Uçkaya G, Delagrange P, Chavanieu A, Grassy G, Berthault M-F, Ktorza A, Cerasi E, Leibowitz G, Kaiser N
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.
J Endocrinol. 2005 Mar;184(3):505-13. doi: 10.1677/joe.1.05818.
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 beta-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 microg/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; beta-cell apoptosis was approximately 70% reduced, without a change in beta-cell proliferation. S 23521 treatment resulted in a 2-fold increase in relative beta-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, beta-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.
胰高血糖素样肽1（GLP-1）类似物被认为是治疗2型糖尿病的潜在药物。我们研究了一种新型GLP-1类似物S 23521（[a8-去R36]GLP-1-[7-37]-NH2）对饮食诱导的2型糖尿病肥胖沙鼠模型的代谢状态、β细胞功能、增殖和存活的影响。在给予高能饮食6天后出现明显高血糖的动物，每天皮下注射100μg/kg S 23521，共15天。接受S 23251治疗的肥胖沙鼠的食物摄入量显著降低；然而，其体重与对照组相比无显著差异。对照组的高血糖症逐渐恶化，而S 23521组的血糖水平维持在治疗前水平。糖尿病进展的预防与死亡率降低相关。此外，治疗组的血清胰岛素、胰岛素生成指数和瘦素水平较高，而血浆甘油三酯和非酯化脂肪酸水平降低。S 23521对胰腺胰岛素有显著影响，其水平比明显耗尽胰岛素储备的对照动物高5倍。免疫组织化学分析显示，未治疗动物的胰岛脱颗粒且形态破坏，而接受S 23521治疗动物的胰岛看起来完整且充满胰岛素；β细胞凋亡减少了约70%，β细胞增殖无变化。S 23521治疗使相对β细胞体积增加了2倍。总体而言，S 23521预防了肥胖沙鼠糖尿病的进展，代谢状况显著改善，包括胰腺胰岛素储备增加、β细胞活力和数量增加。这些作用可能是由于S 23521直接作用于胰岛以及通过减少食物摄入量，强调了在2型糖尿病中预防血糖随时间恶化的可行性。
