THE INSULIN RESISTANCE OF ACANTHOSIS NIGRICANS

这项建议的主要目标是：评估 与黑棘皮病相关的严重胰岛素抵抗 和/或高雄激素血症；以确定三者之间的关系 这种综合征的组成部分相互关联；并发展出一种理性的 对中医辨证论治的认识和认识 涉及病理生理学。口服葡萄糖和胰岛素的反应 葡萄糖挑战，静脉注射胰岛素的急性葡萄糖反应， 并通过正常血糖生成生物胰岛素剂量响应曲线 钳夹技术将提供对胰岛素的详细体内评估 行动。体内的结果将与详细的体外分析进行比较。 胰岛素与新分离的细胞(单核细胞、脂肪细胞)的结合， 胰岛素受体自动磷酸化、基础和胰岛素刺激 葡萄糖在人脂肪细胞中的转运。潜在的内在缺陷 胰岛素的作用将通过家庭研究和分析 受体和受体后功能(葡萄糖氧化和转运) 培养的成纤维细胞取自这些受试者。两国之间的关系 胰岛素抵抗、黑棘皮病和高雄激素血症 在基础状态和序贯治疗后进行评估 饮食干预、磺脲类药物和口服避孕药。 在这些受影响的个人中概述的系统性方法结合在一起 在适当体重匹配的受试者中进行类似的研究，以及 无黑棘皮病的高雄激素血症患者 应允许实现这些目标。更清晰的认识 该综合征中胰岛素作用缺陷的确切性质以及 它与其他相关组件的关系应该提供更多 合理的治疗方法不仅对这种综合征，而且对其他更多 常见疾病状态也是如此。

The major objectives of this proposal are: to assess the nature of the severe insulin resistance seen in association with acanthosis nigricans and/or hyperandrogenemia; to determine the relationship of the three components of this syndrome to one another; and to develop a rational therapeutic approach to the syndrome based on a better understanding of the pathophysiology involved. Glucose and insulin responses tgo an oral glucose challenge, acute glucose reponse to an intravenous insulin bolus, and generation of a biologic insulin dose response curve via the euglycemic clamp technique will provide a detailed in vivo assessment of insulin action. In vivo results will be compared with a detailed in vitro analysis of insulin binding to freshly isolated cells (monocytes, adipocytes), insulin receptor autophosphorylation, and basal and insulin stimulated glucose transport in human adipocytes. Potential intrinsic defects in insulin action will be assessed through family studies and by analysis of receptor and post receptor function (glucose oxidation and transport) in cultured fibroblasts obtained from these subjects. The relationship of insulin resistance, acanthosis nigricans, and hyperandrogenemia will be assessed in the basal state and following sequential therapeutic intervention with diet, a sulfonylurea agent, and an oral contraceptive. The systematic approach as outlined in these affected individuals, combined with similar studies in appropriate weight matched subjects, as well as subjects with evidence of hyperandrogenemia without acanthosis nigricans should allow the accomplishment of the objectives. A clearer understanding of the exact nature of the defects in insulin action in this syndrome and its relation to the other associated components should provide a more rational therapeutic approach not only to this syndrome but other more common disease states as well.