Lynn F C, Pamir N, Ng E H, McIntosh C H, Kieffer T J, Pederson R A
Department of Physiology, University of British Columbia, Vancouver, Canada.
Diabetes. 2001 May;50(5):1004-11. doi: 10.2337/diabetes.50.5.1004.
Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone that is released postprandially from the small intestine and acts in concert with glucagon-like peptide (GLP)-1 to potentiate glucose-induced insulin secretion from the pancreatic beta-cell. In type 2 diabetes, there is a decreased responsiveness of the pancreas to GIP; however, the insulin response to GLP-1 remains intact. The literature suggests that the ineffectiveness of GIP in type 2 diabetes may be a result of chronic homologous desensitization of the GIP receptor. Yet, there has been no conclusive evidence suggesting that GIP levels are elevated in diabetes. The hypothesis of the present study is that one cause of decreased responsiveness to GIP in type 2 diabetes is an inappropriate expression of the GIP receptor in the pancreatic islet. This hypothesis was tested using a strain of diabetic fatty Zucker rats. The obese rats displayed basal GIP levels similar to the control animals; however, they were unresponsive to a GIP infusion (4 pmol.min(-1). kg(-1)), whereas the lean animals displayed a significant reduction in blood glucose (GIP levels, 50% control after 60 min, P < 0.05) as well as a significant increase in circulating insulin. GIP also potently stimulated first-phase insulin secretion from isolated perifused islets (10.3 +/- 3.0 x basal), and GIP and GLP-1 potentiated insulin secretion from the perfused pancreas (6 x control area under the curve [AUC]) from lean animals. GIP yielded no significant effect in the Vancouver diabetic fatty Zucker (VDF) rat pancreases, whereas GLP-1 elicited an eightfold increase of insulin secretion from the perfused VDF pancreas. Islets from lean animals subjected to static incubations with GIP showed a 2.2-fold increase in cAMP, whereas GIP failed to increase islet cAMP in the VDF islets. Finally, the expression of both GIP receptor mRNA and protein was decreased in islets from VDF rats. These data suggest that the decreased effectiveness of GIP in the VDF rat and in type 2 diabetes may be a result of a decreased receptor expression in the islet.
葡萄糖依赖性促胰岛素多肽（GIP）是一种餐后从小肠释放的肽类激素，它与胰高血糖素样肽（GLP）-1协同作用，增强胰腺β细胞对葡萄糖诱导的胰岛素分泌。在2型糖尿病中，胰腺对GIP的反应性降低；然而，对GLP-1的胰岛素反应仍保持完好。文献表明，GIP在2型糖尿病中无效可能是GIP受体慢性同源脱敏的结果。然而，尚无确凿证据表明糖尿病患者的GIP水平升高。本研究的假设是，2型糖尿病患者对GIP反应性降低的一个原因是胰岛中GIP受体的表达不当。使用糖尿病肥胖 Zucker 大鼠品系对这一假设进行了检验。肥胖大鼠的基础GIP水平与对照动物相似；然而，它们对GIP输注（4 pmol·min⁻¹·kg⁻¹）无反应，而瘦动物的血糖显著降低（GIP水平，60分钟后为对照的50%，P<0.05），循环胰岛素显著增加。GIP还能有效刺激分离的灌注胰岛的第一相胰岛素分泌（10.3±3.0倍基础值），GIP和GLP-1能增强瘦动物灌注胰腺的胰岛素分泌（曲线下面积[AUC]为对照的6倍）。GIP对温哥华糖尿病肥胖 Zucker（VDF）大鼠胰腺无显著影响，而GLP-1能使灌注的VDF胰腺的胰岛素分泌增加8倍。用GIP对瘦动物的胰岛进行静态孵育，cAMP增加2.2倍，而GIP未能增加VDF胰岛中的cAMP。最后，VDF大鼠胰岛中GIP受体mRNA和蛋白的表达均降低。这些数据表明，GIP在VDF大鼠和2型糖尿病中有效性降低可能是胰岛中受体表达降低的结果。
