INSULINOTROPIN: A MODULATOR OF B-CELL GLUCOSE SIGNALLING

众所周知，非胰岛素依赖型糖尿病的治疗 糖尿病（NIDDM）并发低血糖的风险，以及 血糖水平的大幅度波动，胰岛素固有的， 磺脲类药物治疗 最近的NIDDM临床研究表明， 肠促胰岛素激素胰高血糖素样肽-1-（7-37）的用途 （促胰岛素，GLP-1）作为这种疾病的替代治疗。 当在NIDDM患者进餐时给药时，GLP-1恢复 胰岛素分泌的第一时相成分缺失， 餐后高血糖波动 由于促胰岛素作用 随着血糖水平开始下降， 低血糖不是一个重要的并发症因素。 虽然 普遍认为NIDDM的特征是无效偶联， β-细胞葡萄糖摄取到胰岛素分泌的比例， 了解GLP-1的短期给药如何纠正这种缺陷 分泌反应 在这里，我们报告的初步调查结果表明，快速 葡萄糖不敏感β细胞向完全应答细胞的转化 通过GLP-1，一种我们称之为葡萄糖能力的现象。 的目的 这项研究旨在确定GLP-1使胰腺癌发生的机制。 通过膜片钳评估的葡萄糖感受态β细胞 电生理分析 穿孔补片细胞附着补片 并且切除的斑片记录将用于研究Ik GLP的调节， 受GLP-1抑制的内向整流钾电流，和 其介导该激素对β细胞的去极化作用。 Ik GLP的生物物理和药理学特性将是 并评估其是否代表 之前未被发现的β细胞钾电流 因为抑制 GLP-1对Ik GLP的影响取决于同时应用 葡萄糖，这两种药物的协同相互作用，以降低血糖， 将通过剂量反应分析来定量β细胞。 这将允许 直接测试的假设，诱导葡萄糖的能力， GLP-1是由葡萄糖反应的剂量依赖性转变引起的 因此，通常被认为是 亚刺激完全有效。 由于GLP之间的串扰- 1和葡萄糖信号系统是抑制Ik的必要条件 GLP，实验将针对鉴定胞质第二 它是一种信使，介导GLP-1的作用。 了解分子 对GLP-1应答的基础事件将提供对原因的深入了解 这种激素在NIDDM的治疗中也具有治疗价值， 随着我们对β-葡萄糖敏感机制的进一步了解， 细胞

It is well recognized that treatment of non-insulin-dependent diabetes mellitus (NIDDM) is complicated by the risks of hypoglycemia, as well as large swings in the blood glucose level, inherent to insulin and sulfonylurea therapy. Recent clinical studies of NIDDM indicate the usefulness of incretin hormone glucagon-like peptide-1-(7-37) (INSULINOTROPIN, GLP-1) as the alternative treatment for this disorder. When administered during a meal to patients with NIDDM, GLP-1 restores the missing first phase component of insulin secretion and delays the post-prandial hyperglycemic excursion. Since the insulinotropic action of GLP-1 is self-terminating as blood glucose levels begin to fall, hypoglycemia is not a significant complicating factor. Although it is generally accepted that NIDDM is characterized by ineffective coupling of beta-cell glucose uptake to insulin secretion, it is not yet understood how short-term administration of GLP-1 corrects this defective secretory response. Here we report preliminary findings indicating rapid conversion of glucose-insensitive beta-cells to fully responsive cells by GLP-1, a phenomenon we term glucose competence. The objective of this study is to determine the mechanism by which GLP-1 renders pancreatic beta-cells glucose-competent, as assessed by patch clamp electrophysiological analysis. Perforated patch, cell-attached patch, and excised patch recordings will be used to study modulation of Ik GLP, an inwardly-rectifying potassium current that is inhibited by GLP-1, and which mediates the depolarizing action of this hormone on beta-cells. The biophysical and pharmacologic properties of Ik GLP will be characterized and an assessment made as to whether it represents a previously unrecognized beta-cell potassium current. since inhibition of Ik GLP by GLP-1 is contingent on the simultaneous application of glucose, the synergistic interaction of these two agents to depolarize beta-cells will be quantified by dose-response analysis. This will allow a direct test of the hypothesis that induction of glucose competence by GLP-1 results from a shift in the dose-dependence of the glucose response so that concentrations of glucose normally considered to be substimulatory become fully effective. Since cross-talk between the GLP- 1 and glucose signalling systems is a requirement for inhibition of Ik GLP, experiments will be directed at identifying the cytosolic second messenger that mediates the action of GLP-1. Understanding the molecular events that underlie the response to GLP-1 will provide insight into why this hormone is of therapeutic value in the treatment of NIDDM, as well as further our understanding of the glucose-sensing mechanism of beta- cells.