INSULIN RESISTANCE, POLYCYSTIC OVARIAN DISEASE AND ACANTHOSIS NIGRICANS

黑棘皮病是胰岛素抵抗的一种皮肤表现。该项目旨在确定在黑棘皮病综合征中引起胰岛素抵抗的具体机制，黑棘皮病最常见于青春期肥胖和少经的女性。在这些青少年中，尽管有严重的胰岛素抵抗，但葡萄糖耐量通常是正常的。但最近的数据表明，代偿性胰岛素高分泌的逐渐丧失是经常发生的，并最终发展为2型糖尿病。其他数据表明，在一些少数民族中，黑棘皮病的患病率明显增加。长期目标是：(a)充分表征胰岛素抵抗的性质，(b)描述遗传因素和获得性因素在该综合征中的相对重要性，(c)确定卵巢功能障碍和皮肤病变与胰岛素抵抗的关系，以及(d)确定哪种治疗方法有效。目标是在未来三年内测试以下假设。(1)严重的胰岛素抵抗直接影响所有胰岛素反应组织的胰岛素作用。或者，这可能仅限于肌肉和脂肪中的胰岛素反应性葡萄糖摄取。在正糖钳夹研究中，稳定同位素标记的葡萄糖和甘油输注将表征胰岛素刺激的葡萄糖摄取到肌肉、胰岛素抑制肝脏葡萄糖输出和胰岛素抑制脂肪细胞甘油释放的剂量反应曲线。(2)这种胰岛素抵抗综合征的自然过程是胰腺β细胞储备丧失，最终发展为显性2型糖尿病。这将通过对所有确定的患者的年度随访评估进行测试，包括测定葡萄糖耐量和定量胰岛素分泌和胰岛素反应性。关于肥胖、卵巢功能障碍、高血压和高脂血症的病程将保留其他数据。(3)如果在先证物中发现特定的缺陷，父母和兄弟姐妹将受到影响。对6名重度患者的父母和兄弟姐妹进行高胰岛素血症评估，并进行体内胰岛素抵抗和生化表征。这些拟议的实验可能为其他常见健康问题（如肥胖和2型糖尿病）中胰岛素作用缺陷的机制提供重要见解。

Acanthosis nigricans is a cutaneous manifestation of insulin resistance. This project aims to determine specific mechanisms that cause insulin resistance in the syndrome of acanthosis nigricans which most commonly presents at puberty in females with obesity and oligomenorrhea. In these young adolescents glucose tolerance is often normal in spite of severe insulin resistance. But recent data suggests that progressive loss of compensatory insulin hypersecretion is frequent and there is eventual development of type 2 diabetes mellitus. Other data suggests a markedly increased prevalence of acanthosis nigricans in some ethnic minorities. The long term goals are to (a) fully characterize the nature of the resistance to insulin, (b) delineate the relative importance of genetic and acquired factors in this syndrome, (c) determine the relationship of the ovarian dysfunction and the skin lesions to insulin resistance, and (d)determine what therapy can be effective. The goals are to test the following hypotheses over the next three years. (1) Severe insulin resistance directly affects insulin action in all insulin responsive tissues. Alternatively, this might be limited to insulin responsive glucose uptake in muscle and fat. Stable isotope-labeled glucose and glycerol infusions during euglycemic clamp studies will characterize the dose response curve for insulin-stimulated glucose uptake into muscle, insulin suppression of hepatic glucose output, and insulin suppression of adipocyte glycerol release. (2) The natural course of this insulin resistance syndrome is to lose pancreatic beta cell reserve and eventually develop overt type 2 diabetes. This will be tested by yearly follow-up assessments in all identified patients, consisting of determing glucose tolerance and quantitating insulin secretion and insulin responsiveness. Additional data will be maintained on the course of the obesity, ovaian dysfunction, hypertension, and hyperlipidemia. (3) Parents and siblings will be affected if a specific defect is identified in the proband. Parents and siblings of six severly affected subjects will be evaluated for hyperininsulinemia and in vivo insulin resistance and biochemical characterization will be performed. These proposed experiments may provide important insights into mechanisms of defective insulin action in other common health problems such as obesity and type 2 diabetes mellitus.