Pospisilik John A, Stafford Sara G, Demuth Hans-Ulrich, McIntosh Christopher H S, Pederson Raymond A
Department of Physiology, University of British Columbia, Vancouver, British Columbia, Canada. Probiodrug AG, Halle (Saale), Germany.
Diabetes. 2002 Sep;51(9):2677-83. doi: 10.2337/diabetes.51.9.2677.
Upon release into circulation, the potent insulin secretagogues glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are rapidly cleaved and inactivated by the enzyme dipeptidyl peptidase IV (DP IV). Long-term administration of specific DP IV inhibitors, so as to enhance circulating active GIP and GLP-1 levels, has been shown to improve glucose tolerance and beta-cell glucose responsiveness and to reduce hyperinsulinemia in the Vancouver diabetic fatty (VDF) rat model of type 2 diabetes. Using the VDF model, the current study was undertaken to examine the effects of long-term DP IV inhibitor treatment on insulin sensitivity. Euglycemic-hyperinsulinemic clamps were performed on two sets of conscious VDF rats treated with or without the DP IV inhibitor P32/98 (20 mg. kg(-1). day(-1) for 12 weeks). The protocol consisted of three sequential 90-min periods with insulin infusion rates of 0, 5, and 15 mU. kg(-1). min(-1) and included a constant infusion of [ (3)H]glucose for measure of hepatic and peripheral insulin sensitivity. Relative to untreated littermates, the treated animals showed a left shift in the sensitivity of hepatic glucose output to insulin (average reduction approximately 6 micro mol. kg(-1). min(-1)) and a marked gain in peripheral responsiveness to insulin, with glucose disposal rates increasing 105 and 216% in response to the two insulin steps (versus 2 and 46% in controls). These results provide the first demonstration of improved hepatic and peripheral insulin sensitivity after DP IV inhibitor therapy, and coupled with apparent improvements in beta-cell function, they offer strong support for the utility of these compounds in the treatment of diabetes.
强效胰岛素促分泌剂葡萄糖依赖性促胰岛素多肽（GIP）和胰高血糖素样肽-1（GLP-1）一旦释放进入循环，就会迅速被二肽基肽酶IV（DP IV）酶切割并失活。长期给予特定的DP IV抑制剂，以提高循环中活性GIP和GLP-1的水平，已被证明可以改善2型糖尿病的温哥华糖尿病脂肪（VDF）大鼠模型中的葡萄糖耐量和β细胞对葡萄糖的反应性，并降低高胰岛素血症。本研究利用VDF模型，探讨长期DP IV抑制剂治疗对胰岛素敏感性的影响。对两组清醒的VDF大鼠进行正常血糖-高胰岛素钳夹实验，一组接受DP IV抑制剂P32/98治疗（20 mg·kg⁻¹·天⁻¹，持续12周），另一组未接受治疗。实验方案包括三个连续的90分钟时间段，胰岛素输注速率分别为0、5和15 mU·kg⁻¹·min⁻¹，并持续输注[³H]葡萄糖以测量肝脏和外周胰岛素敏感性。与未治疗的同窝大鼠相比，治疗组动物肝脏葡萄糖输出对胰岛素的敏感性向左偏移（平均降低约6 μmol·kg⁻¹·min⁻¹），外周对胰岛素的反应性显著增加，在两个胰岛素输注阶段，葡萄糖处置率分别增加了105%和216%（而对照组分别为2%和46%）。这些结果首次证明了DP IV抑制剂治疗后肝脏和外周胰岛素敏感性得到改善，并且与β细胞功能的明显改善相结合，为这些化合物在糖尿病治疗中的应用提供了有力支持。
