Published in Volume
117, Issue 1
(January 2, 2007)J Clin Invest.
Copyright © 2007, American Society for Clinical
The role of gut hormones in glucose homeostasis
1Banting and Best Diabetes Centre, University of Toronto, Toronto,
2Samuel Lunenfeld Research Institute, Department of
Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
Address correspondence to: Daniel J. Drucker, Samuel Lunenfeld Research
Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G
1X5, Canada. Phone: (416) 361-2661; Fax: (416) 361-2669; E-mail:
Published January 2, 2007
The gastrointestinal tract has a crucial role in the control of energy
homeostasis through its role in the digestion, absorption, and assimilation of
ingested nutrients. Furthermore, signals from the gastrointestinal tract are
important regulators of gut motility and satiety, both of which have
implications for the long-term control of body weight. Among the specialized
cell types in the gastrointestinal mucosa, enteroendocrine cells have important
roles in regulating energy intake and glucose homeostasis through their actions
on peripheral target organs, including the endocrine pancreas. This article
reviews the biological actions of gut hormones regulating glucose homeostasis,
with an emphasis on mechanisms of action and the emerging therapeutic roles of
gut hormones for the treatment of type 2 diabetes mellitus.
After food ingestion, the digestion and absorption of nutrients is associated with
increased secretion of multiple gut peptides that act on distant target sites to
promote the efficient uptake and storage of energy. These peptide hormones are
synthesized by specialized enteroendocrine cells located in the epithelium of the
stomach, small bowel, and large bowel and are secreted at low basal levels in the
fasting state. Plasma levels of most gut hormones rise briskly within minutes of
nutrient intake and fall rapidly thereafter, mainly because they are cleared by the
kidney and are enzymatically inactivated. Gut hormones activate neural circuits that
communicate with peripheral organs, including the liver, muscle tissue, adipose
tissue, and islets of Langerhans in the pancreas, to coordinate overall energy
intake and assimilation (Figure 1). Incretin
hormones (gastrointestinal hormones such as glucose-dependent insulinotropic
polypeptide [GIP] and glucagon-like peptide-1 [GLP1] that cause an increase in the
amount of insulin released from the β cells of the islets) augment the
magnitude of meal-stimulated insulin secretion from islet β cells in a
glucose-dependent manner (1). Incretin action
facilitates the uptake of glucose by muscle tissue and the liver while
simultaneously suppressing glucagon secretion by the α cells of the
islets, leading to reduced endogenous production of glucose from hepatic sources.
Actions of selected peptides on key tissues important for the control of
glucose homeostasis.Both GLP1 and GIP promote insulin biosynthesis, insulin secretion, and islet
β cell survival. GLP1 exerts additional actions important for
regulation of glucose homeostasis, including inhibition of glucagon
secretion and gastric emptying, and induction of satiety. GIP, but not GLP1,
directly engages receptors on adipocytes coupled to energy storage. In
contrast, CCK and gastrin do not seem to acutely regulate levels of plasma
glucose but might be important for stimulating the formation of new
β cells by stimulating islet neogenesis.
More recent studies have defined roles for gut hormones in the control of
β cell growth and survival. Both GIP and GLP1 increase levels of cAMP,
leading to expansion of β cell mass and resistance to apoptosis in
preclinical studies (2). Furthermore, the gut
hormones cholecystokinin (CCK) and gastrin activate pathways that promote islet
neogenesis and improve glucose homeostasis in experimental models of type 2 diabetes
mellitus (T2DM). The pleiotropic actions of gut hormones converging on control of
glucose homeostasis have fostered multiple efforts focused on mimicking gut hormone
action for the treatment of T2DM, and several of these strategies, principally
agonists of the GLP1 receptor (GLP1R) and inhibitors of the peptidase that
enzymatically inactivates GIP and GLP1, dipeptidyl peptidase-4 (DPP4; also known as
CD26), have recently been approved for the treatment of T2DM (3). Moreover, islet neogenesis therapy, using
combinations of peptide hormones and EGF, is also in early clinical trials for the
treatment of both type 1 diabetes mellitus (T1DM) and T2DM. This Review outlines our
current understanding of the physiology and therapeutic potential of gut hormone
action and highlights the emerging role of gut hormone–based approaches
for the treatment of T2DM.
Glucose-dependent insulinotropic polypeptide
Although GIP was originally identified as a 42–amino acid peptide that
inhibited gastric motility in dogs, it was subsequently shown to potentiate
glucose-stimulated insulin secretion (4, 5). GIP exerts its actions through the GIP
receptor (GIPR), a member of the 7–transmembrane domain, heterotrimeric
G protein–coupled glucagon receptor superfamily (6, 7). GIPR is
widely expressed in the pancreas, stomach, small intestine, adipose tissue, adrenal
cortex, lung, pituitary gland, heart, testis, vascular endothelium, bone, and brain
The sequence of GIP is highly conserved across species, with over 90% of the amino
acid sequence being identical between human, rat, mouse, porcine, and bovine GIP.
GIP is expressed predominantly in the stomach and the K cells of the proximal small
intestine. 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 contains an
alanine at position 2 and is a substrate for enzymatic inactivation by DPP4, an
aminopeptidase that cleaves dipeptides from the amino terminus of proteins
containing alanine or proline at position 2 (9). Therefore, the half-life of biologically active GIP is less than 2
minutes in rats (10, 11) and approximately 7 minutes and 5 minutes in healthy
individuals and patients with T2DM, respectively (11). GIP is cleared through the kidney, and plasma levels of GIP are
elevated in patients with uremia or chronic renal failure.
Biological actions of GIP. The dominant action of GIP is the stimulation of glucose-dependent insulin
secretion (Table 1). This effect is
mediated through elevation of intracellular cAMP concentration and inhibition of
ATP-sensitive K+ channels, which together induces β cell
exocytosis (12). 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 (13, 14). More recent data indicate that 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 (15).
Summary of GLP1 and GIP actions relevant to glucose control and the treatment
The biological importance of endogenous GIP for the control of glucose
homeostasis has been examined with the use of GIP antagonists,
immunoneutralization of GIP activity, and GIPR-deficient mice. Diminution or
elimination of GIP action using all 3 experimental approaches leads to defective
insulin secretion after oral glucose administration (16–18), consistent with a role for GIP as an essential incretin hormone. An
additional role for GIP, in the control of adipocyte biology, derives from
findings that 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 (18, 19).
Furthermore, GIPR-deficient ob/ob mice show reduced weight
gain, improved glucose tolerance, and reduced adiposity relative to
GIPR-sufficient ob/ob mice (19). Complementary evidence of a role for GIP in adipocyte biology and
insulin action arises from studies using GIPR antagonists (20). 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. Therefore, it
remains unclear whether activation or blockade of GIPR signaling would be an
effective strategy for the treatment of T2DM.
GIP action in human subjects. Circulating levels of basal and meal-stimulated GIP are normal in subjects with
T2DM. But one should note that early studies of the circulating levels of GIP
used assays that measured total immunoreactive GIP. However, as both GIP and
GLP1 are rapidly degraded at the amino terminus, it is important to use
amino-terminal–specific assays to discriminate between biologically
active and amino-terminally degraded forms of GLP1 and GIP in the circulation.
GIP is a potent incretin in normal humans, but the glucoregulatory actions of
exogenous GIP are diminished in diabetic subjects (21, 22).
Although the mechanisms underlying defective GIP action in experimental and
clinical diabetes remain poorly understood, the β cell GIPR
undergoes rapid and reversible homologous desensitization in vitro (23), and defective GIP action in Zucker
diabetic fatty rats has been correlated with reduced levels of Gipr
mRNA in pancreatic islets (24).
Whether intermittent bolus injections of GIP would be more effective at
stimulating insulin secretion than continuous GIP infusion in patients with T2DM
is a subject of ongoing investigation (25). Similarly, the contribution of endogenous GIP to the therapeutic
efficacy of DPP4 inhibitors remains uncertain. 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, and hence there remains interest in the therapeutic potential of
endogenous and exogenous GIP for the treatment of T2DM.
The proglucagon-derived peptides
Proglucagon-derived peptides (PGDPs) are generated by differential posttranslational
processing of the precursor proglucagon in the pancreas, intestine, and brain.
Although glucagon is the principal PGDP produced in α cells of the
islets, prohormone convertase 1 (PC1) generates glicentin, oxyntomodulin, GLP1, and
GLP2 from proglucagon in enteroendocrine L cells. The importance of PC1 processing
of proglucagon in enteroendocrine L cells is illustrated by the phenotype of
PC1-deficient mice, which exhibit multiple defects in prohormone processing,
including a lack of substantial amounts of mature bioactive GLP1 and GLP2. Although
most PGDP-expressing cells are located in the distal bowel and colon, there are also
cells in the more proximal regions of the small bowel that produce both GLP1 and
Nutrient ingestion potently upregulates intestinal expression of the gene encoding
proglucagon and the secretion of PGDPs, and a high-fiber diet (26), protein hydrolysates, and short-chain fatty acids
increase levels of mRNA encoding proglucagon in enteroendocrine L cells (27, 28).
Intestinal injury and resection are both associated with elevated circulating levels
of PGDPs and increased levels of proglucagon mRNA in the remnant
intestine (29, 30). 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 (31).
GLP1. GLP1 circulates as 2 equipotent forms, GLP17-37 and
GLP17-36amide (32–34), but most
circulating GLP1 in humans is GLP17-36amide (35). 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 (35, 36). 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 (36). Clearance of GLP1 has received considerable
attention because of the therapeutic potential of the peptide. The half-life of
circulating native bioactive GLP1 is less than 2 minutes (37, 38),
mostly because it is cleared by the kidney and degraded by DPP4.
GLP1 exerts multiple physiological actions leading to control of energy intake
and nutrient assimilation (1) (Table 1). The original physiological role
described for GLP1 was that of an incretin hormone that stimulates insulin
secretion in a glucose-dependent manner (39–41). GLP1 also
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+ (Table 1). 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 downregulation of
mRNA encoding KIR6.2 and the downregulation of ATP-sensitive K+
channel activity induced by high levels of glucose.
The physiological importance of endogenous GLP1 has been demonstrated using GLP1R
antagonists, immunoneutralizing antisera, and
Elimination of GLP1 activity with GLP1-immunoneutralizing antisera or the GLP1R
antagonist exendin9–39, which is a truncated form of the
lizard GLP1-related peptide exendin-4, results in impaired glucose tolerance,
and diminished glucose-stimulated insulin levels in both animals and humans
Furthermore, basal GLP1 signaling in the fasting state is essential for
regulation of glucose homeostasis, because infusion of exendin9-39
increases levels of fasting glucose and glucagon in human subjects,
demonstrating that even low basal levels of GLP1 exert a tonic inhibitory effect
on glucagon-secreting α cells (45). Similarly,
Glp1r–/– mice are glucose
intolerant and have defective glucose-stimulated insulin secretion and fasting
The insulinotropic and glucagonostatic effects of GLP1 depend on elevated levels
of plasma glucose, thereby reducing the likelihood that treatment of diabetic
subjects with GLP1R agonists would lead to hypoglycemia. In in vitro islet
studies, GLP1 confers glucose sensitivity to β cells and improves
the number of β cells able to respond to glucose. However, GLP1R
signaling is not essential for β cells to sense glucose in mouse
islets (47). The demonstration that GLP1
upregulates molecular components of the glucose-sensing system in β
cells (that is, glucose transporters, ATP-sensitive K+ channels, and
glucokinase) might provide a partial mechanism for understanding the effects of
GLP1 on the glucose responsiveness of β cells (48, 49).
Furthermore, short-term exposure to GLP1R agonists markedly improves
glucose-stimulated insulin secretion in patients with T2DM (50–52).
GLP1 also promotes the proliferation and neogenesis of β cells,
reduces β cell apoptosis, and increases differentiation of
exocrine-like cells toward a more differentiated β cell phenotype
Conversely, elimination of mouse GLP1R signaling is associated with reduced
numbers of large β cell clusters and alterations in α
cell topography (58). Furthermore,
following partial pancreatectomy,
Glp1r–/– mice exhibit a
reduced adaptive islet-regenerative response and greater hyperglycemia than
littermate controls (59).
Glp1r–/– mice are also
more sensitive to the cytotoxic and diabetogenic actions of streptozotocin
(60). The signal transduction
pathways whereby GLP1 mediates its proliferative effects have not been
completely defined but involve PI3K, EGFR transactivation, and p38 MAPK and
PKCζ (61, 62). Furthermore, GLP1 also activates a
transcriptional program critical for cell survival; and pancreatic and duodenal
homeobox gene 1 (PDX1), FOXO1, and insulin receptor substrate 2 (IRS2) have been
identified as essential downstream targets for GLP1R-dependent cytoprotection in
β cells (60, 63, 64). GLP1
also reduces the expression of proapoptotic genes, enhances glucose-stimulated
insulin secretion, and prevents apoptosis induced by high levels of glucose
and/or palmitate in human β cells through mechanisms involving AKT
Biological actions of glicentin, oxyntomodulin, and GLP2. Glicentin is a 69–amino acid PGDP that contains the
29–amino acid sequence of glucagon flanked by peptide extensions at
both the amino and the carboxyl terminus. Although secreted together with GLP1
and GLP2 from enteroendocrine L cells, glicentin has not been shown to regulate
glucose homeostasis. Oxyntomodulin also contains the 29–amino acid
sequence of glucagon with an additional 8–amino acid
carboxy-terminal extension. Oxyntomodulin stimulates intestinal glucose uptake
(67) and insulin secretion (68) 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 (69, 70). 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 (71) and are eliminated in the absence of a functional GLP1R (72). Therefore, it seems that many of the
pharmacological actions of oxyntomodulin represent heterologous activation of
related PGDP receptors.
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 (73). 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 (74, 75) and in humans with short bowel syndrome (76–78). Although acute GLP2 administration increased
levels of plasma glucagon, triglycerides, and FFAs in the postprandial state
(79), there is no evidence that acute
or chronic GLP2 administration directly regulates insulin secretion or glucose
homeostasis in humans (76).
GLP1R agonists and treatment of T2DM
Native bioactive GLP1 rapidly lowers plasma glucose in patients with T2DM (80–82), and a 3-week trial of preprandial subcutaneous GLP1 injections
improved postprandial glycemic control and reduced levels of glucagon in the plasma
of subjects with T2DM (83). Furthermore, the
improved β cell function, and lowered fasting and postprandial glucose
and hemoglobin A1c (HbA1c) levels observed after continuous subcutaneous GLP1
infusion for 6 weeks, were associated with modest weight loss and improved insulin
sensitivity (50). The first GLP1R agonist
approved for the treatment of T2DM was exendin-4, a naturally occurring GLP1-related
peptide isolated from the venom of the lizard Heloderma suspectum
(84). Exendin-4 exhibits 53%
amino acid identity to mammalian GLP1, is a potent GLP1R agonist (85), and is encoded by a gene distinct from that encoding
lizard GLP1 (86). The actions of synthetic
exendin-4 (exenatide) were examined in a series of phase III clinical trials in
which exenatide was given twice daily to patients with T2DM who had not achieved
satisfactory glucose control when taking metformin and/or a sulfonylurea. Exenatide
therapy substantially lowered HbA1c levels in all 3 treatment groups by about 0.9%
(87–89), with 34%–46% of patients achieving a
level of HbA1c less than 7% (87–89). The main side
effect was nausea, although that diminished with ongoing therapy. However, patients
receiving concomitant treatment with sulfonylureas also experienced increased rates
of mild to moderate hypoglycemia. Importantly, exenatide therapy resulted in modest
amounts of weight loss (87–89), with patients continuing on the drug for
82 weeks experiencing a mean weight loss of 4 kg (3). Although exendin-4–specific antibodies have been detected in
41%–49% of patients treated with exenatide (87–89), the antibodies do not correlate with the therapeutic response in most
Treatment with exenatide has also been compared with treatment with the insulin
analogue insulin glargine as adjunctive therapy for patients with T2DM not optimally
controlled by oral agents. Exenatide and insulin glargine produced comparable
reductions in HbA1c levels of approximately 1.1% after 26 weeks of therapy in
patients with a mean initial HbA1c level of 8.2%–8.3% (90). The incidence of gastrointestinal side effects was
substantially greater in patients treated with exenatide; however, exenatide therapy
was associated with a mean weight loss of 2.3 kg, whereas patients treated with
insulin glargine gained approximately 1.8 kg (90). A combination of exenatide and thiazolidinedione therapy also seems to
be effective in reducing HbA1c levels in the presence or absence of concomitant
A number of GLP1R agonists are also in clinical development, including liraglutide, a
DPP4-resistant analogue of GLP1 that binds noncovalently to albumin and is suitable
for administration just once a day because it has a longer half-life than exenatide
(51, 91). Liraglutide lowered HbA1c levels with no associated weight gain in a
12-week monotherapy study (92) and is
currently in phase III clinical trials. A long-acting release (LAR) form of
exenatide, designated exenatide LAR, is also under active investigation (93). When administered once a week, it showed
such promising efficacy in a pilot phase II clinical trial that it is currently
being compared with twice-daily doses of exenatide in a phase III clinical trial of
patients with T2DM. Taken together, the available evidence strongly suggests that
additional long-acting GLP1R agonists with unique pharmacokinetic profiles will
probably be approved for the treatment of T2DM.
Inhibiting DPP4 to enhance levels of GLP1 and GIP
DPP4 is widely expressed in many tissues and cell types and is catalytically active
in both its cell-associated membrane-bound form and its soluble circulating form.
DPP4 catalyzes the cleavage of GIP and GLP1 to bioinactive GIP3-42 and
GLP19-37 or GLP19-36amide, respectively. The importance of
DPP4 for glucose homeostasis is revealed in studies characterizing the phenotype of
DPP4-deficient rodents. DPP4-deficient rats exhibit elevated levels of GLP1 and
improved glucose tolerance (94), and
DPP4-deficient mice exhibit increased levels of plasma GLP1 and GIP (95), enhanced insulin secretion, improved glucose
tolerance, and resistance to diet-induced obesity.
Consistent with the observations in rodents lacking DPP4, DPP4 inhibitors lower blood
glucose, stimulate insulin secretion, and increase the levels of intact GLP1 and GIP
in preclinical models of diabetes (96, 97). Similarly, DPP4 inhibitors produce
substantial reduction of glycemia as well as decreased levels of circulating
glucagon and improvement in the insulin/glucose ratio in humans with T2DM (98, 99).
Two DPP4 inhibitors, vildagliptin and sitagliptin, have completed phase III clinical
trials, and their efficacy in both monotherapy and combination therapy regimens was
examined. Both vildagliptin and sitagliptin markedly lower HbA1c when used either as
initial monotherapy, or in combination with other oral antidiabetic agents such as
biguanides, thiazolidinediones, or sulfonylureas. The results of these phase III
clinical trials are now under regulatory review, and the first DPP4 inhibitor
(sitagliptin) was approved for the treatment of T2DM in the United States in October
2006. The contrasting actions of GLP1R agonists and DPP4 inhibitors are summarized
in Table 2. Although both types of agent
stimulate insulin and inhibit glucagon secretion, GLP1R agonists, but not DPP4
inhibitors, inhibit gastric emptying and promote satiety, leading to weight loss. In
contrast, DPP4 inhibitors seem to be extremely well tolerated without substantial
nausea or vomiting.
Contrasting actions of GLP1R agonists and DPP4 inhibitors
Other gut hormones that can impact glucose homeostasis
In addition to the well-known roles of incretin hormones in the control of glucose
homeostasis, several gut hormones produced in the stomach (ghrelin and gastrin) and
small and large bowel (cholecystokinin [CCK]) exhibit actions important for
glucoregulation and the treatment of T2DM.
CCK and gastrin. Although the classical actions of CCK and gastrin are focused on the control of
gallbladder contraction, satiety, and pancreatic and gastric acid secretion,
both peptides exert actions relevant to the control of glucose homeostasis. 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 (100). Although
glucose homeostasis seems normal in mice with an inactivating mutation in either
the gene encoding CCKAR or the gene encoding CCKBR, gastrin-deficient mice
exhibit mild hypoglycemia and a defective glucagon-secretory response to
insulin-induced hypoglycemia (101). 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 (102), and gastrin promotes islet
neogenesis in transdifferentiated pancreatic tissue in vivo (103). Furthermore, a combination of EGF and gastrin
induces islet neogenesis in mice after alloxan-induced β cell
destruction (104), and in NOD mice with
experimental autoimmune diabetes (105).
Of potential clinical relevance, 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 (106). Furthermore, genetic disruption of the gene
encoding CCK markedly increases the severity of diabetes in
ob/ob 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.
Ghrelin. Ghrelin is a 28–amino acid orexigenic hormone secreted from the
stomach in the fasting state whose actions promote food consumption in rodent
and human studies (107). Ghrelin also
seems to have both physiological and pharmacological actions on the endocrine
pancreas. Acylated bioactive ghrelin is produced in the recently described
ε cell in the pancreatic islets (108), potentially providing a local source of ghrelin that acts on
β cells of the islets. 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
(109). Conversely, exogenous ghrelin
increased glycemic excursion and reduced insulin secretion in rodents in vivo,
and ghrelin seems to directly inhibit insulin secretion in isolated islets in
vitro (109). Similar differences in the
function of endogenous and exogenous ghrelin have been observed in other
studies. For example, the physiological importance of endogenous ghrelin as an
inhibitor of insulin secretion was illustrated by the observation that
ghrelin-deficient ob/ob mice expressed lower amounts of
uncoupling protein 2 in their islets, secreted more insulin, and were more
sensitive to insulin than ghrelin-sufficient ob/ob mice (110). Conversely, central administration
of ghrelin increases the rate at which white and brown adipose tissue, but not
skeletal muscle, uses glucose (111).
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 (112).
Taken together, the available evidence suggests an emerging role for ghrelin in
the central (body weight) and peripheral (β cell function) control
of glucose homeostasis.
Gastrointestinal disorders affecting glucose homeostasis
Intestinal injury and inflammation. Enteroendocrine cell biology is often perturbed in the setting of intestinal
injury; however, there is limited information about changes in the actions of
gut peptides in patients with intestinal disease. Although reduction of
enteroendocrine cell mass and reduced secretion of insulinotropic peptides might
theoretically increase the risk of glucose intolerance, intestinal disorders are
often accompanied by loss of nutrient-absorptive capacity, diarrhea, anorexia,
and weight loss, which offset the clinical impact of incretin deficiency.
However, plasma levels of several gut peptides can be elevated in response to
different forms of intestinal inflammation and gut resection (113–115). Patients with extensive resection of the small and large bowel
exhibit substantial reductions in circulating levels of GLP2 after meal
ingestion, whereas preservation of the colon seems to be important for
maintaining levels of both GLP1 and GLP2 in adult human subjects. In contrast,
the colon seems to be less important for preservation of plasma levels of GLP2
in infants with nutrient malabsorption consequent to intestinal surgery.
Alteration of the normal anatomy of the gastrointestinal tract, as occurs
following gastric bypass surgery, can be associated with dysregulated gut
hormone secretion. Plasma levels of GLP1 and GIP are elevated in some patients
after gastric bypass; this perhaps contributes, together with weight loss and
enhanced insulin sensitivity, to the improved glucose tolerance observed in
subsets of these patients (116).
Similarly, postprandial elevations in levels of the anorectic peptide, peptide
YY, and GLP1 have been described in patients after Roux-en-Y gastric bypass
surgery, and this was associated with enhanced satiety, weight loss, and
improved glucose homeostasis (117, 118). A syndrome of postprandial
hyperinsulinemic hypoglycemia associated with pancreatic nesidioblastosis has
been described in several patients after gastric bypass (119, 120),
and some of these patients have markedly increased levels of plasma GLP1 in the
postprandial state (119). Although
patients with postprandial hyperinsulinemic hypoglycemia probably present with
combined abnormalities in the control of gastric emptying and an acquired defect
in β cell function manifesting as postprandial hypoglycemia, it
remains less clear whether this syndrome is causally related to changes in
levels of gut hormones, and it remains uncertain whether there are true changes
in β cell mass or nesidioblastosis in affected subjects (121).
Genetic disorders. An inactivating mutation in the gene encoding PC1 has been described in several
subjects (122). Although loss of PC1
action might be predicted to include relative deficiency of bioactive GIP and
GLP1, the glucose intolerance, intractable diarrhea, and malabsorption phenotype
in these individuals probably obscures the potential importance of loss of
incretin action in this setting. Similarly, although inactivating mutations in
the gene encoding the transcription factor neurogenin-3 cause profound loss of
gut endocrine cell populations in the small intestine, severe chronic
malabsorptive diarrhea was the clinical presentation in all 3 affected humans
In contrast, specific genetic polymorphisms in the gene encoding transcription
factor 7–like 2 (TCF7L2) are associated with an increased risk of
developing T2DM in 3 independent populations (124). Furthermore, inheriting 2 specific TCF7L2
variants, rs12255372 and rs7903146, has been associated with a relative
reduction in insulin secretion and an increased likelihood of progression from
impaired glucose tolerance to T2DM in the Diabetes Prevention Program study
(125). Although the precise
mechanisms linking TCF7L2 to control of β cell function and glucose
homeostasis remain unclear, this transcription factor seems to be important for
control of proglucagon gene expression, and therefore GLP1
production, in gut endocrine cells. Therefore, examination of whether reduced
levels of meal-stimulated GLP1 responses contribute an increased risk for the
development of T2DM in subjects with different TCF7L2 genotypes
Summary and future directions
The diverse actions of gut peptides in regulating the control of satiety, gut
motility, nutrient digestion and absorption, and disposal and storage of energy have
focused increasing interest on the therapeutic potential of these hormones for the
treatment of disorders of energy homeostasis. Considerable evidence supports an
essential biological role for endogenous GLP1 in the control of β cell
function, and clinical data demonstrating the efficacy of the first GLP1R agonist,
exenatide, are compelling. Notably, most antidiabetic agents are often associated
with weight gain over time, whereas exenatide therapy is frequently associated with
weight loss, an important clinical feature that differentiates GLP1R agonists from
all other available therapies for T2DM. The introduction of DPP4 inhibitors in the
clinic will provide an opportunity to enhance incretin action by single daily
administration of a well-tolerated orally available tablet, a feature appealing to
both physicians and many patients who might be reluctant to initiate injectable
therapies. Furthermore, there remains great interest in understanding whether 1 or
more gut hormones might be useful for β cell protection and/or
regeneration of new β cells for the treatment of T1DM, and clinical
trials using islet neogenesis therapy (in the form of a combination of gastrin and
EGF) might soon provide answers to these questions. Moreover, GLP2 is being
investigated for its ability to restore nutrient absorption and reduce mucosal
damage in the setting of short bowel syndrome and Crohn disease and might soon
represent the first reparative therapy available for patients with intestinal
injury. As most of these hormones are secreted transiently after nutrient ingestion
and then rapidly inactivated and cleared, there has been considerable interest in
the development of degradation-resistant peptide hormone agonists for the treatment
of human disorders. Given the actions of these gut peptides on cell proliferation
and survival, and the inherent potential immunogenicity of modified gut peptides,
the enthusiasm for the use of these new agents should be combined with ongoing
vigilance for potential adverse events as we begin to use these new agents for the
treatment of human disease.
D.J. Drucker is supported in part by a Canada Research Chair in Regulatory Peptides
and by operating grants from the Juvenile Diabetes Research Foundation, the Canadian
Institutes of Health Research, the Canadian Diabetes Association, the National
Cancer Institute of Canada, and the McLaughlin Center for Molecular Medicine.
Nonstandard abbreviations used: CCK, cholecystokinin; DPP4,
dipeptidyl peptidase-4; GIP, glucose-dependent insulinotropic polypeptide; GIPR,
GIP receptor; GLP, glucagon-like peptide; GLP1R, GLP1 receptor; HbA1c,
hemoglobin A1c; PC1, prohormone convertase 1; PGDP, proglucagon-derived peptide;
T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TCF7L2,
transcription factor 7–like 2.
Conflict of interest: D.J. Drucker has served as an advisor or
consultant within the past 12 months to Abbott Laboratories, Amgen Inc., Amylin
Pharmaceuticals Inc., Arisaph Pharmaceuticals Inc., Bayer, Chugai Inc.,
ConjuChem Inc., Eli Lilly Inc., GlaxoSmithKline, Glenmark Pharmaceuticals,
Johnson & Johnson, Merck Research Laboratories, Novartis
Pharmaceuticals, NPS Pharmaceuticals Inc., Phenomix Corp., Takeda, and
Transition Therapeutics Inc. D.J. Drucker holds no stock in these companies.
Citation for this article:J. Clin. Invest.117:24–32 (2007). doi:10.1172/JCI30076.
Drucker, D.J. 2006. The biology of incretin hormones. Cell Metab. 3:153-165.
Drucker, D.J. 2003. Glucagon-like peptides: regulators of cell proliferation,
differentiation, and apoptosis. Mol. Endocrinol. 17:161-171.
Riddle, M.C., Drucker, D.J. 2006. Emerging therapies mimicking the effects of amylin and
glucagon-like peptide 1. Diabetes Care. 29:435-449.
Dupre, J., Ross, S.A., Watson, D., Brown, J.C. 1973. Stimulation of insulin secretion by gastric inhibitory
polypeptide in man. J. Clin. Endocrinol. Metab. 37:826-828.
Pederson, R.A., Schubert, H.E., Brown, J.C. 1975. Gastric inhibitory polypeptide. Its physiologic release and
insulinotropic action in the dog. Diabetes. 24:1050-1056.
Usdin, T.B., Mezey, E., Button, D.C., Brownstein, M.J., Bonner, T.I. 1993. Gastric inhibitory polypeptide receptor, a member of the
secretin-vasoactive intestinal peptide receptor family, is widely
distributed in peripheral organs and the brain. Endocrinology. 133:2861-2870.
Mayo, K.E., et al. 2003. International Union of Pharmacology. XXXV. The glucagon receptor
family. Pharmacol. Rev. 55:167-194.
Yip, R.G., Boylan, M.O., Kieffer, T.J., Wolfe, M.M. 1998. Functional GIP receptors are present on adipocytes. Endocrinology. 139:4004-4007.
Mentlein, R., Gallwitz, B., Schmidt, W.E. 1993. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory
polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine
methionine and is responsible for their degradation in human serum. Eur. J. Biochem. 214:829-835.
Kieffer, T.J., McIntosh, C.H., Pederson, R.A. 1995. Degradation of glucose-dependent insulinotropic polypeptide and
truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl
peptidase IV. Endocrinology. 136:3585-3596.
Deacon, C.F., Nauck, M.A., Meier, J., Hucking, K., Holst, J.J. 2000. Degradation of endogenous and exogenous gastric inhibitory
polypeptide in healthy and in type 2 diabetic subjects as revealed using a
new assay for the intact peptide. J. Clin. Endocrinol. Metab. 85:3575-3581.
Gromada, J., et al. 1998. Glucagon-like peptide 1 (7-36) amide stimulates exocytosis in
human pancreatic beta-cells by both proximal and distal regulatory steps in
stimulus-secretion coupling. Diabetes. 47:57-65.
Trumper, A., et al. 2001. Glucose-dependent insulinotropic polypeptide is a growth factor
for beta (INS-1) cells by pleiotropic signaling. Mol. Endocrinol. 15:1559-1570.
Trumper, A., Trumper, K., Horsch, D. 2002. Mechanisms of mitogenic and anti-apoptotic signaling by
glucose-dependent insulinotropic polypeptide in beta(INS-1)-cells. J. Endocrinol. 174:233-246.
Kim, S.J., et al. 2005. GIP stimulation of pancreatic beta-cell survival is dependent
upon phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (PKB) signaling,
inactivation of the forkhead transcription factor Foxo1 and downregulation
of bax expression. J. Biol. Chem. 280:22297-22307.
Tseng, C.C., Kieffer, T.J., Jarboe, L.A., Usdin, T.B., Wolfe, M.M. 1996. Postprandial stimulation of insulin release by glucose-dependent
insulinotropic polypeptide (GIP). Effect of a specific glucose-dependent
insulinotropic polypeptide receptor antagonist in the rat. J. Clin. Invest. 98:2440-2445.
Baggio, L., Kieffer, T.J., Drucker, D.J. 2000. Glucagon-like peptide-1, but not glucose-dependent insulinotropic
peptide, regulates fasting glycemia and nonenteral glucose clearance in
mice. Endocrinology. 141:3703-3709.
Miyawaki, K., et al. 1999. Glucose intolerance caused by a defect in the entero-insular
axis: a study in gastric inhibitory polypeptide receptor knockout mice. Proc. Natl. Acad. Sci. U. S. A. 96:14843-14847.
Miyawaki, K., et al. 2002. Inhibition of gastric inhibitory polypeptide signaling prevents
obesity. Nat. Med. 8:738-742.
Gault, V.A., et al. 2005. Chemical ablation of gastric inhibitory polypeptide receptor
action by daily (Pro3)GIP administration improves glucose tolerance and
ameliorates insulin resistance and abnormalities of islet structure in
obesity-related diabetes. Diabetes. 54:2436-2446.
Nauck, M.A., et al. 1993. Preserved incretin activity of glucagon-like peptide 1 [7-36
amide] but not of synthetic human gastric inhibitory polypeptide in patients
with type-2 diabetes mellitus. J. Clin. Invest. 91:301-307.
Elahi, D., et al. 1994. The insulinotropic actions of glucose-dependent insulinotropic
polypeptide (GIP) and glucagon-like peptide-1 (7-37) in normal and diabetic
subjects. Regul. Pept. 51:63-74.
Fehmann, H.-C., Goke, R., Goke, B. 1995. Cell and molecular biology of the incretin hormones glucagon-like
peptide 1 and glucose-dependent releasing polypeptide. Endocr. Rev. 16:390-410.
Lynn, F.C., et al. 2001. Defective glucose-dependent insulinotropic polypeptide receptor
expression in diabetic fatty Zucker rats. Diabetes. 50:1004-1011.
Meier, J.J., et al. 2004. Stimulation of insulin secretion by intravenous bolus injection
and continuous infusion of gastric inhibitory polypeptide in patients with
type 2 diabetes and healthy control subjects. Diabetes. 53(Suppl. 3):S220-S224.
Reimer, R.A., McBurney, M.I. 1996. Dietary fiber modulates intestinal proglucagon messenger
ribonucleic acid and postprandial secretion of glucagon-like peptide-1 and
insulin in rats. Endocrinology. 137:3948-3956.
Tappenden, K.A., Thomson, A.B., Wild, G.E., McBurney, M.I. 1996. Short-chain fatty acids increase proglucagon and ornithine
decarboxylase messenger RNAs after intestinal resection in rats. JPEN J. Parenter. Enteral Nutr. 20:357-362.
Tappenden, K.A., McBurney, M.I. 1998. Systemic short-chain fatty acids rapidly alter gastrointestinal
structure, function, and expression of early response genes. Dig. Dis. Sci. 43:1526-1536.
Ulshen, M.H., et al. 1996. Increased ileal proglucagon expression after jejunectomy is not
suppressed by inhibition of bowel growth. Dig. Dis. Sci. 41:677-683.
Taylor, R.G., Beveridge, D.J., Fuller, P.J. 1992. Expression of ileal glucagon and peptide tyrosine-tyrosine genes.
Response to inhibition of polyamine synthesis in the presence of massive
small-bowel resection. Biochem. J. 286:737-741.
Brubaker, P.L., Anini, Y. 2003. Direct and indirect mechanisms regulating secretion of
glucagon-like peptide-1 and glucagon-like peptide-2. Can. J. Physiol. Pharmacol. 81:1005-1012.
Mojsov, S., Kopczynski, M.G., Habener, J.F. 1990. Both amidated and nonamidated forms of glucagon-like peptide I
are synthesized in the rat intestine and the pancreas. J. Biol. Chem. 265:8001-8008.
Orskov, C., Wettergren, A., Holst, J.J. 1993. Biological effects and metabolic rates of glucagonlike peptide-1
7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are
indistinguishable. Diabetes. 42:658-661.
Wettergren, A., Pridal, L., Wojdemann, M., Holst, J.J. 1998. Amidated and non-amidated glucagon-like peptide-1 (GLP-1):
non-pancreatic effects (cephalic phase acid secretion) and stability in
plasma in humans. Regul. Pept. 77:83-87.
Orskov, C., Rabenhoj, L., Wettergren, A., Kofod, H., Holst, J.J. 1994. Tissue and plasma concentrations of amidated and glycine-extended
glucagon-like peptide I in humans. Diabetes. 43:535-539.
Vilsboll, T., Krarup, T., Deacon, C.F., Madsbad, S., Holst, J.J. 2001. Reduced postprandial concentrations of intact biologically active
glucagon-like peptide 1 in type 2 diabetic patients. Diabetes. 50:609-613.
Hansen, L., Deacon, C.F., Orskov, C., Holst, J.J. 1999. Glucagon-like peptide-1-(7-36)amide is transformed to
glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the
capillaries supplying the L cells of the porcine intestine. Endocrinology. 140:5356-5363.
Deacon, C.F., et al. 1995. Both subcutaneously and intravenously administered glucagon-like
peptide 1 are rapidly degraded from the NH2-terminus in type II diabetic
patients and in healthy subjects. Diabetes. 44:1126-1131.
Kreymann, B., Williams, G., Ghatei, M.A., Bloom, S.R. 1987. Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet. 2:1300-1304.
Mojsov, S., Weir, G.C., Habener, J.F. 1987. Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the
glucagon gene is a potent stimulator of insulin release in the perfused rat
pancreas. J. Clin. Invest. 79:616-619.
Orskov, C., Holst, J.J., Nielsen, O.V. 1988. Effect of truncated glucagon-like peptide-1 [proglucagon-(78-107)
amide] on endocrine secretion from pig pancreas, antrum, and nonantral
stomach. Endocrinology. 123:2009-2013.
D’alessio, D.A., et al. 1996. Elimination of the action of glucagon-like peptide 1 causes an
impairment of glucose tolerance after nutrient ingestion by healthy baboons. J. Clin. Invest. 97:133-138.
Edwards, C.M., et al. 1999. Glucagon-like peptide 1 has a physiological role in the control
of postprandial glucose in humans: studies with the antagonist exendin 9-39. Diabetes. 48:86-93.
Wang, Z., et al. 1995. Glucagon-like peptide 1 is a physiological incretin in rat. J. Clin. Invest. 95:417-421.
Schirra, J., et al. 1998. Exendin(9-39)amide is an antagonist of glucagon-like
peptide-1(7-36)amide in humans. J. Clin. Invest. 101:1421-1430.
Scrocchi, L.A., et al. 1996. Glucose intolerance but normal satiety in mice with a null
mutation in the glucagon-like peptide receptor gene. Nat. Med. 2:1254-1258.
Flamez, D., et al. 1998. Mouse pancreatic beta cells exhibit preserved glucose competence
after disruption of the glucagon-like peptide 1 receptor gene. Diabetes. 47:646-652.
Wang, Y.H., et al. 1995. Glucagon-like peptide-1 affects gene transcription and messenger
ribonucleic acid stability of components of the insulin secretory system in
RIN 1046-38 cells. Endocrinology. 136:4910-4917.
Wang, Y., et al. 1997. Glucagon-like peptide-1 can reverse the age-related decline in
glucose tolerance in rats. J. Clin. Invest. 99:2883-2889.
Zander, M., Madsbad, S., Madsen, J.L., Holst, J.J. 2002. Effect of 6-week course of glucagon-like peptide 1 on glycaemic
control, insulin sensitivity, and beta-cell function in type 2 diabetes: a
parallel-group study. Lancet. 359:824-830.
Degn, K.B., et al. 2004. One week’s treatment with the long-acting
glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves
24-h glycemia and alpha- and beta-cell function and reduces endogenous
glucose release in patients with type 2 diabetes. Diabetes. 53:1187-1194.
Fehse, F., et al. 2005. Exenatide augments first- and second-phase insulin secretion in
response to intravenous glucose in subjects with type 2 diabetes. J. Clin. Endocrinol. Metab. 90:5991-5997.
Xu, G., Stoffers, D.A., Habener, J.F., Bonner-Weir, S. 1999. Exendin-4 stimulates both beta-cell replication and neogenesis,
resulting in increased beta-cell mass and improved glucose tolerance in
diabetic rats. Diabetes. 48:2270-2276.
Edvell, A., Lindstrom, P. 1999. Initiation of increased pancreatic islet growth in young
normoglycemic mice (Umea +/?). Endocrinology. 140:778-783.
Stoffers, D.A., et al. 2000. Insulinotropic glucagon-like peptide-1 agonists stimulate
expression of homeodomain protein IDX-1 and increase islet size in mouse
pancreas. Diabetes. 49:741-748.
Perfetti, R., Zhou, J., Doyle, M.E., Egan, J.M. 2000. Glucagon-like peptide-1 induces cell proliferation and
pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass
in the pancreas of old, glucose-intolerant rats. Endocrinology. 141:4600-4605.
Kim, J.G., et al. 2003. Development and characterization of a glucagon-like peptide
1-albumin conjugate: the ability to activate the glucagon-like peptide 1
receptor in vivo. Diabetes. 52:751-759.
Ling, Z., et al. 2001. Glucagon-like peptide 1 receptor signaling influences topography
of islet cells in mice. Virchows Arch. 438:382-387.
De Leon, D.D., et al. 2003. Role of endogenous glucagon-like peptide-1 in islet regeneration
following partial pancreatectomy. Diabetes. 5252:365-371.
Li, Y., et al. 2003. Glucagon-like peptide-1 receptor signaling modulates beta cell
apoptosis. J. Biol. Chem. 278:471-478.
Buteau, J., et al. 2001. Protein kinase Czeta activation mediates glucagon-like
peptide-1-induced pancreatic beta-cell proliferation. Diabetes. 50:2237-2243.
Brubaker, P.L., Drucker, D.J. 2004. Glucagon-like peptides regulate cell proliferation and apoptosis
in the pancreas, gut and central nervous system. Endocrinology. 145:2653-2659.
Park, S., et al. 2005. Exendin-4 uses Irs2 signaling to mediate pancreatic beta cell
growth and function. J. Biol. Chem. 281:1159-1168.
Buteau, J., Spatz, M.L., Accili, D. 2006. Transcription factor FoxO1 mediates glucagon-like peptide-1
effects on pancreatic beta-cell mass. Diabetes. 55:1190-1196.
Farilla, L., et al. 2003. Glucagon-like peptide 1 inhibits cell apoptosis and improves
glucose responsiveness of freshly isolated human islets. Endocrinology. 144:5149-5158.
Buteau, J., et al. 2004. Glucagon-like peptide-1 prevents beta cell glucolipotoxicity. Diabetologia. 47:806-815.
Collie, N.L., Zhu, Z., Jordan, S., Reeve, J.R. 1997. Oxyntomodulin stimulates intestinal glucose uptake in rats. Gastroenterology. 112:1961-1970.
Jarrousse, C., Bataille, D., Jeanrenaud, B. 1984. A pure enteroglucagon, oxyntomodulin (glucagon 37), stimulates
insulin release in perfused rat pancreas. Endocrinology. 115:102-105.
Wynne, K., et al. 2007. Oxyntomodulin increases energy expenditure in addition to
decreasing energy intake in overweight and obese humans: a randomised
controlled trial. Int. J. Obes. (Lond.)In press
Wynne, K., et al. 2005. Subcutaneous oxyntomodulin reduces body weight in overweight and
obese subjects: a double-blind, randomized, controlled trial. Diabetes. 54:2390-2395.
Dakin, C.L., et al. 2001. Oxyntomodulin inhibits food intake in the rat. Endocrinology. 142:4244-4250.
Baggio, L.L., Huang, Q., Brown, T.J., Drucker, D.J. 2004. Oxyntomodulin and glucagon-like peptide-1 differentially regulate
murine food intake and energy expenditure. Gastroenterology. 127:546-558.
Cheeseman, C.I., Tsang, R. 1996. The effect of gastric inhibitory polypeptide and glucagon like
peptides on intestinal hexose transport. Am. J. Physiol. Gastrointest. Liver Physiol. 271:G477-G482.
Boushey, R.P., Yusta, B., Drucker, D.J. 1999. Glucagon-like peptide 2 decreases mortality and reduces the
severity of indomethacin-induced murine enteritis. Am. J. Physiol. 277:E937-E947.
Boushey, R.P., Yusta, B., Drucker, D.J. 2001. Glucagon-like peptide (GLP)-2 reduces chemotherapy-associated
mortality and enhances cell survival in cells expressing a transfected GLP-2
receptor. Cancer Res. 61:687-693.
Jeppesen, P.B., et al. 2001. Glucagon-like peptide 2 improves nutrient absorption and
nutritional status in short-bowel patients with no colon. Gastroenterology. 120:806-815.
Jeppesen, P.B. 2003. Clinical significance of GLP-2 in short-bowel syndrome. J. Nutr. 133:3721-3724.
Jeppesen, P.B., et al. 2005. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant
glucagon-like peptide 2 analogue, improves intestinal function in short
bowel syndrome patients. Gut. 54:1224-1231.
Meier, J.J., et al. 2006. Glucagon-like peptide 2 stimulates glucagon secretion, enhances
lipid absorption, and inhibits gastric acid secretion in humans. Gastroenterology. 130:44-54.
Gutniak, M., Orskov, C., Holst, J.J., Ahren, B., Efendic, S. 1992. Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in
normal subjects and patients with diabetes mellitus. N. Engl. J. Med. 326:1316-1322.
Rachman, J., et al. 1996. Normalization of insulin responses to glucose by overnight
infusion of glucagon-like peptide 1(7-36)amide in patients with NIDDM. Diabetes. 45:1524-1530.
Rachman, J., Barrow, B.A., Levy, J.C., Turner, R.C. 1997. Near normalization of diurnal glucose concentrations by
continuous administration of glucagon-like peptide 1 (GLP-1) in subjects
with NIDDM. Diabetologia. 40:205-211.
Todd, J.F., Wilding, J.P., Edwards, C.M., Ghatei, M.A., Bloom, S.R. 1997. Glucagon-like peptide-1 (GLP-1): a trial of treatment in
non-insulin-dependent diabetes mellitus. Eur. J. Clin. Invest. 27:533-536.
Eng, J., Kleinman, W.A., Singh, L., Singh, G., Raufman, J.P. 1992. Isolation and characterization of exendin 4, an exendin 3
analogue from Heloderma suspectum venom. J. Biol. Chem. 267:7402-7405.
Goke, R., et al. 1993. Exendin-4 is a high potency agonist and truncated
exendin-(9-39)-amide an antagonist at the glucagon-like peptide
1-(7-36)-amide receptor of insulin-secreting β-cells. J. Biol. Chem. 268:19650-19655.
Chen, Y.E., Drucker, D.J. 1997. Tissue-specific expression of unique mRNAs that encode
proglucagon-derived peptides or exendin 4 in the lizard. J. Biol. Chem. 272:4108-4115.
Buse, J.B., et al. 2004. Effects of exenatide (Exendin-4) on glycemic control over 30
weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 27:2628-2635.
DeFronzo, R.A., et al. 2005. Effects of exenatide (exendin-4) on glycemic control and weight
over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 28:1092-1100.
Kendall, D.M., et al. 2005. Effects of exenatide (exendin-4) on glycemic control over 30
weeks in patients with type 2 diabetes treated with metformin and a
sulfonylurea. Diabetes Care. 28:1083-1091.
Heine, R.J., et al. 2005. Exenatide versus insulin glargine in patients with suboptimally
controlled type 2 diabetes: a randomized trial. Ann. Intern. Med. 143:559-569.
Harder, H., Nielsen, L., Tu, D.T., Astrup, A. 2004. The effect of liraglutide, a long-acting glucagon-like peptide 1
derivative, on glycemic control, body composition, and 24-h energy
expenditure in patients with type 2 diabetes. Diabetes Care. 27:1915-1921.
Madsbad, S., Schmitz, O., Ranstam, J., Jakobsen, G., Matthews, D.R. 2004. Improved glycemic control with no weight increase in patients
with type 2 diabetes after once-daily treatment with the long-acting
glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week,
double-blind, randomized, controlled trial. Diabetes Care. 27:1335-1342.
Gedulin, B.R., et al. 2005. Dose-response for glycaemic and metabolic changes 28 days after
single injection of long-acting release exenatide in diabetic fatty Zucker
rats. Diabetologia. 48:1380-1385.
Mitani, H., Takimoto, M., Hughes, T.E., Kimura, M. 2002. Dipeptidyl peptidase IV inhibition improves impaired glucose
tolerance in high-fat diet-fed rats: study using a Fischer 344 rat substrain
deficient in its enzyme activity. Jpn. J. Pharmacol. 88:442-450.
Marguet, D., et al. 2000. Enhanced insulin secretion and improved glucose tolerance in mice
lacking CD26. Proc. Natl. Acad. Sci. U. S. A. 97:6874-6879.
Ahren, B., Holst, J.J., Martensson, H., Balkan, B. 2000. Improved glucose tolerance and insulin secretion by inhibition of
dipeptidyl peptidase IV in mice. Eur. J. Pharmacol. 404:239-245.
Pederson, R.A., et al. 1998. Improved glucose tolerance in Zucker fatty rats by oral
administration of the dipeptidyl peptidase IV inhibitor isoleucine
thiazolidide. Diabetes. 47:1253-1258.
Ahren, B., et al. 2004. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains
insulin levels, and reduces glucagon levels in type 2 diabetes. J. Clin. Endocrinol. Metab. 89:2078-2084.
Ahren, B., et al. 2002. Inhibition of dipeptidyl peptidase IV improves metabolic control
over a 4-week study period in type 2 diabetes. Diabetes Care. 25:869-875.
Ahren, B., Holst, J.J., Efendic, S. 2000. Antidiabetogenic action of cholecystokinin-8 in type 2 diabetes. J. Clin. Endocrinol. Metab. 85:1043-1048.
Boushey, R.P., et al. 2003. Hypoglycemia, defective islet glucagon secretion, but normal
islet mass in mice with a disruption of the gastrin gene. Gastroenterology. 125:1164-1174.
Kuntz, E., Pinget, M., Damge, P. 2004. Cholecystokinin octapeptide: a potential growth factor for
pancreatic beta cells in diabetic rats. Jop. 5:464-475.
Rooman, I., Lardon, J., Bouwens, L. 2002. Gastrin stimulates beta-cell neogenesis and increases islet mass
from transdifferentiated but not from normal exocrine pancreas tissue. Diabetes. 51:686-690.
Rooman, I., Bouwens, L. 2004. Combined gastrin and epidermal growth factor treatment induces
islet regeneration and restores normoglycaemia in C57Bl6/J mice treated with
alloxan. Diabetologia. 47:259-265.
Suarez-Pinzon, W.L., Yan, Y., Power, R., Brand, S.J., Rabinovitch, A. 2005. Combination therapy with epidermal growth factor and gastrin
increases beta-cell mass and reverses hyperglycemia in diabetic NOD mice. Diabetes. 54:2596-2601.
Suarez-Pinzon, W.L., Lakey, J.R., Brand, S.J., Rabinovitch, A. 2005. Combination therapy with epidermal growth factor and gastrin
induces neogenesis of human islet beta-cells from pancreatic duct cells and
an increase in functional beta-cell mass. J. Clin. Endocrinol. Metab. 90:3401-3409.
Druce, M.R., et al. 2005. Ghrelin increases food intake in obese as well as lean subjects. Int. J. Obes. (Lond.) 29:1130-1136.
Prado, C.L., Pugh-Bernard, A.E., Elghazi, L., Sosa-Pineda, B., Sussel, L. 2004. Ghrelin cells replace insulin-producing beta cells in two mouse
models of pancreas development. Proc. Natl. Acad. Sci. U. S. A. 101:2924-2929.
Dezaki, K., et al. 2004. Endogenous ghrelin in pancreatic islets restricts insulin release
by attenuating Ca2+ signaling in beta-cells: implication in the glycemic
control in rodents. Diabetes. 53:3142-3151.
Sun, Y., Asnicar, M., Saha, P.K., Chan, L., Smith, R.G. 2006. Ablation of ghrelin improves the diabetic but not obese phenotype
of ob/ob mice. Cell Metab. 3:379-386.
Theander-Carrillo, C., et al. 2006. Ghrelin action in the brain controls adipocyte metabolism. J. Clin. Invest. 116:1983-1993.
Irako, T., et al. 2006. Ghrelin prevents development of diabetes at adult age in
streptozotocin-treated newborn rats. Diabetologia. 49:1264-1273.
Besterman, H.S., et al. 1982. Gut hormone release after intestinal resection. Gut. 23:854-861.
Besterman, H.S., et al. 1983. Gut hormones in inflammatory bowel disease. Scand. J. Gastroenterol. 18:845-852.
Xiao, Q., Boushey, R.P., Cino, M., Drucker, D.J., Brubaker, P.L. 2000. Circulating levels of glucagon-like peptide-2 in human subjects
with inflammatory bowel disease. Am. J. Physiol. 278:R1057-R1063.
Naslund, E., Backman, L., Holst, J.J., Theodorsson, E., Hellstrom, P.M. 1998. Importance of small bowel peptides for the improved glucose
metabolism 20 years after jejunoileal bypass for obesity. Obes. Surg. 8:253-260.
Le Roux, C.W., et al. 2006. Gut hormone profiles following bariatric surgery favor an
anorectic state, facilitate weight loss, and improve metabolic parameters. Ann. Surg. 243:108-114.
Morinigo, R., et al. 2006. Glucagon-like peptide-1, peptide YY, hunger, and satiety after
gastric bypass surgery in morbidly obese subjects. J. Clin. Endocrinol. Metab. 91:1735-1740.
Patti, M.E., et al. 2005. Severe hypoglycemia post-gastric bypass requiring partial
pancreatectomy: evidence for inappropriate insulin secretion and pancreatic
islet hyperplasia. Diabetologia. 4:2236-2240.
Service, G.J., et al. 2005. Hyperinsulinemic hypoglycemia with nesidioblastosis after
gastric-bypass surgery. N. Engl. J. Med. 353:249-254.
Meier, J.J., Butler, A.E., Galasso, R., Butler, P.C. 2006. Hyperinsulinemic hypoglycemia after gastric bypass surgery is not
accompanied by islet hyperplasia or increased beta-cell turnover. Diabetes Care. 29:1554-1559.
Jackson, R.S., et al. 2003. Small-intestinal dysfunction accompanies the complex
endocrinopathy of human proprotein convertase 1 deficiency. J. Clin. Invest. 112:1550-1560.
Wang, J., et al. 2006. Mutant neurogenin-3 in congenital malabsorptive diarrhea. N. Engl. J. Med. 355:270-280.
Grant, S.F., et al. 2006. Variant of transcription factor 7-like 2 (TCF7L2) gene confers
risk of type 2 diabetes. Nat. Genet. 38:320-323.
Florez, J.C., et al. 2006. TCF7L2 polymorphisms and progression to diabetes in the Diabetes
Prevention Program. N. Engl. J. Med. 355:241-250.