1. 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

2. Rates of Remission of Diabetes
Adjustable Roux-en-Y Biliopancreatic
Gastric Banding Gastric Bypass Diversion
48% 84% >95%
(Slow) (Immediate) (Immediate)

3. Mechanisms for T2DM Remission
after Metabolic Surgery
 Unclear
 Anatomic rearrangement of the
gastrointestinal tract: GUT HORMONES

4. 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

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

6. GI peptides ( Gut Hormones )
• Ghrelin
• GIP
• Amylin
• GLP-1, GLP-2
• Oxymodulin
• CCK and Gastrin
• Peptide YY

7. Gut Hormones
Gut hormones signals the brain (hypothalamus) to
achieve efficient nutrient digestion and absorption: gut-brain
interaction

8. 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.

9. 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.

10. 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.

11. 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 ).

12. 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.

13. 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.

14. 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 ).

15. (ileal brake mechanism)
( nerve )
Ghrelin secretion is stimulated by cholecystokinin and gastrin, and it in turn enhances
antropyloric coordination, a signal transmitted via the vagus nerve.

16. Pramlintide ( Amylin analogue )
Trial in type 1 DM

17. 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.

18. 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.

19. 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

20. 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.

21. 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.

22. 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.

23. The proglucagon-derived peptides
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).

25.  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).
 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.
 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.
 On the other hand, higher levels of PC1 (but not PC2) in the L cells of the
intestine leads to GLP-1 biosynthesis.
 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.

26. 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.

27. 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.

28. 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.

29. 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.

30. The Incretin Effect in Persons without and with Type 2
Diabetes
Control Subjects Patients With Type 2 Diabetes
(n=8) (n=14)
0.6 0.6
80 80 The incretin effect
Incretin
is diminished
Effect 0.5 0.5
in type 2 diabetes.
IR Insulin, mU/L
IR Insulin, mU/L
60 60
0.4 0.4
nmol / L
nmol/L
40 0.3 40 0.3
0.2 0.2
20 20
0.1 0.1
0 0 0 0
0 60 120 180 0 60 120 180
Time, min Time, min
Oral glucose load Intravenous (IV) glucose infusion
Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.
Permission pending. 10

31. GLP-1 Increased Proliferation and Inhibited
Apoptosis of Beta Cells in Zucker Diabetic Rats
Beta-cell proliferation Beta-cell apoptosis
2.5 30
Proliferating beta cells (%)
25
Apoptotic beta cells (%)
2.0
1.4-fold 20
increase 3.6-fold
1.5 (p<0.05) decrease
15 (p<0.001)
1.0
10
0.5 5
0 0
Control GLP-1 Control GLP-1
treatment treatment
Study in Zucker diabetic rats that received a two-day infusion of GLP-1 or saline followed by a glucose
tolerance 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.
13

32. Effects of GLP-1 on Insulin and Glucagon
Shown to Be Glucose Dependent in Type 2 Diabetes
15.0 Placebo
(mmol/L) GLP-1 infusion
12.5
Glucose
10.0 *
7.5 * *
* *
5.0 * *
Infusion
With hyperglycemia
GLP-1 stimulated insulin
250
(pmol/L)
and suppressed glucagon.
Insulin
200
150
100 * * *
50 * * * * When glucose levels
*
approached normal,
insulin levels declined
Glucagon
(pmol/L)
20
15 and glucagon was no
10 * * * * longer suppressed.
5
0 60 120 180 240
Time (minutes)
N=10 patients with type 2 diabetes. Patients were studied on two occasions. A regular meal and drug
schedule was allowed for one day between the experiments with GLP-1 and placebo.
*p<0.05 GLP-1 vs. placebo
Adapted from Nauck MA et al Diabetologia 1993;36:741–744.
11

33. 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.

34. 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.

35. 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.

36. 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.

37. 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.

38. 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.

39. 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.

40. 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.

41. Conclusion

43. Hormonal Changes after Bariatric Surgery

44. Extension Study