Quantitation of Factors Regulating Glucose Tolerance

正常的糖耐量是通过胰岛素分泌和胰岛素作用之间的平衡来维持的 加强葡萄糖处理，调节葡萄糖输出。正常人的基础和餐后情况 胰岛素血症增加，因此血糖不会超过正常范围，在基础和用餐。 这种补偿是由于13个细胞对促分泌剂的敏感性上调以及 下调肝脏首次通过的胰岛素清除。当存在以下情况时，会导致糖耐量受损 对胰岛素抵抗的补偿不足，随着这种功能障碍的进展，糖尿病 发展起来。耐药导致13-细胞受孕的确切机制尚不清楚。 我们正在研究几种可能在高胰岛素血症补偿中发挥作用的机制 胰岛素抵抗。我们开发了等卡路里或高卡路里脂肪喂养的狗模型，它开发了 内脏肥胖症、胰岛素抵抗和明确的代偿模式。我们将决定 无论是餐后还是夜间血糖或游离脂肪酸都可以解释p细胞功能的上调。 我们将使用药理制剂(阿卡波糖和/或 二甲双胍)。我们研究了皮质醇与生长激素和代谢的关系。 通过注入拮抗剂来补偿和干扰这些激素的分泌/作用 全身或进入第三脑室。我们认为胃肠肽 GLP-1是胰岛素抵抗代偿反应的重要介质。我们假设 GLP-1在脂肪喂养模型中受到刺激，并通过门静脉中的特定受体发挥作用。这个 可能的GLP-1反射将被门静脉失神经或门静脉输注GLP-1阻断。 1种拮抗剂。我们将研究门户GLP-1是否在血管内皮细胞的假定作用中发挥重要作用。 可上调处于胰岛素抵抗状态的胰岛的多肽。“补偿金”未能上调 可能是2型糖尿病发病机制中最早的变化。来源和来源识别 这些分子的代谢作用应该会导致更准确地识别出哪些人有患高血压的风险 糖尿病，并考虑到疾病的预防。

Normal glucose tolerance is maintained by a balance between insulin secretion and insulin action to enhance glucose disposal and regulate glucose output. In normal individuals basal and postprandial insulinemia increases so that glycemia does not exceed the normal range at basal and with meals. This compensation is due to upregulation of 13-cell sensitivity to secretagogues, as well as downregulation of first-pass liver insulin clearance. Impaired glucose tolerance results when there is inadequate compensation for insulin resistance, and as this dysfunction progresses, diabetes develops. The precise mechanisms by which resistance results in 13-cellupregulation are not known. We are examining several mechanisms which may play a role in hyperinsulinemic compensation for insulin resistance. We exploit the isocaloric or hypercaloric fat-fed dog model, which develops visceral adiposity, insulin resistance and a well-defined pattern of compensation. We will determine whether postprandial or nocturnal glucose or free fatty acids explain upregulation of p-cell function. We will counter increases in postprandial nutrients with pharmacological agents (acarbose and/or metformin). We examine the relationship between cortisol and growth hormone and metabolic compensation, and disrupt the secretion/action of these hormones with antagonists infused systemically or into the third ventricle of the brain. We consider whether gastrointestinal peptide GLP-1 is an important mediator of the compensatory response to insulin resistance. We hypothesize that GLP-1 is stimulated in the fat-fed model and acts via specific receptors in the portal vein. The putative GLP-1 reflex will be blocked by denervation of the portal vein, or with portal infusion of GLP- 1 antagonists. We will examine whether portal GLP-1 plays a vital role in the putative action of the peptide to upregulate islets in the insulin resistant state. Failure of "compensatrins" to upregulate may be the earliest change in the pathogenesis of Type 2 diabetes. Identification of the origin and metabolic actions of such molecules should lead to more accurate identification of those at risk for diabetes, and allow for prevention of the disease.