Glucagon-Like Peptide-2 Receptor Modulates Islet Adaptation to Metabolic Stress in the ob/ob Mouse

doi:10.1053/j.gastro.2010.05.006

Gastroenterology

Volume 139, Issue 3, September 2010, Pages 857-868

https://doi.org/10.1053/j.gastro.2010.05.006 Get rights and content

Background & Aims

Glucagon-like peptide-2 (GLP-2) is a gut hormone that increases gut growth, reduces mucosal cell death, and augments mesenteric blood flow and nutrient absorption. Exogenous GLP-2(1-33) also stimulates glucagon secretion and enhances gut barrier function with implications for susceptibility to systemic inflammation and subsequent metabolic dysregulation. We examined the importance of GLP-2 receptor (GLP-2R) signaling for glucose homeostasis in multiple models of metabolic stress, diabetes, and obesity.

Methods

Body weight, islet function, glucose tolerance, and islet histology were studied in wild-type, high-fat fed, lean diabetic, Glp2r^−/− and ob/ob:Glp2r^−/− mice.

Results

GLP-2 did not stimulate glucagon secretion from isolated pancreatic islets in vitro, and exogenous GLP-2 had no effect on the glucagon response to insulin-induced hypoglycemia in vivo. Glp2r^−/− mice exhibit no change in glycemia, and plasma glucagon levels were similar in Glp2r^−/− and Glp2r^+/+ mice after hypoglycemia or after oral or intraperitoneal glucose challenge. Moreover, glucose homeostasis was comparable in Glp2r^−/− and Glp2r^+/+ mice fed a high-fat diet for 5 months or after induction of streptozotocin-induced diabetes. In contrast, loss of the GLP-2R leads to increased glucagon secretion and α-cell mass, impaired intraperitoneal glucose tolerance and hyperglycemia, reduced β-cell mass, and decreased islet proliferation in ob/ob:Glp2r^−/− mice.

Conclusions

Our results show that, although the GLP-2R is not critical for the stimulation or suppression of glucagon secretion or glucose homeostasis in normal or lean diabetic mice, elimination of GLP-2R signaling in obese mice impairs the normal islet adaptive response required to maintain glucose homeostasis.

Section snippets

Peptides and Reagents

Exendin-4 was purchased from California Peptide Research Inc (Napa, CA). Humulin R insulin was from Eli Lilly (Toronto, ON). Synthetic human [Gly²] glucagon-like peptide-2 (h[Gly²]GLP-2) acetate was from Pepceuticals Ltd (Nottingham, United Kingdom). Native GLP-2 was purchased from Bachem Inc (Torrance, CA). STZ, Hanks' balanced salt solution (HBSS), Diprotin A, arginine, and TRI reagent were from Sigma (St. Louis, MO). The 45% kcal high-fat diet (HFD) was obtained from Research Diets (New

GLP-2 Does Not Stimulate Glucagon Secretion in Mice

We first assessed whether activation of GLP-2R signaling under conditions of hypoglycemia would further enhance glucagon secretion and lead to a more rapid or exaggerated glycemic recovery from insulin-induced hypoglycemia. Acute administration of the dipeptidyl peptidase 4–resistant GLP-2 receptor agonist h[Gly²]GLP-2³⁰ did not alter glucose excursion (Figure 1A) or plasma glucagon levels (Figure 1B) during an ITT in WT mice. In contrast, the GLP-1R agonist exendin-4 blunted the recovery of

Discussion

Most studies of GLP-2 action have focused on its intestinotrophic and cytoprotective actions in the gastrointestinal tract. More recent experiments have suggested that GLP-2R signaling may also influence glucose metabolism and insulin action. Studies in human beings have shown that acute exogenous administration of native GLP-2(1-33) was associated with increased circulating levels of plasma glucagon.21, 23 Exogenous administration of GLP-2(1-33) in healthy human volunteers increased

Acknowledgments

The authors thank Xiemin Cao for assistance with some experiments.

References (36)

L.L. Baggio et al.
Biology of incretins: GLP-1 and GIP
Gastroenterology
(2007)
B. Yusta et al.
Enteroendocrine localization of GLP-2 receptor expression
Gastroenterology
(2000)
C. Orskov et al.
GLP-2 stimulates colonic growth via KGF, released by subepithelial myofibroblasts with GLP-2 receptors
Regul Pept
(2005)
X. Guan et al.
GLP-2 receptor localizes to enteric neurons and endocrine cells expressing vasoactive peptides and mediates increased blood flow
Gastroenterology
(2006)
P.B. Jeppesen et al.
Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon
Gastroenterology
(2001)
J.J. Meier et al.
Glucagon-like peptide 2 stimulates glucagon secretion, enhances lipid absorption, and inhibits gastric acid secretion in humans
Gastroenterology
(2006)
B. Yusta et al.
ErbB signaling is required for the proliferative actions of GLP-2 in the murine gut
Gastroenterology
(2009)
A. Maida et al.
Differential importance of GIP versus GLP-1 receptor signaling for beta cell survival in mice
Gastroenterology
(2009)
Y. Li et al.
Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis
J Biol Chem
(2003)
B. Hartmann et al.
Immunoneutralization of endogenous glucagon-like peptide-2 reduces adaptive intestinal growth in diabetic rats
Regul Pept
(2002)

M.A. Nauck et al.

Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers

J Clin Endocrinol Metab

(2002)

R.S. Heller et al.

Insulinotropic glucagon-like peptide I receptor expression in glucagon-producing alpha-cells of the rat endocrine pancreas

Diabetes

(1997)

K. Moens et al.

Expression and functional activity of glucagon, glucagon-like peptide 1 and glucose-dependent insulinotropic peptide receptors in rat pancreatic islet cells

Diabetes

(1996)

J. de Heer et al.

Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas

Diabetologia

(2008)

D.J. Drucker et al.

Induction of intestinal epithelial proliferation by glucagon-like peptide 2

Proc Natl Acad Sci U S A

(1996)

C.I. Cheeseman et al.

The effect of gastric inhibitory polypeptide and glucagon like peptides on intestinal hexose transport

Am J Physiol Gastrointest Liver Physiol

(1996)

M. Wojdemann et al.

Glucagon-like peptide-2 inhibits centrally induced antral motility in pigs

Scand J Gastroenterol

(1998)

M. Wojdemann et al.

Inhibition of sham feeding-stimulated human gastric acid secretion by glucagon-like peptide-2

J Clin Endocrinol Metab

(1999)

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Analogues of several gastrointestinal peptide hormones have been developed into effective medicines for treatment of diseases such as type 2 diabetes mellitus (T2DM), obesity and short bowel syndrome (SBS). In this study, we aimed to explore whether the combination of glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) into a potent co-agonist could provide additional benefits compared to existing monotherapies.
A short-acting (GUB09-123) and a half-life extended (GUB09-145) GLP-1/GLP-2 co-agonist were generated using solid-phase peptide synthesis and tested for effects on food intake, body weight, glucose homeostasis, and gut proliferation in lean mice and in diabetic db/db mice.
Sub-chronic administration of GUB09-123 to lean mice significantly reduced food intake, improved glucose tolerance, and increased gut volume, superior to monotherapy with the GLP-2 analogue teduglutide. Chronic administration of GUB09-123 to diabetic mice significantly improved glycemic control and showed persistent effects on gastric emptying, superior to monotherapy with the GLP-1 analogue liraglutide. Due to the short-acting nature of the molecule, no effects on body weight were observed, whereas a marked and robust intestinotrophic effect on mainly the small intestine volume and surface area was obtained. In contrast to GUB09–123, sub-chronic administration of a half-life extended GUB09-145 to lean mice caused marked dose-dependent effects on body weight while maintaining its potent intestinotrophic effect.
Our data demonstrate that the GLP-1/GLP-2 co-agonists have effects on gut morphometry, showing a marked increase in intestinal volume and mucosal surface area. Furthermore, effects on glucose tolerance and long-term glycemic control are evident. Effects on body weight and gastric emptying are also observed depending on the pharmacokinetic properties of the molecule. We suggest that this novel co-agonistic approach could exemplify a novel concept for treatment of T2DM or SBS.
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The role of the gastrointestinal (GI) tract in energy homeostasis through the digestion and absorption of carbohydrates, and the production of incretin hormones remains well recognized in recent years. Studying the functional changes of the GI system following bariatric surgery, particularly involving the secretion of incretin hormones has led into understanding their interaction with areas of the brain to regulate metabolism and energy balance. In Type 2 Diabetes Mellitus (T2DM) and obesity, this homeostatic balance is disrupted, either through alterations in the levels of these hormones or through resistance to their actions. Although bariatric surgery is an effective treatment for T2DM and obesity, it cannot be applied to most patients. Hence, recapitulation of the changes of incretin hormone secretion after bariatric surgery in the post Glucagon-like peptide 1 (GLP-1) analogue era remains an attractive area for further research and the development of new treatments for T2DM and obesity.
Glucagon-like peptide 2 (GLP-2) is a proglucagon-derived peptide produced by intestinal L-cells and by cells within the brainstem and other areas of the central nervous system. GLP-2 is implicated in regulation of energy absorption and maintenance of GI mucosal structure but as recent evidence suggests may also have a beneficial effect in glucose homeostasis, particularly in states associated with increased energy uptake such as obesity.
Differential expression of glucagon-like peptide-2 (GLP-2) is involved in pancreatic islet cell adaptations to stress and beta-cell survival
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Thus, in terms of the limited information available, GLP-2 receptor knockout mice present with normal glucose homeostasis and islet architecture [4]. However, GLP-2 receptor knockout in severely diabetic ob/ob mice leads to increased alpha-, and reduced beta-cell masses, resulting in a deterioration of glucose tolerance, implying that GLP-2 modulates islet adaptations to metabolic stress [4]. Finally, in high fat fed diabetic mice administration of the GLP-2 receptor inhibitor, GLP-2(3–33), impairs glucose tolerance and insulin sensitivity, whereas the long-acting GLP-2 agonist, (Gly2)GLP-2, improves glucose tolerance and increases beta-cell mass [6].
Recent studies have confirmed that locally released proglucagon derived gene products, other than glucagon, have a major influence on pancreatic endocrine function. We assessed the impact of glucagon-like peptide-2 (GLP-2) on beta-cell secretory function, proliferation and apoptosis, as well as glucose tolerance, feeding behaviour and islet adaptions to chemically-induced insulin deficiency and resistance. The GLP-2 receptor was evidenced on cultured rodent and human beta-cells, rodent alpha-cells and isolated mouse islets. GLP-2 had no effect on insulin secretion from beta-cells, or isolated mouse islets. In vivo, GLP-2 administration significantly (P < 0.05 to P < 0.01) decreased food intake in mice. Conversely, GLP-2 had no discernible effects on glucose disposal or insulin secretion. As expected, streptozotocin treatment decreased and hydrocortisone increased beta-cell mass in mice. GLP-2 was visualised in mouse islets and intestinal L-cells. Islet GLP-2 co-localisation with glucagon was significantly decreased (P < 0.01) by both streptozotocin and hydrocortisone. In contrast, both interventions increased (P < 0.05) co-localisation of GLP-2 with somatostatin. Interestingly, GLP-2 positive cells were reduced (P < 0.05) in the intestines of streptozotocin, but not hydrocortisone, treated mice. Further in vitro investigations revealed that GLP-2 protected rodent and human 1.1B4 beta-cells against streptozotocin induced DNA damage. Furthermore, GLP-2 augmented (P < 0.05) BRIN BD11 beta-cell proliferation, but was less efficacious in 1.1B4 cells. These data highlight the involvement of GLP-2 receptor signalling in the adaptations to pancreatic islet cell stress.
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The main biological actions of GLP-2 are related to the regulation of energy absorption and maintenance of mucosal morphology and integrity of the intestine [33], therefore GLP-2 analogue development has been addressed for the treatment of gastrointestinal disease, such as short bowel syndrome, inflammatory bowel disease and chemotherapeutically-induced mucositis [10,50,77]. However, although GLP-2 has not been reported to modulate insulin secretion [58,67], recent data have provided evidence for beneficial effects of GLP-2 on glucose metabolism, particularly in obese mice [3,9,11,15,22,36,68]. This review provides a brief overview on physiological effects of GLP-2 and highlights biological actions related to energy homeostasis.
Glucagon like peptide-2 (GLP-2) is a gastrointestinal hormone released from enteroendocrine L-type cells together with glucagon like peptide-1 in response to dietary nutrients. GLP-2 acts through a specific receptor, the GLP-2 receptor, mainly located in the gut and in the brain. Classically, GLP-2 is considered a trophic hormone involved in the maintenance of intestinal epithelial morphology and function. This role has been targeted for therapies promoting repair and adaptive growth of the intestinal mucosa. Recently, GLP-2 has been shown to exert beneficial effects on glucose metabolism specially in conditions related to increased uptake of energy, such as obesity. Several actions of GLP-2 are related to a positive energy balance: GLP-2 increases not only the absorptive surface, but also expression and activity of epithelial brush-border nutrient transporters and digestive enzymes, intestinal blood flow, postprandial chylomicron secretion and it inhibits gastrointestinal motility, providing the opportunity to increase absorption of nutrients. Other actions, including anorexigenic effects, appear in opposition to the energy intake. In this review, we discuss the GLP-2 functions related to energy homeostasis. GLP-2 could be considered an hormone causing positive energy balance, which, however has the role to mitigate the metabolic dysfunctions associated with hyper-adiposity.
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Numerous endocrine cell subtypes exist within the intestinal mucosa and produce peptides contributing to the regulation of critical physiological processes including appetite, energy metabolism, gut function, and gut health. The mechanisms of action and the extent of the physiological effects of these enteric peptides are only beginning to be uncovered. One peptide in particular, glucagon-like peptide 2 (GLP-2) produced by enteroendocrine L cells, has been fairly well characterized in rodent and swine models in terms of its ability to improve nutrient absorption and healing of the gut after injury. In fact, a long-acting form of GLP-2 recently has been approved for the management and treatment of human conditions like inflammatory bowel disease and short bowel syndrome. However, novel functions of GLP-2 within the gut continue to be demonstrated, including its beneficial effects on intestinal barrier function and reducing intestinal inflammation. As knowledge continues to grow about GLP-2's effects on the gut and its mechanisms of release, the potential to use GLP-2 to improve gut function and health of food animals becomes increasingly more apparent. Thus, the purpose of this review is to summarize: (1) the current understanding of GLP-2's functions and mechanisms of action within the gut; (2) novel applications of GLP-2 (or stimulators of its release) to improve general health and production performance of food animals; and (3) recent findings, using dairy calves as a model, that suggest the therapeutic potential of GLP-2 to reduce the pathogenesis of intestinal protozoan infections.
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: Conflicts of interest The authors disclose the following: D.J.D. is a party to a GLP-2 licensing agreement with the University of Toronto, University Health Network, and NPS Pharmaceuticals Inc. The remaining authors disclose no conflicts.

: Funding These studies were supported in part by CIHR grants MOP-14799 and MOP-93749. J.B. is supported by a Canadian Diabetes Association Doctoral Student Research Award and a Banting and Best Diabetes Centre Novo-Nordisk Studentship. C.L. is supported by a Banting and Best Diabetes Centre Post-Doctoral Fellowship. D.J.D. is supported by a Canada Research Chair in Regulatory Peptides.

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Basic—Alimentary TractGlucagon-Like Peptide-2 Receptor Modulates Islet Adaptation to Metabolic Stress in the ob/ob Mouse

Background & Aims

Methods

Results

Conclusions

Section snippets

Peptides and Reagents

GLP-2 Does Not Stimulate Glucagon Secretion in Mice

Discussion

Acknowledgments

Gastroenterology

Gastroenterology

Regul Pept

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

J Biol Chem

Regul Pept

Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers

J Clin Endocrinol Metab

Insulinotropic glucagon-like peptide I receptor expression in glucagon-producing alpha-cells of the rat endocrine pancreas

Diabetes

Expression and functional activity of glucagon, glucagon-like peptide 1 and glucose-dependent insulinotropic peptide receptors in rat pancreatic islet cells

Diabetes

Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas

Diabetologia

Induction of intestinal epithelial proliferation by glucagon-like peptide 2

Proc Natl Acad Sci U S A

The effect of gastric inhibitory polypeptide and glucagon like peptides on intestinal hexose transport

Am J Physiol Gastrointest Liver Physiol

Glucagon-like peptide-2 inhibits centrally induced antral motility in pigs

Scand J Gastroenterol

Inhibition of sham feeding-stimulated human gastric acid secretion by glucagon-like peptide-2

J Clin Endocrinol Metab

Basic—Alimentary Tract
Glucagon-Like Peptide-2 Receptor Modulates Islet Adaptation to Metabolic Stress in the ob/ob Mouse