucagon are
rare. Cancers of alpha cells (glucagonomas) are
one situation known to cause excessive glucagon
secretion. These tumors typically lead to a
wasting syndrome and, interestingly, rash and
other skin lesions. Although insulin deficiency
is clearly the major defect in type 1 diabetes
mellitus, there is considerable evidence that
aberrant secretion of glucagon contributes to the
metabolic derangements seen in this important
disease. For example, many diabetic patients
with hyperglycemia also have elevated blood
concentrations of glucagon, but glucagon
secretion is normally suppressed by elevated
levels of blood glucose.

65
Control of Glucagon Secretion Two other
conditions are known to trigger glucagon
secretion Elevated blood levels of amino acids,
as would be seen after consumption of a
protein-rich meal In this situation, glucagon
would foster conversion of excess aa to glucose
by enhancing gluconeogenesis. Since high blood
levels of amino acids also stimulate insulin
release, this would be a situation in which both
insulin and glucagon are active. Exercise In
this case, it is not clear whether the actual
stimulus is exercise per se, or the accompanying
exercise-induced depletion of glucose. In terms
of negative control, glucagon secretion is
inhibited by high levels of blood glucose. It is
not clear whether this reflects a direct effect
of glucose on the alpha cell, or perhaps an
effect of insulin, which is known to dampen
glucagon release. Another hormone well known to
inhibit glucagon secretion is somatostatin.

66
Compare Insulin knockout mice to glucagon knock
out mice

67
Somatostatin Somatostatin was first discovered
in hypothalamic extracts and identified as a
hormone that inhibited secretion of GH.
Subsequently, SS was found to be secreted by a
broad range of tissues, including pancreas,
intestinal tract and regions of the central
nervous system outside the hypothalamus.
Structure and Synthesis Two forms of
somatostatin are synthesized. They are referred
to as SS-14 and SS-28, reflecting their aa
length. Both forms of SS are generated by
proteolytic cleavage of prosomatostatin, which
itself is derived from preprosomatostatin. Two
cysteine residues in SS-14 allow the peptide to
form an internal disulfide bond.

68
Somatostatin The relative amounts of SS-14 vs.
SS-28 secreted depends upon the tissue. SS-14
is the predominant form produced in the nervous
system and the sole form secreted from pancreas,
whereas the intestine secretes mostly SS-28. In
addition to tissue-specific differences in
secretion of SS-14 and SS-28, the two forms of
this hormone can have different biological
potencies. SS-28 is roughly 10X more potent in
inhibition of GH secretion, but less potent that
SS-14 in inhibiting glucagon release.

69
Somatostatin Receptors and Mechanism of
Action Five somatostatin receptors have been
identified and characterized, all of which are
members of the G protein-coupled receptor
superfamily. Each of the receptors activates
distinct signalling mechanisms within cells,
although all inhibit adenylyl cyclase. Four of
the five receptors do not differentiate SS-14
from SS-28.

70
Somatostatin Physiologic Effects SS acts by
both endocrine and paracrine pathways to affect
its target cells. A majority of the circulating
SS appears to come from the pancreas and GI
tract. If one had to summarize the effects of
somatostatin in one phrase, it would be
"somatostatin inhibits the secretion of many
other hormones".

71
Somatostatin Physiologic Effects Effects on the
Pituitary Gland Somatostatin was named for its
effect of inhibiting secretion of GH
Experimentally, all known stimuli for GH
secretion are suppressed by SS administration.
Additionally, animals treated with antisera to SS
show elevated blood concentrations of GH, as do
animals that are genetically engineered to
disrupt their SS gene. Ultimately, GH secretion
is controlled by the interaction of SS and GHRH


72
Somatostatin Physiologic Effects Effects on
the Pancreas Cells within islets secrete SS. SS
appears to act primarily in a paracrine manner to
inhibit the secretion of both I and glucagon. It
also has the effect in suppressing pancreatic
exocrine secretions, by inhibiting CCK
-stimulated enzyme secretion and Secretin
stimulated bicarbonate secretion.

73
Somatostatin Physiologic Effects Effects on the
Gastrointestinal Tract SS is secreted by
scattered cells in the GI epithelium, and by
neurons in the enteric nervous system. It has
been shown to inhibit secretion of many of the
other GI hormones, including gastrin, CCK,
Secreting and VIP. In addition to the direct
effects of inhibiting secretion of other GI
hormones, SS has a variety of other inhibitory
effects on the GI tract, which may reflect its
effects on other hormones, plus some additional
direct effects. SS suppresses secretion of
gastric acid and pepsin, lowers the rate of
gastric emptying, and reduces smooth muscle
contractions and blood flow within the intestine.
Collectively, these activities seem to have the
overall effect of decreasing the rate of nutrient
absorption.

74
Somatostatin Physiologic Effects Effects on the
Nervous System SS is often referred to as having
neuromodulatory activity within the central
nervous sytem, and appears to have a variety of
complex effects on neural transmission.
Injection of SS into the brain of rodents leads
to such things as increased arousal and decreased
sleep, and impairment of some motor responses.

75
Somatostatin Pharmacologic Uses SS and its
synthetic analogs are used clinically to treat a
variety of neoplasms. It is also sometimes in
to treat gigantism and acromegaly, due to its
ability to inhibit GH secretion. Why is this a
bad idea?

76
Amylin Amylin is a peptide of 37 aa which is
also secreted by the beta cells of the pancreas.
Some of its actions inhibits the secretion of
glucagon slows the emptying of the stomach
sends a satiety signal to the brain. All of
its actions tend to supplement those of insulin,
reducing the level of glucose in the blood.

77

78
Diabetes 'dia' through - 'betes' to go
1500 B.C. Ancient Egyptians had a number of
remedies for combating the passing of too much
urine (polyuria).
Hindus in the Ayur Veda recorded that insects
and flies were attracted to the urine of some
people, that the urine tasted sweet, and that
this was associated with certain diseases.
1000 B.C. The father of medicine in India,
Susruta of the Hindus, diagnosed Diabetes
Mellitus (DM). Early Greeks had no treatment
for DM, latter Greeks like Aretaeus, Celsus and
Galen described DM. Celsus described the
pathologic condition "diabetes"
79
Diabetes 'dia' through - 'betes' to go
1798 A.D. John Rollo certifies excess sugar in
the blood.
1889 A.D. Mehring and Minkowski produce DM in
dogs by removing the pancreas.
1921 A.D. Banting and Best find insulin is
secreted from the islet cells of the pancreas.
80
Diabetes is a disease that is the 5th leading
cause of death in the USA
81
20.8 Million Americans have Diabetes (7
pop) More have pre-diabetes
82
There are two (or 3) different types of diabetes
and the diseases are very different
83
There are three categories of diabetes mellitus
Insulin-Dependent Diabetes Mellitus (IDDM)
also called "Type 1" diabetes and Non
Insulin-Dependent Diabetes Mellitus
(NIDDM) "Type 2" Inherited Forms of Diabetes
Mellitus (MODY)

84
There are three categories of diabetes mellitus
IDDM (also called Type 1 diabetes) is
characterized by little (hypo) or no circulating
insulin most commonly appears in childhood.
It results from destruction of the beta cells
of the islets. The destruction results from a
cell-mediated AUTOIMMUNE ATTACK of the beta
cells. What triggers this attack is still a
mystery IDDM is controlled by carefully-regulated
injections of insulin. (Insulin cannot be taken
by mouth)

85

86
Inhalable insulin was introduced in mid-2006
The first such product to be marketed was
Exubera, a powdered form of recombinant human
insulin, delivered through an inhaler into the
lungs where it is absorbed. Once it has been
absorbed, it begins working within the body over
the next few hours. Diabetics still need to take
a longer acting basal insulin by injection. It
has been concluded that inhaled insulin "appears
to be as effective, but no better than injected
short-acting insulin. The additional cost is so
much more that it is unlikely to be
cost-effective."\ In October 2007, Pfizer
announced that it would be discontinuing the
production and sale of Exubera due to poor sales.
Several other companies are developing inhaled
forms of the drug to reduce the need for daily
injections among diabetics. PFIZER LOSS 2.8
billion

87
For many years, insulin extracted from the
glands of cows and pigs was used. However, pig
insulin differs from human insulin by one amino
acid beef insulin by three. Although both work
in humans to lower blood sugar, they are seen by
the immune system as "foreign" and induce an
antibody response in the patient that blunts
their effect and requires higher doses. Two
approaches were taken to solve this problem

88
There are three categories of diabetes mellitus
Two approaches have been taken to solve this
problem Convert pig insulin into human insulin
by removing the one amino acid that distinguishes
them and replacing it with the human version.
This approach is expensive, so now the favored
approach is to Insert the human gene for insulin
into E.coli and grow recombinant human insulin
in culture tanks. Insulin is not a GLYCOPROTEIN
so E. coli is able to manufacture a
fully-functional molecule (trade name Humulin).
Yeast is also used (trade name Novolin).
Recombinant DNA technology has also made it
possible to manufacture slightly-modified forms
of human insulin that work faster (Humalog and
NovoLog) or slower (Lantus) than regular human
insulin.

89
Each cell has thousands of proteins. In many
cases a missing or defective protein has no effect
90
Inherited Forms of Diabetes Mellitus Some cases
of diabetes result from mutant genes inherited
from one or both parents. Examples mutant
genes for one or another of the transcription
factors needed for transcription of the insulin
gene . mutations in one or both copies of the
gene encoding the insulin receptor. These
patients usually have extra-high levels of
circulating insulin but defective receptors.
The mutant receptors may fail to be expressed
properly at the cell surface or may fail to
transmit an effective signal to the interior of
the cell.

91
Diagnostic Diabetes diagnosing maturity-onset
diabetes of the young (MODY)
92
Diagnosing MODY
  • What is MODY?
  • Different types of MODY- Glucokinase MODY-
    Transcription factor MODY
  • Separate from Type 1, Type 2 and genetic syndromes

93
MODY (inherited) MODY is caused by a change in a
single gene.  6 genes have been identified that
account for 87 of MODY  HNF1-a
Glucokinase HNF1-b HNF4-a IPF1   Neuro
D1 MOST ARE TFs that modulate insulin
transcription Important to diagnose MODY

94
Diabetes in Young Adults (15-30 years)
Type 2
Type 1
MODY
MIDD
5 10 15 20 25 30 35 40 45
50 55 60 65 70 75 80 85 90
Age of diagnosis
95
Diagnostic criteria for MODY
  • Early-onset diabetes
  • Not insulin-dependent diabetes
  • Autosomal dominant inheritance
  • Caused by a single gene defect altering beta-cell
    function, obesity unusual

Tattersall (QJM 1974)
96
The Genetic Causes of MODY
MODY
11MODY x
75Transcription factors
14Glucokinase(MODY2)
3HNF1?
3HNF4?
lt1IPF1
lt1 NeuroD1
69HNF1?(MODY3)
Frayling, et al Diabetes 2001
97
Two subtypes of MODY Glucokinase and
Transcription factor
20
16
12
Glucose
(mmol/l)
8
.
.
4
0
0
20
40
60
80
100
Age (yr..)
Pearson, et al Diabetes 2001
98
Glucokinase and Transcription factor diabetes
MODY
Transcription factormutations
Glucokinasemutations
(HNF-1?, HNF-1b, HNF-4?)

Onset at birthStable hyperglycemiaDiet
treatmentComplications rare
Adolescence/young adult onsetProgressive
hyperglycemia1/3 diet, 1/3 other, 1/3
InsulinComplications frequent
99
MODY Type 2 Type1 Non insulin
dependent Yes Yes No Parents
affected 1 1-2 0-1 Age of
onset lt 25yr Yes unusual
YesObesity /- /-Acanthosis
- -NigricansRacial groups low
high low(Type 2 prevalence)
100
MODYDiagnostic Genetic Testing why do it?
  • Makes diagnosis defines monogenic and defines
    subtype
  • Differentiates from type 1
  • Helps define prognosis
  • Helps family counselling
  • Helps treatment decisions

101
Inherited Forms of Diabetes Mellitus a mutant
version of the gene encoding glucokinase, the
enzyme that phosphorylates glucose in the first
step of glycolysis. Mutant version of insulin
gene TFs mutations in the gene encoding part of
Kchannel in the plasma membrane of the b cell.
The channels fail to close properly causing the
cell to become hyperpolarized and blocking
insulin secretion. mutations in several
mitochondrial genes which reduce insulin
secretion by b cells. These diseases are
inherited from the mother as only her
mitochondria survive in the fertilized egg.
While symptoms usually appear in childhood or
adolescence, patients with inherited diabetes
differ from most children with NIDDM in having a
history of diabetes in the family and not being
obese.

102
Inherited Forms of Diabetes Mellitus MODY GENES
like Mutant glucokinase insulin gene TFs
Kchannel of the b cell. IR some
mitochondria genes

103
Of 20 million Americans with Diabetes, only 10
have type I diabetes
104
Most diabetics Have Type II diabetes T2DM or NIDDM
105
90 of diabetics in industrialized nations have
Type II diabetes
106
Type II diabetes Defined by insulin resistance
insulin resistance-inability to respond to insulin
107
Hyperglycemia causes retinopathy, neuropathy, and
nephropathy
108
Type II diabetes-patients are insulin resistance
so cant get glucose into cells
109
How do you get high blood glucose? Glucose comes
from the food you eat and is also made in your
liver and muscles. Your blood carries the
glucose to all the cells in your body. Insulin
controls glucose disposal into fat and skeletal
muscle The pancreas releases insulin into the
blood. Insulin helps the glucose from food get
into your cells. If your body doesn't make
enough insulin or if the insulin doesn't work the
way it should, glucose can't get into your cells.
It stays in your blood instead. Your blood
glucose level then gets too high, causing
pre-diabetes or diabetes.

110
Type II diabetes research related to adipocytes
111
Adipocytes
accumulate lipid
accumulate lipid
insulin sensitive
insulin sensitive
Endocrine functions
Endocrine function
112
Most patients with Type II diabetes are obese gt
85
113
Strong link between NIDDM and Obesity
114
Many diseases due to loss or defect of one
protein Sickle Cell Anemia Huntingtons
Disease Type I Diabetes MODY
115
Many diseases due to loss or defects in many
proteins Heart Disease Cancer Type II Diabetes
116
Very hard to cure diseases that have multiple
proteins defective
117
What is pre-diabetes? Pre-diabetes is a
condition in which blood glucose levels are
higher than normal but are not high enough for a
diagnosis of diabetes. People with pre-diabetes
are at increased risk for developing type 2
diabetes and for heart disease and stroke. The
good news is if you have pre-diabetes, you can
reduce your risk of getting diabetes. With modest
weight loss and moderate physical activity, you
can delay or prevent type 2 diabetes and even
return to normal glucose levels.

118
How does Exercise work Exercise results in an
increase in GLUT4 vesicles moving to the PM The
effect is independent of insulin The effects of
insulin and exercise are additive. Exercise,
even in the absense of WEIGHT LOSS can reduce
blood glucose levels and increase insulin
sensitivity

119
What are the signs of diabetes? being very
thirsty urinating often feeling very hungry or
tired losing weight without trying having sores
that heal slowly having dry, itchy skin losing
the feeling in your feet or having tingling in
your feet having blurry eyesight may have had
one or more of these signs before you found out
you have diabetes. Or may have had no signs at
all. A blood test to check your glucose levels
will show if you have pre-diabetes or diabetes.

120
A1C, also known as glycated hemoglobin or
glycosylated hemoglobin, indicates a patient's
blood sugar control over the last 2-3 months.
A1C is formed when glucose in the blood binds
irreversibly to hemoglobin to form a stable
glycated hemoglobin complex. Since the normal
life span of red blood cells is 90-120 days, the
A1C will only be eliminated when the red cells
are replaced A1C values are directly
proportional to the concentration of glucose in
the blood over the full life span of the red
blood cells.

121


122
A1C values are not subject to the fluctuations
that are seen with daily blood glucose
monitoring. The A1C value is an index of mean
blood glucose over the past 2-3 months but is
weighted to the most recent glucose values.
Values show the past 30 days as 50 of the
A1C, the preceding 60 days giving 25 of the
value and the preceding 90 days giving 25 of
the value. This bias is due to the body's natural
destruction and replacement of RBC. Because RBCs
are constantly being destroyed and replaced, it
does not take 120 days to detect a clinically
meaningful change in A1C following a significant
change in mean blood glucose.

123

WHY IS IT SO HARD TO TREAT NIDDM
124
Medications for NIDDM Many types of diabetes
pills can help people with T2DM lower their
blood glucose. Each type of pill helps lower
blood glucose in a different way.
Sulfonylureas- stimulate your pancreas to make
more insulin.Biguanides decrease the amount of
glucose made by your liver.a glucosidase
inhibitors slow the absorption of the starches
you eat.

125
Medications for NIDDM Thiazolidinediones
TZDs-make you more sensitive to insulin.
Meglitinides -stimulate your pancreas to make
more insulin.D-phenylalanine derivatives -help
your pancreas make more insulin
quickly.Combination oral medicines put together
different kinds of pills.

126
  • Gila monsters are one of only two venomous
    lizards in the world, the other being the closely
    related beaded lizards

127
  • A fairly new diabetes treatment from Eli Lilly
    and Amylin that is extracted from the saliva of
    the Gila monster received approval from the Food
    and Drug Administration in April 2005
  • Byetta, which was co-developed by both companies,
    improves blood sugar control in patients with
    type 2 diabetes. The drug, developed from a
    compound in the toxic saliva of a rare lizard
    found only in the Southwest U.S. and Mexico.
  • Came on Market in June of 2005
  • Used in patients who aren't getting enough
    insulin through oral medication

128
  • DRAWBACK
  • Has to be injected twice a day

129
  • Some History
  • 1980s an endocrinologist named Dr. John Eng
    worked of the VA Medical Center in the Bronx His
    mentor - Dr. Rosalyn S. Yalow, won the 1977 Nobel
    Prize in Physiology or Medicine for the
    development of RIAs of peptide hormones.
  • Dr. Eng wanted to discover new hormones.
  • RIA are insensitive and not a good way to
    discover new hormones. But chemical assays are
    sensitive. So he developed a new type of chemical
    assay and looked for hormones that no one had
    discovered.

130
  • Some History
  • Dr. Eng first discovered a new hormone in the
    venom of the Mexican beaded lizard, which in 1990
    he named exendin-3. But this hormone was
    vasoactive, which means that it contracts or
    dilates blood vessels.
  • Prompted Dr. Eng to look at the venom of the Gila
    monster, which is not vasoactive. There he
    discovered a hormone, which he named exendin-4,
    that was similar in structure to glucagon-like
    peptide 1 (GLP-1).

131
  • Some History
  • GLP-1 regulates blood glucose and satiety, as a
    potential drug it has a short half-life requiring
    multiple daily injections. He published his key
    paper on exendin-4 in a 1992 issue of The Journal
    of Biological Chemistry.
  • But exendin-4 works for 12 or more hours. "That's
    how it is better," Dr. Eng says. So, Amylin
    Pharmaceuticals invested millions of dollars to
    develop it.

132
  • Some History
  • When Dr. Eng began to realize exendin-4's
    potential to control diabetes, he told the
    Department of Veterans Affairs that the agency
    should patent it. " VA declined, because at that
    time inventions must be veteran specific," he
    recalls. The VA did retain a royalty-free
    license.
  • "That put me in a difficult position," he says,
    "because it meant I had to essentially make a
    bet. Patenting it came out of my pocket with no
    guarantee that anything would come of it. I ended
    up with this patent, and I couldn't develop it.
    So I went around to drug companies."

133
  • Some History
  • Finally, in 1996, Dr. Eng licensed the patent to
    Amylin, which calls it AC2993. The company
    completed the Phase 1 study in 1998 and filed an
    investigational new drug application with the FDA
    in 1999. Phase 2 studies, announced at the ADA's
    2001 Annual Meeting, showed an approximate 1
    reduction in A1c after 28 days. Since A1c
    measures average blood glucose of the past 2-3
    months, this is a lot.
  • Amylin had success in Phase 3 trials.

134
  • Some History
  • Used by 2 injections a day. "The initial target
    population is for people with NIDDM who have not
    progressed to taking insulin," "It stimulates
    insulin production when it is needed and is only
    active when glucose is high." It also reduces
    appetite, causing some weight loss.
  • Amylin is also working on alternatives to shots
    and a long-acting formulation of one shot a
    month, AC2993 LAR.

135
  • Some History
  • Who would have imagined that a Gila monster
    could be so valuable to people with diabetes? But
    Dr. Eng did. Ironically, the venom he worked with
    came from a lab in Utah, and he says he has never
    seen a Gila monster. 

136
  • Not as many proteins as we thought.
  • Not surprising we have some "super-geneslike one
    that encodes glucagon (increases glucose).
  • As it turns out, the gene for glucagon also
    codes for at least 2 other hormones, called
    glucagon-like peptides 1 and 2 (GLP-1, GLP-2).
    Not only do the GLPs come from the same gene as
    glucagon, but have a very similar aa sequence as
    well.
  • Despite these parallels, the GLPs have very
    different functions than glucagon, and there is a
    lot of excitement about using these hormones to
    treat problems ranging from diabetes and obesity
    to chemotherapy-induced intestinal damage.

137
  • From a diabetes perspective, the interesting
    GLP is GLP-1.
  • GLP-1 is secreted from cells in the gut in
    response to a meal, and helps to integrate many
    of the normal physiological responses that occur
    after eating.
  • For one, GLP-1 induces insulin secretion from the
    pancreas, and simultaneously reduces glucagon
    release. This release of insulin actually seems
    to occur only when the ambient glucose
    concentration is high, thus reducing the chance
    that hypoglycemia will develop (an especially
    attractive feature in a diabetes therapy).

138
  • Over a longer period, GLP-1 actually increases
    the number of insulin-producing b cells.
  • GLP-1 also acts directly on the GI tract,
    reducing the rate at which food spills out of the
    stomach and into the SI, making the absorption
    and storage of energy more efficient.

139
  • Finally, and perhaps most intriguingly, GLP-1
    acts on the CNS to signal a sense of fullness so
    that we don't overeat.
  • So isnt GLP-1 prescribed to everyone with T2DM?
    Well, there are a few problems, The most daunting
    has been that our bodies destroy GLP-1 within a
    few minutes. This means that it needs to be
    continuously infused (Because it is a protein,
    GLP-1 cannot be given orally), which is clearly
    not going to work for most people. The enzyme
    that destroys GLP-1 is called dipeptidyl-peptidase
    IV (DPP IV), and intense focus has been placed
    on figuring out ways to disable the enzyme so
    that GLP-1 can do it's thing for longer periods
    of time.

140
  • One way to get around the problem of DPP IV is to
    administer a form of GLP-1 that is resistant to
    destruction. Such forms of GLP-1 have already
    been found, and the source is delightfully
    unexpected--the poisonous saliva of the Gila
    monster lizard. GLP-1 (called exendin-4) from
    these reptiles has a few key differences from the
    form found in humans, one consequence of which is
    immunity to DPP IV.
  • pharmaceutical companies made synthetic forms of
    exendin-4 (one imagines that it's easier to make
    the chemical from scratch than it is to harvest
    toxic lizard spit).
  • Phase 2 clinical trials of exendin-4 in patients
    with T2DM showed improvements in hemoglobin A1c
    levels comparable to those seen with currently
    available ant diabetic drugs. Other studies show
    reductions of caloric intake after exendin-4
    administration.

141
  • Another strategy that is being pursued is the
    use of drugs that will inhibit DPP IV directly.
  • Studies have shown that 24 hours after taking
    such a drug, patients with mild T2DM have reduced
    fasting, post-meal, and average blood sugar
    levels.
  • The primary advantage of this approach (vs.
    exendin-4) is that DPP IV inhibitors can be given
    orally. On the other hand, DPP IV affects other
    hormones besides GLP-1, and there is concern that
    blocking the enzyme could cause other problems.
  • One reassuring piece of data is that mice that
    are genetically engineered to lack DPP IV are
    viable and appear to do well, and this provides
    some reassurance that the strategy is sound.
    Still, longer term studies with both DPP IV
    inhibitors need to be performed to assess
    possible toxicity. It is also unclear if the
    beneficial effects of GLP-1 will be sustained
    over time, and this too will have to be tested.
    Nonetheless, a drug that that causes weight loss
    as well as improved insulin secretion in type 2
    diabetes is a potential blockbuster.

142

GLP-1 extendin-4 DDP1V
143
Diabetes Myths Myth 1  You can catch diabetes
from someone else. Myth 2  People with
diabetes can't eat sweets or chocolate. Myth
3  Eating too much sugar causes diabetes. 
Myth 4  People with diabetes should eat special
diabetic foods. Myth 5  If you have diabetes,
you should only eat small amounts of starchy
foods, such as bread, potatoes and pasta. 
Myth 6  People with diabetes are more likely to
get colds and other illnesses.  . Myth 7 
Insulin causes atherosclerosis (hardening of the
arteries) and high blood pressure.

144
Diabetes Myths Myth 8  Insulin causes weight
gain, and because obesity is bad for you, insulin
should not be taken.  Myth 9  Fruit is a
healthy food.  Therefore, it is ok to eat as much
of it as you wish.  Myth 10  You dont need to
change your diabetes regimen unless your A1C is
greater than 8
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