MOLECULAR GENETICS OF INSULIN RESISTANCE AND NONINSULIN-DEPENDENT DIABETES

NIDDK糖尿病分支对严重胰岛素抵抗的病因有长期的兴趣。最初，我们已经确定了胰岛素受体基因的突变，并研究了一组患有胰岛素受体自身抗体的患者。最近，我们专注于脂肪萎缩综合征：一组异质性综合征，其特征是缺乏脂肪组织和严重的胰岛素抵抗。在与Abhimanyhu Garg博士（德克萨斯大学西南分校）和Anne Bowcock博士（华盛顿大学圣路易斯分校）的合作中，我们报道了常染色体显性家族性部分脂肪营养不良患者的Lamin a /C基因突变。去年，我们报道了先天性全身性脂肪营养不良与染色体9q34的联系。我们正在继续努力招募新的血统，以缩小后一种情况的间隔。我们已经完成了一项临床研究，证明了曲格列酮治疗各种形式脂肪营养不良患者代谢异常的疗效。这项研究还表明，曲格列酮也会增加这些患者的体脂。这些患者正在接受一种新的噻唑烷二酮的随访，以确定这些患者体内的增加是否会随着长期暴露于噻唑烷二酮化合物而增加。最近，我们发起了一项新的研究，将测试脂肪细胞来源的瘦素激素替代在改善脂肪萎缩综合征代谢异常方面的功效。这项研究为研究瘦素对肌肉和肝脏的外周影响提供了一个独特的机会。虽然主要关注的是脂肪肥大综合征，但我们仍在继续努力了解其他严重胰岛素抵抗状态的自然历史。我们也有合作研究阐明阿尔斯特罗姆综合征和多发性家族性脂肪瘤病的遗传病因。

The Diabetes Branch of NIDDK has a long-standing interest in the etiology of severe insulin resistance. Initially, we have identified mutations in the insulin receptor gene and studied a group of patients with autoantibodies against the insulin receptor. More recently, we have concentrated on lipoatrophy syndromes: a group of heterogeneous syndromes characterized by lack of adipose tissue and severe insulin reisitance. In a collaboration with Dr. Abhimanyhu Garg (University of Texas Southwestern) and Anne Bowcock (University of Washington, St. Lois), we have reported mutations on the Lamin A/C gene in patients with an autosomal dominant form of familial partial lipodystrophy. Last year, we have reported a linkage of congenital generalized lipodystrophy to chromosome 9q34. We are continuing our efforts to recruit new pedigrees in order to narrow the interval for the latter condition. We have completed a clinical study that demonstrated the efficacy of troglitazone in treatment of metabolic abnormalities in patients with various forms of lipodystrophy. This study also demonstrated that troglitazone increased body fat in these patients as well. The follow up of these patients are ongoing on a newer thiazolidinedione in order to determine if the increase in body will be incremental with prolonged exposure to thiazolidinedione compounds in these patients. More recently, we have initiated a novel research study that will test the efficacy of the adipocyte-derived leptin hormone replacement in ameliorating the metabolic abnormalities in lipoatrophy syndromes. This study provides a unique opportunity to study the peripheral effects of leptin on the muscle and liver. While the major focus has been on lipaotrophy syndromes, we are continuing our efforts to understand the natural history of other severe insulin resistant states. We also have collaborative studies to elucidate the genetic etiology of Alstrom's syndrome and multiple familial lipomatosis.