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)并发低血糖风险，以及 血糖水平的大幅波动，这是胰岛素和 磺脲类药物治疗。最近对NIDDM的临床研究表明 胰升糖素样肽-1-(7-37)的作用 (INSULINOTROPIN，GLP-1)作为这种疾病的替代治疗。 当NIDDM患者在用餐期间服用GLP-1时，GLP-1恢复 缺失的胰岛素分泌第一时相成分并延迟了 餐后高血糖短途旅行。由于胰岛素的促胰岛素作用 当血糖水平开始下降时，GLP-1的表达会自我终止， 低血糖不是一个重要的并发症因素。尽管它是 普遍认为NIDDM的特征是耦合无效 β细胞葡萄糖摄取对胰岛素分泌的影响，目前还不是 了解短期服用GLP-1如何纠正这一缺陷 分泌性反应。在这里，我们报告的初步发现表明，快速 葡萄糖不敏感的β细胞向完全反应细胞的转化 通过GLP-1，我们将这种现象称为葡萄糖能力。这样做的目的是 研究旨在确定GLP-1导致胰腺病变的机制 膜片钳技术评估β细胞的葡萄糖能力 电生理分析。穿孔贴片，细胞贴片， 并且切除的贴片记录将用于研究Ik GLP的调制， 被GLP-1抑制的内向整流钾电流，以及 它介导了这种荷尔蒙对β细胞的去极化作用。 Ik GLP的生物物理和药理性质将是 特征，并对其是否表示 先前未被识别的β细胞钾电流。既然抑制了 GLP-1对Ik GLP的影响取决于同时应用 葡萄糖，这两种试剂的协同作用使去极化 贝塔细胞将通过剂量反应分析进行量化。这将允许 对这样一种假设的直接检验，即通过 GLP-1是葡萄糖反应的剂量依赖关系改变的结果 所以葡萄糖的浓度通常被认为是 次刺激变得完全有效。因为普洛斯之间的串话- 1和葡萄糖信号系统是抑制Ik的必要条件 GLP，实验将针对识别胞质秒 介导GLP-1活动的信使。理解分子 作为对GLP-1反应的基础的事件将提供对为什么 这种激素在治疗NIDDM方面也有治疗价值。 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.