INSULIN RESISTANCE OF ACANTHOSIS NIGRICANS

这项持续的研究项目旨在全面确定 导致胰岛素抵抗的具体机制 在以黑棘皮病皮肤为特征的常见人类综合征中， 损伤和显著内源性高胰岛素血症。 最常见的 这种情况的表现是在青春期的女性谁也有 肥胖和月经过少。 在青少年中，葡萄糖耐量 尽管有严重的胰岛素抵抗，但通常是正常的，但最近的数据表明， 代偿性胰岛素的逐渐丧失 分泌过多和最终发展为非胰岛素依赖性 糖尿病（NIDDM）。 进一步的数据表明， 增加了一些少数群体中皮肤病的发病率。 的 该项目的长期目标是（a）充分描述 对胰岛素的抵抗，（B）描述以下因素的相对重要性 这种综合征的遗传和获得因素，（c）确定 卵巢功能障碍及皮肤病变与胰岛素的关系 （d）确定哪种治疗可以有效地治疗 改善这种状况。 明年的短期目标是 测试以下假设。 (1)这些受试者中有许多患有严重 胰岛素抵抗具有一个或多个功能性内点突变 胰岛素受体的结构域。 为了验证这一假设，我们将确定 胰岛素受体基因有限部分的确切基因序列 对应于酪氨酸激酶结构域。 (2)黑棘皮病 皮肤病变，我们已经记录到有一个高患病率， 一般人群总是严重内源性 高胰岛素血症是胰岛素抵抗的补偿， 获得或继承。 这一假设将通过评估 胰岛素敏感性的每一个病人确定与黑棘皮病。 (3)这种胰岛素抵抗综合征有其自然的过程松散 胰腺β细胞储备并最终发展为明显的NIDDM。 这将 通过对所有确定的 患者，包括确定葡萄糖耐量和定量 胰岛素分泌和胰岛素反应性。 其他数据将 维持在肥胖、卵巢功能障碍、高血压、 和高脂血症。 (4)潜在胰岛素受体缺陷的评价 在每一个严重受影响的患者的父母将揭示一个或多个 特殊的结构异常 这一建议将由 评价胰岛素受体结构特性，胰岛素受体基因 表达和胰岛素受体基因结构在父母的12个 严重受影响的患者被确定具有特定的结构缺陷。 这些拟议的实验可能提供重要的洞察机制， 其他常见的健康问题，如肥胖， 和NIDDM。

This continuing research project is intended to comprehensively determine the specific mechanisms which result in resistance to the action of insulin in a common human syndrome characterized by the acanthosis nigricans skin lesion and marked endogenous hyperinsulinemia. The most common presentation of this condition is at puberty in females who also have obesity and oligomenorrhea. In young adolescents, glucose tolerance is often normal in spite of severe insulin resistance but recent data suggests that there is frequently progressive loss of compensatory insulin hypersecretion and the eventual development of non-insulin dependent diabetes mellitus (NIDDM). Further data suggests this dramatically increases incidence of the skin lesion among some minority groups. The long term goals of this project are (a) to fully characterize the nature of the resistance to insulin, (b) to delineate the relative importance of genetic and acquired factors in this syndrome, (c) to determine the relationship of the ovarian dysfunction and the skin lesions to the insulin resistance, and (d) to determine what therapy can be effective in ameliorating this condition. The short term goals in the next year are to test the following hypotheses. (1) Many of these subjects with severe insulin resistance have one or more point mutations within functional domains of the insulin receptor. To test this hypothesis we will determine the exact gene sequence of limited portions of insulin receptor gene corresponding to the tyrosine kinase domains. (2) The acanthosis nigricans skin lesion which we have documented to have a high prevalence in the general population is always a marker for severe endogenous hyperinsulinemia which is in compensation for insulin resistance, either acquired or inherited. This hypothesis will be pursued by evaluating the insulin sensitivity of every patient identified with acanthosis nigricans. (3) This insulin resistance syndrome has as its natural course to loose pancreatic beta cell reserve and eventually develop overt NIDDM. This will be tested by performing yearly follow-up assessments in all identified patients, consisting of determining glucose tolerance and quantitating insulin secretion and insulin responsiveness. Additional data will be maintained on the course of the obesity, ovarian dysfunction, hypertension, and hyperlipidemia. (4) Evaluation of potential insulin receptor defects in each parent of severely affected patients will reveal one or more specific structural abnormalities. This suggestion will be tested by evaluating insulin receptor structural properties, insulin receptor gene expression, and insulin receptor gene structure in the parents of twelve severely affected patients identified to have a specific structural defect. These proposed experiments may provide important insight into mechanisms of defective insulin action in other common health problems such as obesity and NIDDM.