Gut Hormone and its implications in Glucose Homeostasis

林文玉醫師大里仁愛醫院新陳代謝內分泌科

Rates of Remission of Diabetes

AdjustableGastric Banding

Roux-en-YGastric Bypass

BiliopancreaticDiversion

>95%(Immediate)

48%(Slow)

84%(Immediate)

Mechanisms for T2DM Remissionafter Metabolic Surgery

Unclear

Anatomic rearrangement of the

gastrointestinal tract: GUT HORMONES

Effect of Gastric Bypass on Glucose Homeostasis

• Long-term positive effect on both the resolution of type 2 diabetes and in prevention new cases with type 2 diabetes.

• Longitudinal study of obese subjects with IGT, for 5 years, anti-obesity surgery lowered the rate of progression to type 2 DM by > 30 folds.

• Gastric bypass has profound positive effect on glucose homeostasis. Immediately after surgery, before BMI change, FBS and serum insulin lowered, and insulin resistance improved.

Diabetes, Vol. 55, Supplement 2, December 2006

Improvement of Glycemia after Metabolic Surgery is Independent of Body Weight Loss

GI peptides ( Gut Hormones )

• Ghrelin• GIP• Amylin• GLP-1, GLP-2• Oxymodulin• CCK and Gastrin• Peptide YY

Gut Hormones

Gut hormones signals the brain (hypothalamus) toachieve efficient nutrient digestion and absorption: gut-brain interaction

Ghrelin• Ghrelin is produced and released from enteroendocrine X/A-like cells in

the gastric mucosa. Ghrelin-containing neural cells are localized in the arcuate nucleus of the hypothalamus, a well-known center for appetite regulation, suggesting involvement of ghrelin in the regulation of feeding behavior.

• Ghrelin was discovered as the endogenous ligand for the orphan G protein–coupled growth hormone secretagogue receptor (GHS-R) and was demonstrated to specifically stimulate growth hormone release from rat pituitary cells in vitro as well as in vivo.

• The growth hormone secretagogue receptor appears in two distinct forms: the ghrelin receptor (GRLN) (formerly known as GHS-R 1a) has orexigenic and motility-stimulating properties, whereas GHS-R 1b is thought to be inactive or to have opposite effects.

Ghrelin• Several studies on rats and humans confirm that ghrelin initiates

food intake.• Circulating ghrelin levels are increased up to threefold in states of

negative energy balance, such as anorexia nervosa, starvation, and cachexia, and also after weight loss in obesity and are conversely decreased in conditions such as obesity, hyperglycemia,and feeding.

• Ghrelin also plays a role in the regulation of GI motility and acid secretion. Thus intravenous administration of ghrelin stimulates gastric motility and acid secretion in rats, and the effects are abolished by pretreatment with atropine or bilateral cervical vagotomy.

• Intravenous ghrelin increased gastric emptying correlated with sensations of hunger in normal-weight humans.

Ghrelin as counterregulatory hormone

• Ghrelin stimulates growth hormone, but also cortisol and adrenaline, three of the classic counterregulatory hormones. Results are less convincing for the fourth, glucagon.

• In the liver, ghrelin blocks gluconeogenesis and glycogen synthesis mediated by insulin, and, in adipocytes, ghrelin blocks the release of the insulin-sensitizing peptide adiponectin.

• Acylated bioactive ghrelin is also produced by pancreas islet ε-cells and may affect β-cells through a paracrine action. Blocking the function of endogenous ghrelin with the use of an antagonist for its receptor (the growth hormone secretagogue receptor) markedly lowered fasting glucose concentrations, attenuated glycemic excursion, and enhanced insulin responses during a glucose tolerance test, suggesting an inhibitory role for ghrelin in the control of insulin secretion.

Ghrelin as counterregulatory hormone

• Ghrelin levels are lower in obese subjects than in normal-weight subjects. A 3,000-kcal meal suppressed ghrelin less in obese subjects than did a 1,000-kcal meal in lean subjects.

• Dietary weight loss increases plasma levels of ghrelin, so one would expect plasma ghrelin to increase after GBP, but results are inconsistent ( vagal nerve fibers are cut during the procedure, interfering with the release of ghrelin mediated by vagal stimulation ).

Ghrelin: Central and peripheral role

• Central administration of ghrelin increases the rate at which white and brown adipose tissue, but not skeletal muscle, uses glucose.

• Intriguingly, ghrelin treatment of neonatal rats exposed to streptozotocin attenuated the development of diabetes and was associated with increased islet neogenesis, suggesting that ghrelin might have a proliferative or cytoprotective effect on β cells.

Amylin (Islet Amyloid Polypeptide (IAPP)

• A 37-residue peptide hormone. It is cosecreted with insulin from the pancreatic β-cells in a ratio of approximately 100:1.

• IAPP is processed from an 89-residue coding sequence. Proislet Amyloid Polypeptide (proIAPP,Proamylin, Amyloid Polypeptide Precursor, Proislet Protein) is produced in the pancreatic β-cells as a 67 amino acid, 7404 Dalton pro-peptide and undergoes post-translational modification including protease cleavage to produce amylin.

• The overall effect to slow the rate of appearance (Ra) of glucose from the meal is accomplished via coordinate slowing down gastric emptying, inhibition of digestive secretion [gastric acid, pancreatic enzymes, and bile ejection], and a resulting reduction in food intake.

• Appearance of new glucose is slowed down by inhibiting secretion of the gluconeogenic hormone glucagon.

Amylin (Islet Amyloid Polypeptide (IAPP)

• hIAPP slows gastric emptying, an action mediated by the central nervous system requiring an intact vagus nerve and area postrema.

• Nitric oxide (NO) is an important neurotransmitter in the gut and has been demonstrated to be a key physiological mediator of nonadrenergic noncholinergic (NANC) relaxation of gastrointestinal smooth muscle of the stomach, pylorus, and the duodenum, thereby facilitating gastric emptying by partially inhibiting pyloric and proximal duodenal contractions. 相反

• Slowing gastric emptying prevents from postmeal hyperglycemia.• Ileal break mechanism: This feedback is caloric load dependent, relates to

the length of small intestine exposed to nutrient, and regulates the overall rate of emptying to about 2–3 kcal/min ( GLP-1, GIP, Amylin ).

( nerve )

Ghrelin secretion is stimulated by cholecystokinin and gastrin, and it in turn enhances antropyloric coordination, a signal transmitted via the vagus nerve.

(ileal brake mechanism)

Pramlintide ( Amylin analogue )Trial in type 1 DM

Pramlintide ( Amylin analogue ) FDA Review

Pramlintide therapy results in a small but statistically significant reduction in HbA1c ( 0.5% ).

This reduction is associated with a two fold increase of severe hypoglycemia during the first month of treatment.

In addition, a four fold increase in hypoglycemia- associated MVAs and non-MVA trauma, was observed in patients with type 1 diabetes.

Amylin (Islet Amyloid Polypeptide (IAPP)

• ProIAPP has been linked to Type 2 diabetes and the loss of islet β-cells. Islet amyloid formation, initiated by the aggregation of proIAPP, may contribute to this progressive loss of islet β-cells. It is thought that proIAPP forms the first granules that allow for IAPP to aggregate and form amyloid which may lead to amyloid-induced apoptosis of β-cells.

• IAPP is co-secreted with insulin. Insulin resistance in Type 2 diabetes produces a greater demand for insulin production which results in the secretion of proinsulin. ProIAPP is secreted simultaneously, however, the enzymes that convert these precursor molecules into insulin and IAPP, respectively, are not able to keep up with the high levels of secretion, ultimately leading to the accumulation of proIAPP.

GIP ( glucose-dependent insulinotrophic peptide, 42 a.a. )

Produced by K cells in the stomach, duodenum and jenunum, released response to meal ingestion.

GIP secretion is stimulated by nutrient ingestion and the rate of nutrient absorption; fat is a potent stimulus for GIP secretion in humans, whereas carbohydrates are more effective secretagogues in other species.

GIP exerts its actions through the GIP receptor (GIPR), that inhibited gastric motility and potentiated insulin secretion.

GIP contains an alanine at position 2 and is a substrate for enzymatic inactivation by DPP4

GIP• The dominant action of GIP is the stimulation of glucose-dependent

insulin. This effect is mediated through elevation of intracellular cAMP concentration and inhibition of ATP-sensitive K+ channels, which together induces β cell exocytosis.

• GIP also promotes insulin biosynthesis and exhibits growth factor–like activity for β cells in vitro through activation of cAMP/protein kinase A–dependent, MAPK-dependent, and PI3K-dependent pathways.

• GIP also activates antiapoptotic pathways in a forkhead box O1–dependent (FOXO1-dependent) manner in islet cells in vitro, and continuous GIP infusion enhances β cell survival by reducing expression of the proapoptotic protein BAX and increasing expression of the antiapoptotic protein BCL2 in diabetic rodents in vivo.

GIP• GIPR is expressed by adipocytes.• Gipr–/– mice have reduced fat depots, use fat as a preferred energy

substrate, are resistant to diet-induced obesity, and have improved insulin sensitivity.

• GIPR-deficient ob/ob mice show reduced weight gain, improved glucose tolerance, and reduced adiposity relative to GIPR-sufficient ob/ob mice.

• Daily administration of the GIPR antagonist Pro(3)GIP to ob/ob mice reduced weight gain, improved fasting and postprandial glycemic excursion, and enhanced both insulin secretion and insulin sensitivity, independent of changes in food consumption and body weight.

• Hence GIP actions on the β cell improve insulin secretion, whereas GIP promotes energy storage and reduces insulin action via effects on adipocytes.

GIP• GIP is a potent incretin in normal humans, but the glucoregulatory actions

of exogenous GIP are diminished in diabetic subjects.• Defective GIP action and rapid and reversible homologous desensitization

of β cell GIPR in vitro: correlated with reduced levels of Gipr mRNA in pancreatic islets.

• It remains possible that successful treatment of diabetes with DPP4 inhibitors or other therapeutic agents might be associated with partial or complete restoration of GIP responsivity: potential of endogenous and exogenous GIP for the treatment of T2DM.

Schematic representation of the structure and processing of proglucagon. Panel A shows the processing pattern in the pancreatic A-cell. The peptides shown are GRPP (proglucagon 1–30), glucagon (proglucagon 33–61), IP-1 (proglucagon 64–69), and MPGF (proglucagon 72–158). MPGF is only partially processed to GLP-1 (proglucagon 72–107). Panel B shows the peptide processing in the intestinal L-cell to generate glicentin (proglucagon 1–69), truncated GLP-1 (tGLP-1, proglucagon 78–107), IP-2 (proglucagon 111–122), and GLP-2 (proglucagon 126–158). Glicentin is partially processed to GRPP and oxyntomodulin (proglucagon 33–69).

The proglucagon-derived peptides

① Proglucagon is synthesized in the α cells of the pancreas and is processed to bioactive glucagon, glicentin-related polypeptide (GRPP), intervening peptide 1 (IP-1), and the major proglucagon fragment (MPGF), with the formation of only minimal amounts of glucagon-like peptide 1 (GLP-1).

② The processing of proglucagon in the α cell of the pancreas differs from that of the L cell of the intestine due to different levels of the prohormone convertases, PC1 and PC2.

③ In the α cell of the pancreas, the major hormonal product is glucagon with only trace amounts of GLP-1 formed, due to the exclusive presence of PC2 in that cell.

④ On the other hand, higher levels of PC1 (but not PC2) in the L cells of the intestine leads to GLP-1 biosynthesis.

⑤ Glucagon acts to raise plasma glucose levels by stimulating hepatic glycogenesis and gluconeogenesis, whereas the bioactive form of GLP-1, GLP-17–36 amide, lowers plasma glucose levels by stimulating insulin release.

Proglucagon-derived peptides• Nutrient ingestion potently up-regulates intestinal expression of the gene

encoding proglucagon and the secretion of PGDPs, and a high-fiber diet protein hydrolysates, and short-chain fatty acids increase levels of mRNA encoding proglucagon in enteroendocrine L cells.

• Intestinal injury and resection are both associated with elevated circulating levels of PGDPs and increased levels of proglucagon mRNA in the remnant intestine.

• PGDP secretion by enteroendocrine L cells is stimulated by neural signals, peptide hormones such as GIP (in rodents but not humans), and direct nutrient contact.

GLP 1• GLP1 circulates as 2 equipotent forms, GLP1 (7-37) and GLP1(7-36)amide,

but most circulating GLP1 in humans is GLP1 (7-36 )amide.• Plasma levels of full-length GLP1 are typically within the 5- to 10-pM range

in the fasting state and increase to approximately 50 pM after meal ingestion.

• A small, but detectable, defect in meal-stimulated GLP1 secretion has been observed in subjects with obesity or T2DM about 60–120 minutes after food consumption.

• The half-life of circulating native bioactive GLP1 is less than 2 min, mostly because it is cleared by the kidney and degraded by DPP4.

Physiological effect of GLP 1

• Stimulates insulin secretion in a glucose dependent manner.• GLP1 increases transcription of the gene encoding insulin and enhances

both the stability of the mRNA encoding insulin and biosynthesis of insulin by mechanisms that involve pathways that are both dependent on and independent of cAMP and protein kinase A, as well as pathways that increase the intracellular concentration of Ca2+.

• GLP1 also improves β cell function by inducing increased expression of sulfonylurea receptor and inwardly rectifying K+ channel (KIR6.2) in β cells.

• It also prevents the down-regulation of mRNA encoding KIR6.2 and the down-regulation of ATP-sensitive K+ channel activity induced by high levels of glucose.

GLP1R antagonists, immunoneutralizing antisera, and Glp1r–/– mice.

• Elimination of GLP1 activity with GLP1-immunoneutralizing antisera or the GLP1R antagonist exendin 9–39, results in impaired glucose tolerance, and diminished glucose-stimulated insulin levels in both animals and humans.

• Basal GLP1 signaling in the fasting state is essential for regulation of glucose homeostasis; even low basal levels of GLP1 exert a tonic inhibitory effect on glucagon-secreting α cells.

• Glp1r–/–mice are glucose intolerant and have defective glucose-stimulated insulin secretion and fasting hyperglycemia.

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GLP-1 Increased Proliferation and InhibitedApoptosis of Beta Cells in Zucker Diabetic Rats

Study in Zucker diabetic rats that received a two-day infusion of GLP-1 or saline followed by a glucosetolerance test. Pancreatic sections were drawn to measure islet mass, β-cell proliferation, and apoptosis.

Adapted from Farilla L et al Endocrinology 2002;143:4397–4408.

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Effects of GLP-1 on Insulin and GlucagonShown to Be Glucose Dependent in Type 2 Diabetes

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Time (minutes)N=10 patients with type 2 diabetes. Patients were studied on two occasions. A regular meal and drugschedule was allowed for one day between the experiments with GLP-1 and placebo.

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GLP-1 stimulated insulinand suppressed glucagon.

When glucose levelsapproached normal,insulin levels declinedand glucagon was nolonger suppressed.

Infusion

Oxyntomodulin• Contains the 29–amino acid sequence of glucagon with an additional

8–amino acid carboxy-terminal extension.• Oxyntomodulin stimulates intestinal glucose uptake and insulin

secretion and inhibits gastric emptying, food intake, and meal-stimulated gastric acid secretion.

• Oxyntomodulin also induces satiety, inhibits food intake, and increases energy expenditure in humans.

• Although oxyntomodulin is a weak agonist of both GLP1R and the glucagon receptor, the anorectic actions of oxyntomodulin are blocked by the GLP1R antagonist exendin9-39 and are eliminated in the absence of a functional GLP1R.

GLP 2• GLP2 is a 33–amino acid peptide, secreted with GLP1 from

enteroendocrine cells in a nutrient-dependent manner. GLP2 rapidly induces hexose transport in jejunal basolateral membrane vesicles.

• The main biological consequence of exogenous GLP2 administration is expansion of the mucosal epithelium in the small bowel. The intestinotrophic actions of GLP2 have been demonstrated in rodents with intestinal injury and in humans with short bowel syndrome.

• Although acute GLP2 administration increased levels of plasma glucagon, triglycerides, and FFAs in the postprandial state, there is no evidence that acute or chronic GLP2 administration directly regulates insulin secretion or glucose homeostasis in humans.

CCK and gastrin• The classical actions of CCK and gastrin are focused on the control of gallbladder

contraction, satiety, and pancreatic and gastric acid secretion.• CCK has 2 main receptors, CCKAR (also known as CCK1R) and CCKBR (also known

as CCK2R), and it is CCKBR that mediates the effects of CCK on the control of glucose homeostasis by the pancreas.

• Both gastrin and CCK have been shown to stimulate glucagon release from human islets in vitro. However, CCK also stimulates insulin secretion in rodents in a glucose-dependent manner, and infusion of a form of CCK containing 8 amino acids (CCK-8) increases plasma insulin concentration and reduces glucose excursion following meal ingestion in normal and T2DM subjects.

• Both CCK and gastrin also exert proliferative effects on pancreatic β cells. CCK-8 promotes regeneration of β cells in rats after nicotinamide- and streptozotocin-induced β cell destruction. Gastrin promotes islet neogenesis in transdifferentiated pancreatic tissue in vivo.

CCK and gastrin• A combination of EGF and gastrin induces islet neogenesis in mice after

alloxan-induced β cell destruction, and in NOD mice with experimental autoimmune diabetes.

• The combination of EGF and gastrin promotes the formation of new β cells from pancreatic ductal epithelium in vitro and increases the number of functioning β cells after transplantation of human islets into NOD×SCID mice.

• Hence there is ongoing interest in the use of a combination of EGF and gastrin for regeneration of β cell mass, a concept that is currently being tested in human clinical trials in subjects with either T1DM or T2DM.

Peptide YY• PYY is a 36-amino acid, first isolated and characterized in 1980. PYY is

found throughout the human small intestine at tissue concentrations that increase distally, with the highest levels detected in the colon and rectum.

• PYY is released postprandially from the L cells of the gut, where it is co-stored with glucagon-like peptide-1 (GLP-1).

• Full-length PYY: delayed gastric emptying and reduced gastric secretion in man.

• The major form of PYY is the N-terminally truncated PYY3–36. The different forms of PYY have different receptor affinities, reflecting their different biological effects.

• PYY3–36 has high affinity only for the Y2 and a lesser affinity for Y1 and Y5 receptors.

Peptide YY• In 2002, peripheral administration of PYY3–36 at physiological doses

significantly reduced food intake in rodents and man.• Aged female mice lacking PYY have increased body weight and fat mass.

Male knockout mice are resistant to obesity but have higher fat mass and lower glucose tolerance than wild types when fed a high-fat diet.

• PYY3–36 may be less responsible for the postprandial reduction in food intake than regulating the size or timing of subsequent meals. PYY3–36 reduced food intake 2 h after the infusion had stopped, when circulating PYY had returned to basal levels, and continued to reduce food intake for the subsequent 12 h.

Peptide YY• Circulating PYY levels are lower in the obese, and food intake and body

weight were reduced in animals chronically treated with peripheral PYY3–36. Importantly, PYY3–36 can reduce food intake in obese volunteers, suggesting that obesity is not a PYY-resistant state.

• The effects of PYY3–36 on food intake are secondary to unpleasant side effects ( still contentious ).

• PYY acts at physiological levels to mediate postprandial satiety and only causes nausea at pathophysiological levels.

• Fasting levels of PYY are chronically elevated in several gastrointestinal diseases associated with appetite loss.

• It has been suggested that PYY might act as an endogenous defense against diarrhea.

Pancreatic peptide• PP is a 36-amino acid peptide released from the endocrine pancreas.• PP signals via the Y family of receptors and binds with greatest affinity to

the Y4 and Y5 receptors. PP may directly activate neurons in the area postrema, where Y4 receptors are highly expressed.

• Lipid digestion is required to generate the lipid-induced rise in circulating PP.• It was not until 2003 that iv infusion of PP at 10 pmol/kgmin levels to healthy

human volunteers reduced food intake.• The anorectic effects of iv PP administration in humans probably secondary

to delayed gastric emptying ( not consistent ).• A 90-min infusion of PP significantly reduced not only acute food intake at a

buffet meal 2 h after the infusion but also reduced food intake for the following 24 h.

Conclusion

Hormonal Changes after Bariatric Surgery

Extension Study