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。该项目旨在确定导致黑棘皮病综合征胰岛素抵抗的具体机制，该综合征最常出现在青春期肥胖和月经过少的女性中。在这些青少年中，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，代偿性胰岛素高分泌的进行性丧失是常见的，最终会发展为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这一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)确定什么治疗方法可以有效。我们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胰岛素在所有胰岛素反应组织中的作用。或者，这可能仅限于肌肉和脂肪对胰岛素敏感的葡萄糖摄取。在正常血糖钳夹研究期间，稳定的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进入肌肉、胰岛素抑制肝脏葡萄糖输出以及胰岛素抑制脂肪细胞甘油释放的剂量反应曲线。(2)胰岛素抵抗综合征的自然病程是失去胰岛β细胞储备，最终发展为显性2型糖尿病。这将通过对所有确定的患者进行年度跟踪评估来检验，包括确定葡萄糖耐量和量化胰岛素分泌和胰岛素反应性。关于肥胖、卵巢功能障碍、高血压和高脂血症病程的其他数据将被保留。(3)如果在先证者身上发现特定缺陷，父母和兄弟姐妹将受到影响。将对六名受影响严重的受试者的父母和兄弟姐妹进行高胰岛素血症评估，并在体内进行胰岛素抵抗和生化特征分析。这些拟议的实验可能为胰岛素缺陷在其他常见健康问题(如肥胖症和2型糖尿病)中的作用机制提供重要的见解。

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.