Modulation of ingestive behavior and gastrointestinal motility by ghrelin in diabetic animals and humans.
ABSTRACT Acyl ghrelin, a 28-amino acid peptide hormone, is the endogenous cognate ligand for the growth hormone secretagogue receptor. Ghrelin is involved in stimulating growth hormone release, eliciting feeding behavior, inducing adiposity and stimulating gastrointestinal motility. Ghrelin is unique for its post-translational modification of O-n-octanoylation at serine 3 through ghrelin O-acyltransferase, and is the only peripheral signal to enhance food intake. Plasma ghrelin levels manifest "biphasic changes" in diabetes mellitus (DM). In the early stage of DM, the stomach significantly increases the secretion of ghrelin into the plasma, and elevated plasma ghrelin levels are correlated with diabetic hyperphagic feeding and accelerated gastrointestinal motility. In the late stage of DM, plasma ghrelin levels may be lower, which might be linked with anorexia/muscle wasting, delayed gastrointestinal transit, and even gastroparesis. Therefore, the unique ghrelin system may be the most important player compared to the other hindgut hormones participating in the "entero-insular axis". Further studies using either knockdown or knockout of ghrelin gene products and ghrelin O-acyltransferase may unravel the pathogenesis of DM, and show benefits in combating this disease and metabolic syndrome.
- SourceAvailable from: Marco Anselmino
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ABSTRACT: Roux-en-Y gastric bypass (RYGB) is effective in controlling blood glucose in obese patients with type 2 diabetes (T2DM). The alterations of gut hormones involving in glucose metabolism may play an important role. Our aim was to explore the short-term effects of Billroth II gastrojejunostomy (a similar type of RYGB) on glucose metabolism and gut hormone modulations in nonobese patients with different levels of blood glucose tolerance. Twenty one nonobese gastric cancer patients with different levels of blood glucose tolerance were submitted to Billroth II gastrojejunostomy. Among them, seven had T2DM, seven with impaired glucose tolerance (IGT) and the other seven had normal glucose tolerance (NGT). Body weight, glucose parameters, responses of plasma glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and gastric inhibitory polypeptide (GIP) to 75 g glucose were measured at baseline and 3 months after surgery. Similar weight losses were observed in all groups. Blood glucose was reduced in T2DM and IGT patients. Fasting and 30-min plasma glucose were increased significantly in NGT. GLP-1 showed insignificant alterations in all groups. PYY was evaluated in T2DM and IGT but remained unchanged in the NGT group. Decreased fasting and AUC GIP were observed in patients with T2DM; however, fasting and 30-min GIP were increased in NGT patients. Billroth II gastrojejunostomy is effective in reducing blood glucose in nonobese patients with T2DM and IGT but could deteriorate early blood glucose in nonobese NGT in a 3-month time period. Variations of glucose and gut hormone changes in the three groups suggest a role of proximal intestine in the pathophysiology of T2DM.Archives of medical research 08/2013; · 1.88 Impact Factor
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ABSTRACT: Context: In obese patients with type 2 diabetes (T2DM), Roux-en-Y-gastric-bypass (RYGB) and sleeve gastrectomy (SLG) improve glycemic control. Objective: The objective of this study was to investigate the mechanisms of surgery-induced T2DM improvement and role of gastrointestinal hormones. Patients, Setting, and Intervention: In 35 patients with T2DM, we performed a mixed-meal test before and 15 days and 1 year after surgery (23 RYGB and 12 SLG). Main Outcome Measures: Insulin sensitivity, �-cell function, and amylin, ghrelin, PYY, pancreatic polypeptide (PP), glucagon, and glucagon-like peptide-1 (GLP-1) responses to the meal were measured. Results: T2DM remission occurred in 13 patients undergoing RYGB and in 7 patients undergoing SLG. Similarly in the RYGB and SLG groups, �-cell glucose sensitivity improved both early and long term (P � .005), whereas insulin sensitivity improved long term only (P � .006), in proportion to body mass index changes (P � .001). Early after RYGB, glucagon and GLP-1 responses to the meal increased, whereas the PP response decreased. At 1 year, PYY was increased, and PP, amylin, ghrelin, and GLP-1 were reduced. After SLG, hormonal responses were similar to those with RYGB except that PP was increased, whereas amylin was unchanged. In remitters, fasting GLP-1 was higher (P � .04), but its meal response was flat compared with that of nonremitters; postsurgery, however, the GLP-1 response was higher. Other hormone responses were similar between the 2 groups. In logistic regression, presurgery �-cell glucose sensitivity (positive, P � .0001) and mealstimulated GLP-1 response (negative, P � .004) were the only predictors of remission. Conclusions: RYGB and SLG have a similar impact on diabetes remission, of which baseline �-cell glucose sensitivity and a restored GLP-1 response are the chief determinants. Other hormonal responses are the consequences of the altered gastrointestinal anatomy.Journal of Clinical Endocrinology & Metabolism 09/2013; · 6.43 Impact Factor
J Chin Med Assoc • May 2010 • Vol 73 • No 5
© 2010 Elsevier Taiwan LLC and the Chinese Medical Association. All rights reserved.
Acyl ghrelin, a 28-amino acid peptide hormone, has
been identified as the endogenous cognate ligand for
the growth hormone secretagogue receptor (GHS-R).1
It was discovered by “reverse pharmacology”.1,2After
acyl ghrelin binds to GHS-R, it induces the release of
growth hormone.3Ghrelin is mainly synthesized in
specific endocrine cells, designated X/A-like cells, in the
gastric oxyntic glands.1,4Des-acyl ghrelin, the major
form of ghrelin in plasma,2may be acylated into acyl
ghrelin through ghrelin O-acyltransferase (GOAT) in
the stomach.5In addition to inducing growth hor-
mone release, acyl ghrelin enhances food intake, and
it is the only peripheral signal to increase meal size.6
Acyl ghrelin also stimulates adiposity, which is inde-
pendent of its hyperphagic effects.7Therefore, ghrelin
is an interesting molecule of high clinical relevance to
human obesity and metabolic syndrome.8With regard
to the gastrointestinal tract, acyl ghrelin accelerates gas-
tric emptying9and elicits gastroduodenal phase III-
like contractions10in rats.
Diabetes mellitus (DM) is a common clinical prob-
lem with increasing prevalence in the world. There
are 2 main types of DM. Both types are caused by
derangement of insulin’s function and activity in the
body.11Type 1 DM most often develops in childhood
or adolescence and causes hyperglycemia due to
insufficient production of insulin, while over 90% of
all DM cases are type 2 DM. DM may manifest many
Modulation of Ingestive Behavior and
Gastrointestinal Motility by Ghrelin in Diabetic
Animals and Humans
Chih-Yen Chen1,2*, Mineko Fujimiya3, Alessandro Laviano4, Full-Young Chang1,2,
Han-Chieh Lin1,2, Shou-Dong Lee1,2
1Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital and
2Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, R.O.C.;
3Department of Anatomy, Sapporo Medical University School of Medicine, Sapporo, Japan; and
4Department of Clinical Medicine, Sapienza University of Rome, Italy.
Acyl ghrelin, a 28-amino acid peptide hormone, is the endogenous cognate ligand for the growth hormone secretagogue
receptor. Ghrelin is involved in stimulating growth hormone release, eliciting feeding behavior, inducing adiposity and
stimulating gastrointestinal motility. Ghrelin is unique for its post-translational modification of O-n-octanoylation at serine
3 through ghrelin O-acyltransferase, and is the only peripheral signal to enhance food intake. Plasma ghrelin levels man-
ifest “biphasic changes” in diabetes mellitus (DM). In the early stage of DM, the stomach significantly increases the
secretion of ghrelin into the plasma, and elevated plasma ghrelin levels are correlated with diabetic hyperphagic feeding
and accelerated gastrointestinal motility. In the late stage of DM, plasma ghrelin levels may be lower, which might be
linked with anorexia/muscle wasting, delayed gastrointestinal transit, and even gastroparesis. Therefore, the unique
ghrelin system may be the most important player compared to the other hindgut hormones participating in the “entero-
insular axis”. Further studies using either knockdown or knockout of ghrelin gene products and ghrelin O-acyltransferase
may unravel the pathogenesis of DM, and show benefits in combating this disease and metabolic syndrome. [J Chin Med
Key Words: acyl ghrelin, diabetes mellitus, feeding, gastrointestinal motility, ghrelin O-acyltransferase
*Correspondence to: Dr Chih-Yen Chen, Division of Gastroenterology, Department of Medicine,
Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan, R.O.C.
● Received: February 3, 2010
● Accepted: April 16, 2010
gastrointestinal symptoms such as nausea, vomiting,
diarrhea, constipation, abdominal pain,12and even
hyperphagia.13,14Some symptoms can be attributed
to gastrointestinal dysmotility. Acyl ghrelin dose-
dependently inhibits insulin secretion in mice,15and
the relationship between ghrelin and glucose metabo-
lism has been previously discussed in our review.8A
recent study revealed that MK-677, an acyl ghrelin
mimetic, increases blood glucose and HbA1c levels in
healthy aged volunteers after 1 year of administration.16
Mice lacking acyl ghrelin demonstrate lower fasting
blood glucose, a better insulin-induced blood-glucose-
lowering effect, as well as higher plasma insulin and
lower blood glucose levels after intraperitoneal glucose
injection.17These acyl ghrelin knockout mice are pro-
tected against hyperinsulinemia and hyperglycemia
induced by a high-fat diet.18,19GHS-R knockout mice
exhibit lower blood glucose and serum insulin lev-
els,20,21and greater “metabolic flexibility” under diet-
induced metabolic stress.22Furthermore, acyl ghrelin
and GHS-R double knockout mice show a greater
blood glucose drop during 50% caloric restriction.21
Inhibition of GOAT8and GOAT knockout23is pro-
posed to have potential for anti-diabetic therapeutics.
Since acyl ghrelin plays an important role in inducing
food intake, eliciting gastroduodenal phase III-like
contractions, accelerating gastric emptying, and glucose
homeostasis, the present mini-review will focus on
the influence of ghrelin on ingestive behavior and gut
motility in diabetic animals and humans.
Regulation of Ghrelin Secretion and the
Influence of Ghrelin on Ingestive
Behavior in Diabetes
Ghrelin-immunoreactive cell density was found to be
reduced in type 1 non-obese and type 2 obese dia-
betic mice.24This observation could explain the slow
gastric emptying and slow intestinal transit encoun-
tered in human diabetic gastroenteropathy, based on
the fact that ghrelin has gastrointestinal prokinetic
effects. However, the correlation between ghrelin lev-
els and diabetic gastrointestinal dysmotility needs to
be further investigated before drawing a definite con-
clusion. In streptozotocin-induced diabetic rats, the
number of ghrelin-immunoreactive cells in the gastric
fundus is consistently found to be decreased, whereas
insulin treatment reversed this finding, implying that
a decrease in ghrelin-immunoreactive cells reflects a
decrease in ghrelin content in X/A-like cells but not a
decrease of ghrelin-producing cells.25Body weight and
serum insulin levels in the streptozotocin-induced
rats was decreased, whereas plasma acyl ghrelin and
total ghrelin levels and gastric preproghrelin mRNA
expression levels were significantly increased.25When
considered together, these results indicate that DM, a
negative energy balance condition, may enhance pre-
proghrelin mRNA expression in the stomach and
ghrelin secretion into the bloodstream. Acyl ghrelin
and des-acyl ghrelin have been demonstrated to inhibit
apoptosis and stimulate proliferation of pancreatic β
cell lines and human islets of Langerhans.26This finding
indicates that acyl ghrelin, as well as des-acyl ghrelin,
might protect β cells against apoptosis and increase β
cell survival. A subsequent study revealed that acyl
ghrelin treatment for 21 days increases pancreatic
insulin, pancreatic and duodenal homeobox 1 gene
(Pdx1) mRNA and the number of replicating cells in
streptozotocin-treated neonatal rats.27This finding
showed that acyl ghrelin and des-acyl ghrelin promote
regeneration of β cells in streptozotocin-treated ani-
mals. Collectively, in addition to the effects compen-
satory for the loss of body weight and serum insulin
levels in streptozotocin-induced rats, the increases in
plasma acyl ghrelin and total ghrelin levels and gastric
preproghrelin mRNA expression levels could prevent
further β cell damage and facilitate β cell regeneration.
Therefore, early administration of acyl ghrelin might
prevent or ameliorate the development of DM in
disease-prone subjects after β cell destruction.27
Uncontrolled DM is characterized by marked
behavioral perturbations, such as severe hyperphagia
and increased circulating ghrelin levels could cause
the development of diabetic hyperphagia.12,13In
streptozotocin-induced rats, plasma total ghrelin levels
are increased well before the onset of hyperphagic feed-
ing, supporting the hypothesis that increased ghrelin
signaling contributes to the stimulatory effect on food
intake in the early stage of DM.13A subthreshold dose
of intracerebroventricular administration of acyl ghrelin
was found to increase food intake by 357% in diabetic
rats compared with that in controls, indicating in-
creased behavioral sensitivity to acyl ghrelin in the
absence of the opposing effects of leptin and insulin in
DM.13Similarly, plasma fasting acyl ghrelin levels are
increased, whereas des-acyl ghrelin levels are decreased
in patients with obesity-related type 2 DM compared
with lean subjects.28Metformin therapy was found to
prolong the postprandial fall in total plasma ghrelin
levels, and thus had concomitant effects on appetite
in type 2 DM, contributing to its actions in promoting
weight loss and attenuating weight gain in these
patients.29A recent study demonstrated that barley
intake dose-dependently decreases plasma glucose and
insulin levels, whereas postprandial reduction of plasma
J Chin Med Assoc • May 2010 • Vol 73 • No 5
C.Y. Chen, et al
des-acyl ghrelin is suppressed by barley intake in a
dose-dependent manner, compared with glucose and
white rice.30Since des-acyl ghrelin might have anorex-
igenic31,32and insulin-mimetic33effects, either through
binding to an additional as-yet unidentified receptor8
or buffering33of acyl ghrelin’s actions, it has been
advocated that a combination of white rice and barley
may play a beneficial role in preventing and treating
human type 2 DM.30However, total plasma ghrelin
levels are negatively correlated with HbA1c in diabetic
patients, suggesting that long-term poor glycemic
control might impair ghrelin secretion,34and that
plasma ghrelin levels could be lower in the late stage
of DM. Consistently, fasting total plasma ghrelin levels
are decreased in insulin-resistant obese adults compared
with those in equally obese insulin-sensitive controls,
implying that insulin resistance and compensatory
hyperinsulinemia are independently associated with
suppression of ghrelin.35In addition, salivary levels of
acyl ghrelin and des-acyl ghrelin are similarly decreased
in obese diabetic subjects in comparison with non-
obese diabetic and healthy controls.36These alterations
may have a causal role in the development and severity
Impacts of Ghrelin on Gastrointestinal
Motility in Diabetes
Circulating acyl ghrelin levels fluctuate and the peaks
are associated with the gastric migrating motor complex
cycle,37indicating the indispensable role of endogenous
acyl ghrelin in modulating gastrointestinal motility.
Experiments with a streptozotocin-induced DM rat
model showed elevated plasma acyl ghrelin levels in
diabetic rats, and the elevated levels were accompanied
with accelerated solid gastric emptying and enhanced
postprandial antro-pyloric coordination.38Treatment
with anti-acyl ghrelin antibodies suppressed the accel-
erated gastric emptying and stimulated antro-pyloric
coordination. An elevated plasma acyl ghrelin level-
induced accelerated gastric emptying could predispose
to overeating, which would, in turn, exacerbate DM
in the diabetic early stage. In contrast, gastric emptying
becomes slow in the late stage of DM, and severe gas-
troparesis sometimes occurs. These findings have clini-
cal implications in the prevention for the development
of complications in DM, such as diabetic gastroparesis,
as in the late stage of DM. Sham feeding is characterized
by an increase in pancreatic polypeptide and ghrelin
in normal healthy humans, whereas changes in pan-
creatic polypeptide and ghrelin levels in diabetic gas-
troparesis are significantly less than those in normal
subjects.39Ghrelin subsequent to lunch significantly
decreases in patients without gastroparesis, but not in
gastroparetic patients.40Taken together, these findings
suggest that decreased plasma ghrelin levels are linked
with a slow gastrointestinal transit in the late stage of
DM. Loss of rhythmicity in ghrelin levels of diabetic
gastroparesis highlights the importance of integrity of
the neurohumoral-intestinal axis.32Patients with dia-
betic gastroparesis show no decrease of plasma acyl
ghrelin after glucose loading, unlike patients without
gastroparesis or healthy controls,41indicating that dia-
betic gastroparesis might be related to ghrelin-associated
neurohormonal abnormalities. Conceivably, intravenous
infusion of acyl ghrelin improves impaired gastric emp-
tying in patients with diabetic gastroparesis, and this
effect is independent of vagal tone.42Therefore, we
propose that analogs of acyl ghrelin may represent a
new class of prokinetic agents in future treatment for
patients with diabetic gastroparesis.
Conclusions and Future Perspectives
Obesity has replaced cigarette smoking as a severe new
burden on public health.43Obesity-related metabolic
syndrome, and DM, which negatively affects quality
of life and life expectancy, also cannot be overlooked.
Ghrelin is an exceptionally intriguing gastric hormone,
and actively participates in the modulation of ingestive
behavior and gastrointestinal motility. Plasma ghrelin
levels are elevated in the early stage of DM, which
correlates with hyperphagic feeding and accelerated
gastrointestinal motility. In contrast, plasma ghrelin
levels can be decreased in the late stages of DM, which
may be linked with poor appetite, body weight loss
and gastroparesis. The “entero-insular axis” has clinical
implications for the treatment of human DM.44Hind-
gut hormones, such as glucose-dependent insulin-
otropic polypeptide and glucagon-like peptide 1, hold
great promise. However, a recent study indicated that
selective bypass of the proximal intestine by an endo-
luminal sleeve, mimicking human Roux-en-Y gastric
bypass (the only way to resolve DM), reduces body
weight and food intake, and improves fasting hy-
perglycemia and glucose tolerance in rats with diet-
induced obesity.45These results suggest that the
“foregut theory” may be preferable to the “hindgut
theory”. Therefore, ghrelin deserves more attention in
the pathogenesis of DM. Two recent studies showed
that measurement of total ghrelin did not adequately
reflect acyl ghrelin and des-acyl ghrelin levels.46,47
Therefore, in contrast to the original concept, levels
of total ghrelin are not an ideal surrogate for those of
J Chin Med Assoc • May 2010 • Vol 73 • No 5
Ghrelin in diabetic food intake & GI motility
acyl ghrelin.8Further studies, particularly using state-
of-the-art techniques to separately measure acyl ghrelin,
des-acyl ghrelin, and obestatin, are necessary to clarify
the differential roles of ghrelin gene products in the
pathogenesis of DM. Ghrelin manifests “biphasically”
in DM. GOAT enhancers, acyl ghrelin and/or des-acyl
ghrelin, and GHS-R agonists, may rescue damaged β
cells and even endothelial progenitor cell function in
individuals with type 2 DM,48while GOAT inhibitors,
immunization against acyl ghrelin/acyl ghrelin anti-
bodies, des-acyl ghrelin, and GHS-R antagonists, may
be useful in the treatment of hyperphagic feeding and
accelerated gastrointestinal motility in the early stage
of DM. Conversely, GOAT enhancers, acyl ghrelin, as
well as its mimetics and GHS-R agonists, may provide
therapeutic targets in the treatment of diabetic anorexia-
cachexia and gastroparesis in the late stage of DM. In
conclusion, manipulating the unique GOAT/ghrelin/
GHS-R system may provide relevant approaches to
prevent, ameliorate and treat disturbance of ingestive
behavior and gastrointestinal motility in human DM.
This work was supported by intramural grants from
Taipei Veterans General Hospital (V95C1-096 and
V96C1-112), Taiwan and a grant from Sapporo
Medical University for the Promotion of Medical
Science in 2009, Japan. The authors also appreciate
the kind help of Chi Chin-Wen, PhD, Hung Mei-Whey,
MS, and the Clinical Research Core Laboratory,
Taipei Veterans General Hospital.
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Ghrelin in diabetic food intake & GI motility