INSULIN RESISTANCE, POLYCYSTIC OVARIAN DISEASE AND ACANTHOSIS NIGRICANS

黑色素沉着症是胰岛素抵抗的皮肤表现。该项目旨在确定导致黑棘皮病综合征胰岛素抵抗的具体机制，黑棘皮病最常见于青春期肥胖和月经过少的女性。 在这些年轻的青少年中，尽管存在严重的胰岛素抵抗，但葡萄糖耐量通常是正常的。 但最近的数据表明，代偿性胰岛素分泌过多的进行性丧失是频繁的，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）充分描述胰岛素抵抗的性质，（B）描述遗传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，和（d）确定什么治疗是有效的。 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中的胰岛素作用。 或者，这可能限于肌肉和脂肪中的胰岛素响应性葡萄糖摄取。在正葡萄糖钳夹研究期间，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中、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失去胰腺β细胞储备，最终发展为明显的2型糖尿病。 这将通过每年对所有确定的患者进行随访评估进行测试，包括确定葡萄糖耐量和定量胰岛素分泌和胰岛素反应性。 将保留关于肥胖、卵巢功能障碍、高血压和高脂血症病程的其他数据。 (3)如果在先证者中发现特定的缺陷，父母和兄弟姐妹将受到影响。 将评价6例严重受累受试者的父母和兄弟姐妹的高胰岛素血症和体内胰岛素抵抗，并进行生化表征。 这些拟议的实验可能会提供重要的见解，在其他常见的健康问题，如肥胖和2型糖尿病的缺陷胰岛素作用的机制。

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.