Quantitation of Factors Regulating Glucose Tolerance

正常的葡萄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， 增强葡萄糖处置并调节葡萄糖输出。在正常个体中，基础和餐后 胰岛素血症增加，使得胰岛素水平在基础和进餐时不超过正常范围。 这种补偿是由于13细胞对促分泌素的敏感性上调，以及 下调首过肝脏胰岛素清除率。葡萄糖耐量受损的结果，当有 胰岛素抵抗的补偿不足，随着这种功能障碍的进展，糖尿病 发展起来的耐药导致13-celluloregulation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代偿中起作用的机制， 胰岛素抵抗我们利用等热量或高热量脂肪喂养的狗模型， 内脏肥胖、胰岛素抵抗和明确的代偿模式。我们将确定 餐后或夜间葡萄糖或游离脂肪酸是否解释了β-细胞功能的上调。 我们将用药物（阿卡波糖和/或 二甲双胍）。我们研究皮质醇和生长激素之间的关系， 补偿，并用输注的拮抗剂破坏这些激素的分泌/作用 全身性地或进入大脑的第三脑室。我们考虑胃肠肽是否 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异性受体发挥作用。的 假定的GLP-1反射将通过门静脉的去神经支配或门静脉输注GLP-1而被阻断。 1拮抗剂。我们将研究门脉GLP-1是否在门脉高压症的假定作用中起重要作用。 肽来上调胰岛素抵抗状态下的胰岛。“补偿蛋白”上调失败 可能是2型糖尿病发病机制的最早改变。原产地的识别和 这些分子的代谢作用应该导致更准确地识别那些有风险的人， 糖尿病，并允许预防疾病。

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.