HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Üçkaya, G Articles by Kaiser, N Search for Related Content PubMed PubMed Citation Articles by Üçkaya, G Articles by Kaiser, N

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.