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¹ Endocrinology and Metabolism Service, Department of Internal Medicine and The Hadassah Diabetes Center, Hadassah – Hebrew University Medical Center, P.O. Box 12000, Jerusalem 91120, Israel
² Institut de Recherches Internationales Servier (I.R.I.S.), 6 place des Pleiades, 92415 Courbevoie Cedex, France
³ Centre de Biochimie Structurale, CNRS UMR 5048-UM 1-INSERM UMR 554, 29 rue de Navacelles, 34090 Montpellier Cedex 5, France
⁴ Laboratoire de Physiopathologie de la Nutrition, CNRS UMR 7059, UniversitéParis 7, 75251 Paris, Cedex 05, France

(Requests for offprints should be addressed to N Kaiser; Email: kaiser{at}md.huji.ac.il)

Glucagon-like peptide 1 (GLP-1) analogues are considered potential drugs for type 2 diabetes. We studied the effect of a novel GLP-1 analogue, S 23521 ([a⁸-des R³⁶] GLP-1-[7–37]-NH₂), on the metabolic state and ß-cell function, proliferation and survival in the Psammomys obesus model of diet-induced type 2 diabetes. Animals with marked hyperglycaemia after 6 days of high-energy diet were given twice-daily s.c. injection of 100 µg/kg S 23521 for 15 days. Food intake was significantly decreased in S 23251-treated P. obesus; however, there was no significant difference in body weight from controls. Progressive worsening of hyperglycaemia was noted in controls, as opposed to maintenance of pre-treatment glucose levels in the S 23521 group. Prevention of diabetes progression was associated with reduced mortality. In addition, the treated group had higher serum insulin, insulinogenic index and leptin, whereas plasma triglyceride and non-esterified fatty acid levels were decreased. S 23521 had pronounced effect on pancreatic insulin, which was 5-fold higher than the markedly depleted insulin reserve of control animals. Immunohistochemical analysis showed islet degranulation with disrupted morphology in untreated animals, whereas islets from S 23521-treated animals appeared intact and filled with insulin; ß-cell apoptosis was approximately 70% reduced, without a change in ß-cell proliferation. S 23521 treatment resulted in a 2-fold increase in relative ß-cell volume. Overall, S 23521 prevented the progression of diabetes in P. obesus with marked improvement of the metabolic profile, including increased pancreatic insulin reserve, ß-cell viability and mass. These effects are probably due to actions of S 23521 both directly on islets and via reduced food intake, and emphasize the feasibility of preventing blood glucose deterioration over time in type 2 diabetes.

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