Basic—Alimentary TractGlucagon-Like Peptide-2 Receptor Modulates Islet Adaptation to Metabolic Stress in the ob/ob Mouse
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.
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2017, PeptidesCitation Excerpt :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].
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2014, Regulatory PeptidesCitation Excerpt :Barhami and Coll. reported that in genetically obese mice elimination of GLP-2R signalling impaired the normal islet adaptative response required to maintain glucose homeostasis [15] while the study of Shi and Coll. [14] showed that the GLP-2R deletion in pro-opiomelanocortin [POMC] neurons impairs postprandial glucose tolerance and hepatic insulin sensitivity.
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.