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 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 non-peptide 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.

Polymorphisms of the motilin gene in inflammatory bowel disease.
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.

VIP is a 28 aa peptide structurally related to secretin.
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

A huge # of biological effects have been attributed to VIP.
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.

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".

In both pancreas and gut, 3 types of products are generated:
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)

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 insulin-dependent and NIDDM. For this reason, GLP-1 is being used in diabetes therapy.

GLP-1 is also synthesized in the brain, and may play a role in
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 contraction of gall bladder

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 C-terminus. Experimentally, it has glucagon-like 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 principal components of the enteric nervous system are 2 networks (or plexuses) of neurons-both 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.

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.

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.

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.

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 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.

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 best studied hormones are gastrin, CCK, and secretin
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.

This ATPase is magnesium-dependent, and not inhibitable by ouabain.
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.

Acetylcholine (muscarinic type receptor) Gastrin
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 hormone-secreting 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.

acid at less than pH 2 is a direct inhibitor of acid release
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)

Over 2 dozen hormones have been identified in various parts of GI
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

Gastrin is a mixture of several peptides- most active -14 aa.
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").

This mixture of peptides acts on
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.

the hypothalamus to suppress appetite;
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).

acts on the hypothalamus to stimulate feeding;
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 are classified into 4 types
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.

major form of dietary fat is triglyceride, or neutral lipid.
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:

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.

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.

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

The Insulin Receptor (IR) and Mechanism of Action
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 Insulin receptor substrate 1 or IRS-1.
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.

Uniporters-transfer one molecule at a time Facillitated diffusion
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 GLUT5- GLUT7 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 = GLUT1 Glucose Glucose Glucose Cytoplasm Glucose Nucleus

GLUT4-a tissue specific insulin sensitive glucose transporter

Fat and Skeletal Muscle Cells have GLUT4
Glucose = GLUT1 Glucose = GLUT4 Glucose Glucose Glucose Glucose Glucose Fat and Skeletal Muscle Cells have GLUT4 Nucleus

Insulin binds its cell surface receptor
= GLUT1 Glucose INSULIN = GLUT4 Insulin binds its cell surface receptor Glucose Glucose GLUT4 vesicles travel to PM Nucleus

Lots of glucose inside cell
= GLUT1 Glucose INSULIN = 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
Hyperglycemia-high 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 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.

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.

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 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 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 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.

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+]

Insulin made in the beta cells MAINTAIN GLUCOSE HOMEOSTASIS
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"

1798 A.D. John Rollo certifies excess sugar in the blood.
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 5th 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)

IDDM (also called Type 1 diabetes)
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)

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:

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 is caused by a change in a single gene.
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 Age of diagnosis

Diagnostic criteria for MODY
Diagnosis of diabetes before 25 years in at least 1 & ideally 2 family members Early-onset diabetes Not insulin-dependent diabetes Autosomal dominant inheritance Caused by a single gene defect altering beta-cell function, obesity unusual Off insulin treatment or measurable C-peptide at least 3 (ideally 5) years after diagnosis Must be diabetes in one parent (2 generations) and ideally a grandparent or child ( 3 generations) Tattersall (QJM 1974)

The Genetic Causes of MODY MODY
75% Transcription factors 11% MODY x 14% Glucokinase (MODY2) 3% HNF4 3% HNF1 <1% IPF1 <1% NeuroD1 69% HNF1 (MODY3) Frayling, et al Diabetes 2001

Two subtypes of MODY Glucokinase and Transcription factor
Transcription factor (HNF-1a) 20 16 12 Glucose Glucokinase (mmol/l) 8 . . Normal 4 20 40 60 80 100 Age (yr..) Pearson, et al Diabetes 2001

Glucokinase and Transcription factor diabetes
MODY Transcription factor mutations Glucokinase 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. Type 2. Type1 Non insulin dependent. Yes. Yes. No
MODY Type 2 Type1 Non insulin dependent Yes Yes No Parents affected Age of onset < 25yr Yes unusual Yes Obesity +/ /- Acanthosis Nigricans Racial groups low high low (Type 2 prevalence)

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

Defined by insulin resistance
Type II diabetes Defined by insulin resistance insulin resistance-inability to respond to insulin

Hyperglycemia causes retinopathy, neuropathy, and nephropathy

Type II diabetes-patients are insulin resistance so can’t get glucose into cells

Your blood carries the glucose to all the cells in your body.
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 sensitive insulin sensitive Endocrine functions Endocrine 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.

Exercise results in an increase in GLUT4 vesicles moving to the PM
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 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

Each type of pill helps lower blood glucose in a different way.
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.

Thiazolidinediones TZDs-make you more sensitive to insulin.
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 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 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.

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 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.

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.

Myth #1 You can catch diabetes from someone else.
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 %

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.

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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.

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Presentation on theme: "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."— Presentation transcript:

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