Pederson R A, White H A, Schlenzig D, Pauly R P, McIntosh C H, Demuth H U
Department of Physiology, University of British Columbia, Vancouver, Canada.
Diabetes. 1998 Aug;47(8):1253-8. doi: 10.2337/diab.47.8.1253.
The hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP)-1 act on the pancreas to potentiate glucose-induced insulin secretion (enteroinsular axis). These hormones (incretins) are rapidly hydrolyzed by the circulating enzyme dipeptidyl peptidase IV (DP IV) into biologically inactive NH2-terminally truncated fragments. This study describes the effect of inhibiting endogenous DP IV with a specific DP IV inhibitor, isoleucine thiazolidide (Ile-thiazolidide), on glucose tolerance and insulin secretion in the obese Zucker rat. In initial studies, the specificity of Ile-thiazolidide as an inhibitor of incretin degradation was determined using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. These results showed that inhibiting DP IV activity with Ile-thiazolidide blocked the formation of NH2-terminally truncated GIP and GLP-1. Oral administration of Ile-thiazolidide resulted in rapid inhibition of circulating DP IV levels by 65% in obese and lean Zucker rats. Suppression of DP IV levels enhanced insulin secretion in both phenotypes with the most dramatic effect occurring in obese animals (150% increase in integrated insulin response vs. 27% increase in lean animals). Ile-thiazolidide treatment improved glucose tolerance in both phenotypes and restored glucose tolerance to near-normal levels in obese animals. This was attributed to the glucose-lowering actions of increasing the circulating half-lives of the endogenously released incretins GIP and, particularly, GLP-1. This study suggests that drug manipulation of plasma incretin activity by inhibiting the enzyme DP IV is a valid therapeutic approach for lowering glucose levels in NIDDM and other disorders involving glucose intolerance.
葡萄糖依赖性促胰岛素多肽（GIP）和胰高血糖素样肽（GLP）-1作用于胰腺，增强葡萄糖诱导的胰岛素分泌（肠胰岛轴）。这些激素（肠促胰岛素）会被循环酶二肽基肽酶IV（DP IV）迅速水解为生物活性丧失的N端截短片段。本研究描述了用特异性DP IV抑制剂异亮氨酸噻唑烷（Ile-噻唑烷）抑制内源性DP IV对肥胖Zucker大鼠葡萄糖耐量和胰岛素分泌的影响。在初步研究中，使用基质辅助激光解吸/电离飞行时间质谱法确定了Ile-噻唑烷作为肠促胰岛素降解抑制剂的特异性。这些结果表明，用Ile-噻唑烷抑制DP IV活性可阻止N端截短的GIP和GLP-1的形成。口服Ile-噻唑烷可使肥胖和瘦型Zucker大鼠的循环DP IV水平迅速降低65%。抑制DP IV水平可增强两种表型的胰岛素分泌，其中对肥胖动物的影响最为显著（整体胰岛素反应增加150%，而瘦型动物增加27%）。Ile-噻唑烷治疗改善了两种表型的葡萄糖耐量，并使肥胖动物的葡萄糖耐量恢复到接近正常水平。这归因于增加内源性释放的肠促胰岛素GIP，特别是GLP-1的循环半衰期的降糖作用。本研究表明，通过抑制DP IV酶来药物调控血浆肠促胰岛素活性是降低非胰岛素依赖型糖尿病（NIDDM）和其他涉及葡萄糖不耐受疾病血糖水平的一种有效治疗方法。
