Effects Of Glp-1 On Glucose Homeostasis

GLP-1[7-36]酰胺是一种天然产生的促胰岛素肽，可调节餐后状态β细胞的胰岛素分泌。2型糖尿病患者需要药物剂量使血糖正常化。它是一种含有30个氨基酸的肽，但在几分钟内，n端（HA）的前两个氨基酸被二肽基肽酶IV去除，使剩余的GLP-1[9-36]酰胺作为一种促胰岛素肽失去活性。在餐后状态下，至少75%的GLP-1以[9-36]的形式存在。我们之前的研究人员发现，GLP-1[7-36]酰胺输注不仅增加胰岛素分泌，而且增加肝脏中葡萄糖的处置，不依赖于胰岛素。为了将GLP-1[7-36]酰胺的作用与其代谢物[9-36]分开，并与Grady Meneilly， M.D.（温哥华总医院）和Dariush Elahi， Ph.D.（马萨诸塞州伍斯特大学）合作，我们将GLP-1[9-36]酰胺输注给瘦和肥胖受试者，以阐明它是否只有内在的代谢作用。我们发现GLP-1[9-36]酰胺输注导致肥胖受试者肝脏葡萄糖摄取增加，而瘦弱受试者则没有。这与我们在GLP-1[7-36]酰胺输注中发现的情况一致。葡萄糖摄取增加的作用机制尚不清楚。

GLP-1 [7-36] amide is a naturally produced insulinotropic peptide which modulates insulin secretion from beta cells in the post-prandial state. Pharmacological doses are required to normalize blood glucose in type 2 diabetes. It is produced as a 30-amino acid peptide but within a few minutes the first two amino acids of the N-terminus (HA) are removed by a dipeptidyl peptidase IV, rendering the remaining GLP-1 [9-36] amide inactive as an insulinotropic peptide. In the post-prandial state, at least 75% of the GLP-1 is in the [9-36] form. Our previous investigators had found that GLP-1 [7-36] amide infusions not only increased insulin secretion but increased glucose disposal in liver, independent of insulin. In order to separate effects of GLP-1 [7-36] amide from its metabolite [9-36] and in conjunction with Grady Meneilly, M.D. (Vancouver General Hospital] and Dariush Elahi, Ph.D. (University of Worcester, MA) we have been infusing GLP-1 [9-36] amide to lean and obese subjects in order to elucidate if it had only intrinsic metabolic effects. We have found that GLP-1 [9-36] amide infusions result in increased glucose uptake by liver in obese, but not lean, subjects. This mirrors what we found with GLP-1 [7-36] amide infusion. The mechanism of action underlying the increased glucose uptake remains unresolved.