THE INSULIN RESISTANCE OF ACANTHOSIS NIGRICANS

这一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 在一种以黑棘皮病为特征的常见人类综合征中 损害和明显的内源性高胰岛素血症。最常见的 这种情况出现在青春期的女性，她们也有 肥胖和月经过少。在青少年中，葡萄糖耐量是 尽管存在严重的胰岛素抵抗，但通常是正常的，但最近的数据表明 经常会出现代偿性胰岛素的渐进性丢失 高分泌与非胰岛素依赖型糖尿病的最终发展 糖尿病(NIDDM)。进一步的数据表明这是戏剧性的。 在一些少数群体中增加了皮肤损害的发生率。这个 该项目的长期目标是：(A)充分说明 胰岛素抵抗，(B)描述胰岛素抵抗的相对重要性 本综合征的遗传和获得性因素，(C)确定 卵巢功能障碍和皮损与胰岛素的关系 抵抗力，以及(D)确定哪种疗法对 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的 胰岛素抵抗有一个或多个功能性内点突变 胰岛素受体的结构域。为了检验这一假设，我们将确定 胰岛素受体基因有限部分的准确基因序列 与酪氨酸激酶结构域相对应。(2)黑棘皮病 我们记录的皮肤损害在中国有很高的发病率 一般人群总是严重内源性疾病的标志 高胰岛素血症也是对胰岛素抵抗的补偿 后天获得的或继承的。这一假设将通过评估 每一位确诊为黑棘皮病患者的胰岛素敏感性。 (3)这种胰岛素抵抗综合征的自然过程是松弛的。 胰岛β细胞储备，最终发展为显性NIDDM。这将是 通过执行年度跟踪评估来测试所有已确定的 患者，包括测定糖耐量和定量 胰岛素分泌和胰岛素反应性。其他数据将是 在肥胖，卵巢功能障碍，高血压， 和高脂血症。(4)评估潜在的胰岛素受体缺陷 在每个受严重影响的患者的父母身上都会显示一个或多个 特殊的结构异常。这项建议将通过以下方式进行检验 评估胰岛素受体结构特性，胰岛素受体基因 12名儿童父母胰岛素受体基因表达和结构的研究 受严重影响的患者被确定为具有特定的结构缺陷。 这些拟议的实验可能会为我们提供对 胰岛素在肥胖等其他常见健康问题中的作用缺陷 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.