Transcript Glucose - The Stephens Lab

Motilin
Motilin is a 22 aa peptide secreted by
endocrinocytes in the mucosa of the proximal SI.
Based on aa sequence, motilin is unrelated to
other hormones.
Motilin participates in controlling the pattern of
smooth muscle contractions in the upper GI
tract.
Motilin
There are two basic states of motility of the stomach and
SI:
the fed state, when foodstuffs are present
and the interdigestive state between meals.
Motilin is secreted into the circulation during the
fasted state at intervals of roughly 100 minutes.
These bursts of motilin secretion are temporily
related to the onset of "housekeeping
contractions", which sweep the stomach and SI
clear of undigested material.
Motilin is secreted by Mo cells of the SI that increases
the MIGRATING MYOELECTRIC COMPLEX
component of GI motility and stimulates the
production of PEPSIN.
Control of motilin secretion is largely unknown,
although some studies show that alkaline pH in the
duodenum stimulates its release.
Interestingly however, at low pH it inhibits gastric
motor activity, whereas at high pH it has a stimulatory
effect.
Apart from in humans, motilin receptors are found in
pigs', rats',cows' and cats' gastrointestinal tracts and in
rabbits' central nervous systems.
Motilin
An interesting aspect of the motilin story is that
erythromycin and related antibiotics act as nonpeptide motilin agonists, and are sometimes used
for their ability to stimulate GI motility.
Administration of a low dose of erythromycin will
induce a migrating motor complex, which
provides additional support for the conclusion
that motilin secretion triggers this pattern of GI
motility, rather than results from it.
Motilin
Most recently, an orphan GPCR related to
growth hormone secretagogues receptor
(GHS-R) has been isolated and characterized
from human stomach as the motilin receptor
(MTLR or GPR38; 52% identity with GHS-R).
Polymorphisms of the motilin gene in
inflammatory bowel disease.
Gastric Inhibitory Peptide
Gastric inhibitory peptide (GIP) is a member of the
secretin family of hormones.
It was discovered as a factor in extracts of intestine
that inhibited gastric motility and secretion of
acid, and initially called enterogastrone.
Like secretin, it is secreted from mucosal epithelial
cells in the first part of the small intestine.
Another activity of GIP is its ability to enhance the
release of insulin in response to infusions of
glucose. For this action, it has also been referred
to as glucose-dependent insulinotropic peptide.
Vasoactive Intestinal Peptide
VIP is a 28 aa peptide structurally related to
secretin.
- originally isolated from intestinal extracts and
shown to be a potent vasodilator.
- demonstrated that VIP is very widely distributed
in the peripheral and CNS
Vasoactive Intestinal Peptide
- A huge # of biological effects have been
attributed to VIP.
- With respect to the digestive system, VIP seems
to induce smooth muscle relaxation (lower
esophageal sphincter, stomach, gallbladder),
stimulate secretion of water into pancreatic juice
and bile, and cause inhibition of gastric acid
secretion and absorption from the intestinal
lumen.
Vasoactive Intestinal Peptide
Certain tumors arising from the
pancreatic islets or nervous
tissue (called VIPomas) secrete
excessive quantities of VIP, and
are associated with chronic,
watery diarrhea.
Enteroglucagon and Glucagon-Like Peptides
Glucagon is best known as a peptide hormone
secreted from pancreatic islets and participates
in control of glucose metabolism.
Glucagon is synthesized initially as the protein
proglucagon, which, in mammals, is encoded by
a single gene.
Within alpha cells of the pancreas, proglucagon is
processed by proteolytic cleavage into glucagon
itself, and several biologically inactive peptides.
Enteroglucagon and Glucagon-Like Peptides
Interestingly, the proglucagon gene is also
expressed in the terminal SI and LI, where it is
cleaved into a number of peptides other than
glucagon.
This alternative pathway for processing of
proglucagon occurs in gut endocrinocytes called
L cells. Because these peptides were discovered
by cross reactions with antisera against
glucagon, they were originally given the name
"enteroglucagon", and are sometimes referred
to collectively as "proglucagon-derived
peptides".
Enteroglucagon and Glucagon-Like Peptides
The major, characterized patterns of proglucagon
processing are depicted in the next few slides.
In both pancreas and gut, 3 types of products are
generated:
Peptides with known biological activity (yellow
color): glucagon and glucagon-like peptide-1
(GLP-1)
Enteroglucagon and Glucagon-Like Peptides
Peptides that may have biological activity, but
which are poorly characterized or active only at
what are considered non-physiologic
concentrations (cyan color): glucagon-like
peptide-2 (GLP-2) and oxyntomodulin
Peptides without apparent biological activity
(gray color): glicentin, glicentin-related
pancreatic peptide, major proglucagon
fragment.
Regardless of activity, each of these peptides is secreted into blood
after ingestion of a meal containing carbohydrates or lipids.
Glucagon-like peptide-1 has a major effect of
enhancing the release of insulin in response
to a glucose stimulus, and coincidentally,
suppressing secretion of glucagon. As a
result, injections of this hormone lower
blood glucose levels, not only in normal
people, but in those having insulindependent and NIDDM. For this reason,
GLP-1 is being used in diabetes therapy.
GLP-1 has been shown to potently inhibit
several aspects of digestive function,
including gastric emptying, gastric
secretion and pancreatic secretion. Like
many gut peptides,
GLP-1 is also synthesized in the brain, and
may play a role in
control of food intake
Glucagon-like peptide-2 is not well
characterized, but some reports suggest
that it stimulates proliferation of intestinal
epithelial cells.
Oxyntomodulin is identical to glucagon, but
with an 8 amino acid extension on the Cterminus. Experimentally, it has glucagonlike activity, but this is of doubtful
physiologic significance, as it binds the
glucagon receptor with low affinity relative
to glucagon.
Other effects that have been demonstrated
include inhibition of gastric secretion and
motility, and inhibition of pancreatic
secretion.
The Enteric Nervous System
The nervous system exerts a profound influence on all
digestive processes, namely motility, ion transport
associated with secretion and absorption, and GI blood
flow.
Some of this control emanates from connections between
the digestive system and CNS, but just as importantly,
the digestive system is endowed with its own, local
nervous system referred to as the enteric or intrinsic
nervous system.
The magnitude and complexity of the enteric nervous
system is immense - it contains as many neurons as the
spinal cord.
The Enteric Nervous System
The principal components of the enteric nervous
system are 2 networks (or plexuses) of neuronsboth of which are embedded in the wall of the
digestive tract and extend from esophagus to
anus:
The Enteric Nervous System
2 networks (or plexuses)
The myenteric plexus is located between the longitudinal
and circular layers of muscle in the tunica muscularis
and, appropriately, exerts control primarily over
digestive tract motility.
The submucous plexus, as its name implies, is buried in the
submucosa. Its principal role is in sensing the
environment within the lumen, regulating GI blood flow
and controlling epithelial cell function. In regions where
these functions are minimal, such as the esophagus, the
submucous plexus is sparse and may actually be
missing
GI Nerves
The image shows part of the myenteric plexus in a section of cat
duodenum. The yellow circles outline several enteric neurons.
The Enteric Nervous System
Within enteric plexuses are 3 types of neurons,
most of which are multipolar:
Sensory neurons receive information from sensory
receptors in the mucosa and muscle. At least 5
different sensory receptors have been identified
in the mucosa, which respond to mechanical,
thermal, osmotic and chemical stimuli.
Chemoreceptors sensitive to acid, glucose and
amino acids have been demonstrated which, in
essence, allows "tasting" of lumenal contents.
Sensory receptors in muscle respond to stretch
and tension.
The Enteric Nervous System
Within enteric plexuses are 3 types of neurons, most of which are
multipolar:
Motor neurons within the enteric plexuses control
GI motility and secretion, and possibly
absorption. In performing these functions, motor
neurons act directly on a large number of
effector cells, including smooth muscle, secretory
cells (chief, parietal, mucous, enterocytes,
pancreatic exocrine cells) and GI endocrine cells.
Interneurons are largely responsible for
integrating information from sensory neurons
and providing it to ("programming") enteric
motor neurons.
The Enteric Nervous System
Enteric neurons secrete an intimidating array of
neurotransmitters (NTs).
One major NT produced by enteric neurons is
acetylcholine.
In general, neurons that secrete acetylcholine are
excitatory, stimulating smooth muscle
contraction, increases in intestinal secretions,
release of enteric hormones and dilation of blood
vessels.
The Enteric Nervous System
Norepinephrine (NE) is also used extensively for
neurotransmission in the GI tract, but it derives
from extrinsic sympathetic neurons;
the effect of NE is almost always inhibitory and
opposite that of acetylcholine.
The Enteric Nervous System
The enteric nervous system can and does function autonomously, but
normal digestive function requires communication links between
this intrinsic system and the central nervous system.
These links take the form of parasympathetic and sympathetic fibers
that connect either the central and enteric nervous systems or
connect the CNS directly with the digestive tract.
Through these cross connections, the gut can provide sensory
information to the CNS, and the CNS can affect gastrointestinal
function.
Connection to the CNS also means that signals from outside of the
digestive system can be relayed to the digestive system: for
instance, the sight of appealing food stimulates secretion in the
stomach.
The Enteric Nervous System
In general, sympathetic stimulation causes inhibition of GI secretion
and motor activity, and contraction of gastrointestinal sphincters
and blood vessels.
Conversely, parasympathetic stimuli typically stimulate these
digestive activities.
Some of the prominent communiques enabled by nervous
interconnections within the digestive tract have been named as
reflexes and serve to illustrate a robust system of control.
Examples include the gastrocolic reflex, where distention of the
stomach stimulates evacuation of the colon, and the enterogastric
reflex, in which distention and irritation of the small intestine
results in suppression of secretion and motor activity in the
stomach.
The Enteric Endocrine System
The second of the two systems that control digestive function is the
endocrine system, which regulates function by secreting
hormones.
Digestive function is affected by hormones produced in many
endocrine glands, but the most profound control is exerted by
hormones produced within the GI tract.
The GI tract is the largest endocrine organ in the
body and the endocrine cells within it are
referred to collectively as the enteric endocrine
system.
The best studied hormones are gastrin, CCK, and
secretin
The Parietal Cell: Mechanism of Acid Secretion
The best-known component of gastric juice is HCl, the
secretory product of the parietal, or oxyntic cell.
It is known that the capacity of the stomach to
secrete HCl is almost linearly related to parietal
cell numbers.
When stimulated, parietal cells secrete HCl at a
concentration of roughly 160 mM (equivalent to
a pH of 0.8).
The acid is secreted into large cannaliculi, deep
invaginations of the plasma membrane which are
continuous with the lumen of the stomach.
Mechanism of Acid Secretion
The H+ concentration in parietal cell secretions is
roughly 3 million fold higher than in blood, and
chloride is secreted against both a concentration
and electric gradient.
Thus, the ability of the partietal cell to secrete acid
is dependent on active transport.
The key player in acid secretion is a H+/K+ ATPase
or "proton pump" located in the cannalicular
membrane.
This ATPase is magnesium-dependent, and not
inhibitable by ouabain.
Mechanism of Acid Secretion
The current model for explaining acid secretion is as follows:
H+ are generated within the parietal cell from dissociation of water.
The hydroxyl ions formed in this process rapidly combine with
carbon dioxide to form bicarbonate ion, a reaction cataylzed by
CARBONIC ANHYDRASE
Bicarbonate is transported out of the basolateral membrane in
exchange for chloride. The outflow of bicarbonate into blood
results in a slight elevation of blood pH known as the "alkaline
tide". This process serves to maintain intracellular pH in the
parietal cell.
Chloride and potassium ions are transported into the lumen of
the cannaliculus by conductance channels, and such is necessary
for secretion of acid.
Mechanism of Acid Secretion
The current model for explaining acid secretion is as follows:
Hydrogen ion is pumped out of the cell, into the lumen, in
exchange for potassium through the action of the
proton pump; potassium is thus effectively recycled.
Accumulation of osmotically-active hydrogen ion in the
cannaliculus generates an osmotic gradient across the
membrane that results in outward diffusion of water the resulting gastric juice is 155 mM HCl and 15 mM
KCl with a small amount of NaCl.
Control of Acid Secretion
Parietal cells bear receptors for three
stimulators of acid secretion, reflecting a
triumverate of neural, paracrine and
endocrine control:
Acetylcholine (muscarinic type receptor)
Gastrin
Histamine (H2 type receptor)
The Enteric Endocrine System
In contrast to endocrine glands like the anterior pituitary
gland, in which essentially all cells produce hormones,
the enteric endocrine system is diffuse: single hormonesecreting cells are scattered among other types of
epithelial cells in the mucosa of the stomach and SI.
For example, most of the epithelial cells in the stomach are
dedicated to secreting mucus, HCl or a proenzyme
called pepsinogen into the lumen of the stomach.
Scattered among these secretory epithelial cells are G cells,
which are endocrine cells that synthesize and secrete the
hormone gastrin.
The Enteric Endocrine System.
Being a hormone, gastrin is secreted into blood, not
into the lumen of the stomach.
Similarly, other hormones produced by the enteric
endocrine system are synthesized and secreted
by cells within the epithelium of the small
intestine.
The Enteric Endocrine System
Like all endocrine cells, cells in enteric endocrine system do not
simply secrete their hormone continuously, which would not be
very useful as a control system.
Rather, they secrete hormones in response to fairly specific stimuli
and stop secreting their hormone when those stimuli are no
longer present.
What stimulates the endocrinocytes in the enteric endocrine system?
As you might deduce, in most cases these endocrine cells respond
to changes in the environment within the lumen of the digestive
tube. Because these cells are part of the epithelium, their apical
border is in contact with the contents of the lumen, which allows
them to continually "taste" or sample the lumenal environment
and respond appropriately.
INHIBITORY CONTROL
acid at less than pH 2 is a direct inhibitor of acid release
acid in duodenum releases secretin which inhibits gastric
secretion
fatty acids, peptides stimulate release of GIP (gastric inhibitory
polypeptide) and CCK (cholecystokinin)
Hormones of the Gut
Over 2 dozen hormones have been identified in various
parts of GI
All of them are peptides.
Many of them are also found in other tissues, especially
the brain.
Many act in a paracrine manner as well as being carried
in the blood as true hormones.
Their importance to health is uncertain as few known
deficiency disorders have been found for any of them.
Gastrin, secretin, CCK, gherelin, SS,, NPY, PYY3-36
Hormones of the Gut
Gastrin is a mixture of several peptides- most active -14 aa.
It is secreted by cells in the stomach and duodenum
It stimulates the exocrine cells of the stomach to secrete gastric
juice -a mixture of
HCl and the proteolytic enzyme pepsin.
Secretin-27 aa
It is secreted by cells in the duodenum when they are exposed to
the acidic contents of the emptying stomach.
It stimulates the exocrine portion of the pancreas to secrete
bicarbonate into the pancreatic fluid (thus neutralizing the acidity
of the intestinal contents).
Hormones of the Gut
Cholecystokinin (CCK)-A mixture of peptides, of which
an octapeptide (8 amino acids) is the most active.
It is secreted by cells in the duodenum and jejunum
when they are exposed to food.
Acts on on the gall bladder stimulating it to contract and
force its contents of bile into the intestine
on the pancreas stimulating the release of pancreatic
digestive enzymes into the pancreatic fluid.
CCK also acts on vagal neurons leading back to the
medulla oblongata which give a satiety signal (i.e.,
"that's enough food for now").
Hormones of the Gut
Somatostatin
This mixture of peptides acts on
the stomach where it inhibits the release of
gastrin
the duodenum where it inhibits the release of
secretin and cholecystokinin
the pancreas where it inhibits the release of
glucagon.
Taken together, all of these actions lead to a
reduction in the rate at which nutrients are
absorbed from the contents of the intestine.
Somatostatin is also secreted by the hypothalamus and the
pancreas
Hormones of the Gut
PYY3-36
Peptide YY3-36 contains 34 amino acids, many of
them in the same positions as those in
neuropeptide Y.
But the action of PYY3-36 is just the reverse of that
of NPY, being a potent feeding inhibitor.
It is released by cells in the intestine after meals.
The amount secreted increases with the number of
calories that were ingested.
Hormones of the Gut
PYY3-36 acts on
the hypothalamus to suppress appetite;
the pancreas to increase its exocrine secretion of digestive
juices;
the gall bladder to stimulate the release of bile.
The appetite suppression mediated by PYY3-36 works
more slowly than that of CCK and more rapidly than that
of leptin.
In a recent human study, volunteers given PYY3-36 were
less hungry and ate less food over the next 12 hours than
those who received saline (neither group knew what they
were getting).
Hormones of the Gut
Ghrelin-28 aa
is secreted by endocrine cells in the stomach,
especially when one is hungry;
acts on the hypothalamus to stimulate feeding;
This action counteracts the inhibition of feeding
by leptin and PYY3-36 .
Hormones of the Pancreas
Endocrine Pancreas and EXOCRINE
The pancreas houses two distinctly different tissues.
The bulk of its mass is exocrine tissue and associated ducts,
which produce an alkaline fluid loaded with digestive
enzymes which is delivered to the SI to digest foodstuffs.
Scattered throughout the exocrine tissue are several
hundred thousand clusters of endocrine cells which
produce the hormones insulin and glucagon, plus a few
other hormones.
Gross and Microscopic Anatomy of the Pancreas
The pancreas is a elongated organ, light tan or pinkish in color, that
lies in close proximity to the duodenum. It is covered with a very
thin connective tissue capsule which extends inward as septa,
partitioning the gland into lobules.
The image below shows a canine pancreas in relation to the stomach
and duodenum.
Pancreatic exocrine cells are arranged in grape-like clusters
called acini.
The exocrine cells themselves are packed with membrane-bound
secretory granules which contain digestive enzymes that are
exocytosed into the lumen of the acinus. From there these
secretions flow into larger and larger, intralobular ducts, which
eventually coalesce into the main pancreatic duct which drains
directly into the duodenum.
The pancreas is surrounded by a very thin connective tissue capsule
that invaginates into the gland to form septae, which serve as
scaffolding for large blood vessels.
Further, these septae divide the pancreas into distinctive lobules, as
can clearly be seen in the image of mouse pancreas below
The Acinus
exocrine pancreas is classified as a compound tubuloacinous gland. cells that synthesize and secrete digestive enzymes are arranged
in grape-like clusters called acini
In standard histologic sections it is difficult to discern their
characteristic shape. In the image of equine pancreas below, one
fairly-good cross section through an acinus is circled; note the
wedge-shaped cells arranged around a small lumen:
Pancreatic Ducts
Digestive enzymes from acinar cells ultimately are
delivered into the duodenum.
Secretions from acini flow out of the pancreas
through a tree-like series of ducts.
Duct cells secrete a watery, bicarbonate-rich fluid
which flush the enzymes through the ducts and
play a pivotal role in neutralizing acid within the
small intestine.
Pancreatic ducts are classified into 4 types
Pancreatic ducts are classified into 4 types
Intercalated ducts- receive secretions from acini.
Intralobular ducts - are seen within lobules and receive
secretions from intercalated ducts.
Interlobular ducts are found between lobules - vary
considerably in size - transmit secretions from intralobular
ducts to the major pancreatic duct.
main pancreatic duct receives secretion from interlobular
ducts and penetrates through the wall of the duodenum. In
some species, including man, the pancreatic duct joins the
bile duct prior to entering the intestine.
A low magnification image of equine pancreas (H&E stain) showing
a large interlobular duct in association with a pancreatic artery
(A) and vein (V). An intralobular duct (D) is seen on the right
side.
Control of Pancreatic Exocrine Secretion
As you might expect, secretion from the exocrine pancreas
is regulated by both neural and endocrine controls.
During interdigestive periods, very little secretion takes
place, but as food enters the stomach and, a little later,
chyme flows into the SI, pancreatic secretion is strongly
stimulated.
Like the stomach, the pancreas is innervated by the vagus
nerve, which applies a low level stimulus to secretion in
response to anticipation of a meal. However, the most
important stimuli for pancreatic secretion comes from
three hormones secreted by the enteric endocrine
system:
Cholecystokinin: made and secreted by
enteric endocrine cells located in the
duodenum. Its secretion is strongly
stimulated by the presence of partially
digested proteins and fats in the SI.
As chyme floods into the SI, CCK is released
into blood and binds to receptors on
pancreatic acinar cells, ordering them to
secrete large quantities of digestive
enzymes.
Secretin: also a product of endocrinocytes located
in the epithelium of the proximal small intestine.
secreted in response to acid in the duodenum,
which of course occurs when acid-laden chyme
from the stomach flows through the pylorus.
The predominant effect of secretin on the pancreas
is to stimulate duct cells to secrete water and
bicarbonate. As soon as this occurs, the enyzmes
secreted by the acinar cells are flushed out of the
pancreas, through the pancreatic duct into the
duodenum.
Gastrin: very similar to CCK, is secreted in large amounts
by the stomach in response to gastric distention and
irritation. In addition to stimulating acid secretion by
the parietal cell, gastrin stimulates pancreatic acinar
cells to secrete digestive enzymes.
Stop and think about this for a minute - control of
pancreatic secretion makes perfect sense. Pancreatic
secretions contain enzymes which are needed to digest
proteins, starch and triglyceride. When these substances
enter stomach, and especially the SI, they stimulate release
of gastrin and CCK, which in turn stimulate secretion of
the enzymes of destruction.
Pancreatic secretions are also the major
mechanism for neutralizing gastric acid in
the small intestine.
When acid enters the small gut, it stimulates
secretin to be released, and the effect of this
hormone is to stimulate secretion of lots of
bicarbonate. As proteins and fats are digested
and absorbed, and acid is neutralized, the
stimuli for CCK and secretin secretion
disappear and pancreatic secretion falls off.
Exocrine Secretions of the Pancreas
Pancreatic juice is composed of 2 secretory products
critical to proper digestion: digestive enzymes and
bicarbonate.
The enzymes are synthesized and secreted from the
exocrine acinar cells, whereas bicarbonate is secreted
from the epithelial cells lining small pancreatic ducts.
Digestive Enzymes
The pancreas secretes a magnificent battery of enzymes
that collectively have the capacity to reduce virtually all
digestible macromolecules into forms that are capable
of, or nearly capable of being absorbed. Three major
groups of enzymes are critical to efficient digestion:
PROTEASES
Digestion of proteins is initiated by pepsin in the stomach,
but the bulk of protein digestion is due to the pancreatic
proteases.
Several proteases are synthesized in the pancreas and
secreted into the lumen of the SI.
The two major pancreatic proteases are trypsin and
chymotrypsin, which are synthesized and packaged into
secretory vesicles as an the inactive proenzymes
trypsinogen and chymotrypsinogen.
PROTEASES
As you might anticipate, proteases are rather dangerous
enzymes to have in cells, and packaging of an inactive
precursor is a way for the cells to safely handle these
enzymes.
The secretory vesicles also contain a trypsin inhibitor
which serves as an additional safeguard should some of
the trypsinogen be activated to trypsin; following
exocytosis this inhibitor is diluted out and becomes
ineffective - the pin is out of the grenade.
proteases
Once trypsinogen and chymotrypsinogen are released into
the lumen of the SI, they must be converted into their
active forms in order to digest proteins.
Trypsinogen is activated by the enzyme enterokinase,
which is embedded in the intestinal mucosa.
Once trypsin is formed it activates chymotrypsinogen, as
well as additional molecules of trypsinogen. The net
result is a rather explosive appearance of active
protease once the pancreatic secretions reach the SI.
proteases
Trypsin and chymotrypsin digest proteins into peptides
and peptides into smaller peptides, but they cannot
digest proteins and peptides to single amino acids.
Some of the other proteases from the pancreas, for
instance carboxypeptidase, have that ability, but the
final digestion of peptides into amino acids is
largely the effect of peptidases in SI epithelial cells.
Pancreatic Lipase
major form of dietary fat is triglyceride, or neutral lipid.
A triglyceride molecule cannot be directly absorbed across the
intestinal mucosa.
Must first be digested into a 2-monoglyceride and 2 free fatty acids.
The enzyme that performs this hydrolysis is pancreatic lipase,
which is delivered into the lumen of the gut as a constituent of
pancreatic juice.
Sufficient quantities of bile salts must also be present in the lumen of
the intestine in order for lipase to efficiently digest dietary
triglyceride and for the resulting fatty acids and monoglyceride
to be absorbed. This means that normal digestion and absorption
of dietary fat is critically dependent on secretions from both the
pancreas and liver.
Pancreatic Lipase
Pancreatic lipase has recently been in the limelight
as a target for management of obesity.
The drug orlistat (Xenical) is a pancreatic lipase
inhibitor that interferes with digestion of
triglyceride and thereby reduces absorption of
dietary fat.
Clinical trials support the contention that
inhibiting lipase can lead to significant
reductions in body weight in some patients.
SIDE EFFECTS: The most common
side effects of orlistat are oily
spotting on underwear, flatulence,
urgent bowel movements, fatty or
oily stools, increased number of
bowel movements, abdominal pain
or discomfort, and inability to
hold back stool (incontinence).
From their web site (10/31/2007)
The active ingredient in alli attaches to some
of the natural enzymes in the digestive
system, preventing them from breaking
down about a quarter of the fat you eat.
Undigested fat cannot be absorbed and
passes through the body naturally. The
excess fat is not harmful.
In fact, you may recognize it in the toilet
as something that looks like the oil on
top of a pizza.
Amylase
The major dietary carbohydrate for many species is
starch, a storage form of glucose in plants.
Amylase is the enzyme that hydrolyses starch to maltose (a
glucose-glucose disaccharide), as well as the
trisaccharide maltotriose and small branchpoints
fragments called limit dextrins.
The major source of amylase in all species is pancreatic
secretions, although amylase is also present in saliva of
some animals, including humans.
Other Pancreatic Enzymes
In addition to the proteases, lipase and amylase, the
pancreas produces a host of other digestive
enzymes, including
ribonuclease,
deoxyribonuclease,
gelatinase
and elastase.
Bicarbonate and Water
Epithelial cells in pancreatic ducts are the source of the
bicarbonate and water secreted by the pancreas.
The mechanism underlying bicarbonate secretion is
essentially the same as for acid secretion from parietal
cells and is dependent on the enzyme carbonic
anhydrase.
In pancreatic duct cells, the bicarbonate is secreted into
the lumen of the duct and hence into pancreatic juice.
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. Even today, many diabetic
patients are treated with insulin
extracted from pig pancreases.
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.
Since insulin was
discovered in 1921,
it has become one
of the most
thoroughly
studied molecules in
scientific history.
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.
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:
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.
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 ATP:ADP 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.
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.
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.
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.
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-Sbonds. The alpha chains
are entirely extracellular and house insulin
binding domains, while the linked beta chains
penetrate through the PM.
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.
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.
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.
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
transporter
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.
Family of Glucose transport proteins
Uniporters-transfer 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 senstitive glucose transporter
GLUT5GLUT7
NOT to be confused with Na+glucose transporter in lumen
of SI which is a symporter, couple the movement of
glucose (against) with Na+ (with gradient)
GLUT1-glucose
transporter on the
plasma membrane
of every cell in your
body
Glucose
Glucose
= GLUT1
Glucose
Glucose
Cytoplasm
Nucleus
Glucose
GLUT4-a tissue specific insulin
sensitive glucose transporter
Glucose
= GLUT1
Glucose
= GLUT4
Glucose
Glucose
Glucose
Glucose
Glucose
Fat and Skeletal Muscle Cells have
GLUT4
Nucleus
INSULIN
Glucose
= GLUT1
= GLUT4
Insulin binds its cell
surface receptor
Glucose
Glucose
GLUT4 vesicles
travel
to PM
Nucleus
INSULIN
Glucose
= GLUT1
= GLUT4
Glucose
Glucose
Glucose
Glucose
Glucose
Lots of
glucose
inside cell
Nucleus
What tissue uses
the most
glucose??
Very important that
glucose is in cells
and not in blood
Hyperglycemiahigh blood glucose
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.
I- IR-IRS1-PI3K-AKT(PKB)-glut 4
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.
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 glucose6-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.
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.
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.
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.
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.
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.
INSULIN IN AN ANABOLIC HORMONE
From a whole body perspective, insulin has a fatsparing 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.
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+]
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
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"
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.
Diabetes is a
disease that is the
th
5 leading cause of
death in the USA
20.8 Million
Americans have
Diabetes (7% pop)
More have pre-diabetes
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)
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)
There are three categories of diabetes mellitus:
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 have been taken to solve this
problem:
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.
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.
Diagnostic Diabetes:
diagnosing maturity-onset
diabetes of the young
(MODY)
Diagnosing MODY
• What is MODY?
• Different types of MODY
- Glucokinase MODY
- Transcription factor MODY
• Separating from Type 1, Type 2 and
genetic syndromes
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 TF’s that modulate insulin transcription
Important to diagnose MODY
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
Diagnostic criteria for MODY
•Early-onset diabetes
•Not insulin-dependent
diabetes
•Autosomal dominant
Diagnosis of diabetes before 25
years in at least 1 & ideally 2
family members
Off insulin treatment or
measurable C-peptide at least 3
(ideally 5) years after diagnosis
inheritance
•Caused by a single gene
defect altering beta-cell
function, obesity unusual
Tattersall (QJM 1974)
Must be diabetes in one parent
(2 generations) and ideally a
grandparent or child ( 3
generations)
The Genetic Causes of MODY
MODY
75%
11%
14%
Transcription factors
MODY x
Glucokinase
(MODY2) 69%
3%
3% <1% <1%
HNF1 HNF4 HNF1b IPF1NeuroD1
(MODY3)
Frayling, et al Diabetes 2001
Two subtypes of MODY
Glucokinase and Transcription factor
Transcription
factor
(HNF-1)
20
16
Glucose
(mmol/l)
12
Glucokinase
8
.
Normal
4
0
0
20
40
60
80
100
Age (yr..)
Pearson, et al Diabetes 2001
Glucokinase and Transcription factor diabetes
MODY
Glucokinase
mutations
Transcription factor
mutations
(HNF-1, HNF-1b, HNF-4)
Onset at birth
Stable hyperglycemia
Diet treatment
Complications rare
Adolescence/young adult onset
Progressive hyperglycemia
1/3 diet, 1/3 other, 1/3 Insulin
Complications frequent
MODY
Non insulin dependent
Parents affected
Yes
1
Type 2
Type1
Yes
No
1-2
0-1
Age of onset < 25yr
Yes
unusual
Yes
Obesity
+/-
+++
+/-
Acanthosis
Nigricans
-
++
-
Racial groups
(Type 2 prevalence)
low
high
low
MODY
Diagnostic 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
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 K+channel 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.
Inherited Forms of Diabetes Mellitus
MODY GENES
like Mutant glucokinase
insulin gene TFs
K+channel of the b cell.
IR
some mitochondria genes
Of 20+ million
Americans with
Diabetes, only 10%
have type I
diabetes
Most diabetics
Have Type II
diabetes
T2DM or NIDDM
90% of diabetics in
industrialized
nations have Type
II diabetes
Type II diabetes
Defined by insulin
resistance
insulin resistanceinability to respond
to insulin
Hyperglycemia
causes retinopathy,
neuropathy, and
nephropathy
Type II diabetespatients are insulin
resistance so can’t
get glucose into
cells
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.
Type II diabetes
research related to
adipocytes
Adipocytes
accumulate
lipid
accumulate
lipid
insulin
insulinsensitive
sensitive
Endocrine
Endocrine
functions
function
Most patients with
Type II diabetes
are obese
> 85%
Strong link
between NIDDM
and Obesity
Many diseases due
to loss or defect of
one protein
Sickle Cell Anemia
Huntington’s Disease
Type I Diabetes
MODY
Many diseases due
to loss or defects in
many proteins
Heart Disease
Cancer
Type II Diabetes
Very hard to cure
diseases that have
multiple proteins
defective
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.
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
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.
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.
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.
WHY IS IT SO HARD
TO TREAT NIDDM
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.
 glucosidase inhibitors slow the absorption of
the starches you eat.
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.
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
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.
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).
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.
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."
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.
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.
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.
Not as many proteins as we thought.
Not surprising we have some "super-genes“like one
that encodes glucagon (increases glucose).
As it turns out, the gene for glucagon also codes
for at least 2 other hormones, called glucagonlike 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.
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).
Over a longer period, GLP-1 actually
increases the number of insulinproducing 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.
Finally, and perhaps most intriguingly, GLP-1
acts on the CNS to signal a sense of fullness so
that we don't overeat.
So isn’t 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.
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.
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.
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.
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 don’t need to change your diabetes regimen
unless your A1C is greater than 8 %