Molecular Genetics Of Insulin Resistance And Noninsulin-

胰岛素抵抗和非胰岛素的分子遗传学

• 批准号: 6810380
• 负责人: PHILLIP GORDEN
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6810380
• 关键词: adipocytes; autoantibody; clinical research; diabetes mellitus genetics; family genetics; gene mutation; genetic disorder; hormone therapy; human subject; human therapy evaluation; insulin receptor; insulin sensitivity /resistance; leptin; lipodystrophy; liver cells; longitudinal human study; metabolism disorder chemotherapy; muscle cells; noninsulin dependent diabetes mellitus; adipocytes; autoantibody; clinical research; diabetes mellitus genetics; family genetics; gene mutation; genetic disorder; hormone therapy; human subject; human therapy evaluation; insulin receptor; insulin sensitivity /resistance; leptin; lipodystrophy; liver cells; longitudinal human study; metabolism disorder chemotherapy; muscle cells; noninsulin dependent diabetes mellitus

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 lipodystrophy 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). We have reported mutations on the Lamin A/C gene in patients with an autosomal dominant form of familial partial lipodystrophy and also reported a mutation in a form of congenital generalized lipodystrophy on chromosome 9q34. The gene codes for an enzyme that is important in triglyceride synthesis. Our major effort has been in a clinical trial of leptin therapy and lipodystrophy. Leptin levels are low in these patients and leptin replacement therapy results in a reduction in hemoglobin A1C, fasting blood glucose, triglyceride values, a reduction in liver size, and an improvement in liver function. Thus,leptin therapy appears to have a major beneficial effect for metabolic abnormalities seen in these patients. Furthermore, in those patients who have normal reproductive organs, leptin therapy results in a robust increase in gonadotropin secretion following GNRH, and this is associated with the beginning of menses in these otherwise amenorrhic patients. We are continuing our studies on the genetics of lipodystrophy, the natural history of other insulin resistance syndromes and espcecially the follow-up of the clinical effects of leptin on lipodystrophy. More recently, we have initiated a novel research study that tests the efficacy of the adipocyte-derived leptin hormone replacement in ameliorating the metabolic abnormalities in patients with insulin receptor mutations. This study provides a unique opportunity to study the peripheral effects of leptin on the muscle and liver, and preliminary results show a favorable response. 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.

NIDDK的糖尿病分支对严重胰岛素抵抗的病因具有长期的兴趣。最初，我们已经确定了胰岛素受体基因中的突变，并研究了一组针对胰岛素受体的自身抗体的患者。最近，我们集中于脂肪营养不良综合征：一组异质综合征，其特征是缺乏脂肪组织和严重的胰岛素再证明。与Abhimanyhu Garg博士（德克萨斯大学西南大学）合作。我们报道了针对家族性部分脂肪营养不良的常染色体显性形式的层粘连蛋白A/C基因突变，还报道了以11季度染色体上的先天性普遍脂肪营养不良形式的突变。在甘油三酸酯合成中很重要的酶的基因代码。我们的主要努力是在瘦素疗法和脂肪营养不良的临床试验中。这些患者的瘦素水平较低，瘦素替代疗法导致血红蛋白A1C，空腹血糖，甘油三酸酯值，肝脏大小的降低和肝功能改善。因此，瘦素疗法似乎对这些患者的代谢异常具有主要的有益作用。此外，在那些患有正常生殖器官的患者中，瘦素疗法在GNRH后会导致促性腺激素分泌的强劲增加，这与这些原本闭经患者的月经的开始有关。我们正在继续研究脂肪营养不良的遗传学，其他胰岛素抵抗综合征的自然史以及尤其是瘦素对脂肪营养不良的临床作用的随访。最近，我们启动了一项新的研究，该研究测试了脂肪细胞衍生的瘦素激素替换在改善胰岛素受体突变患者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围作用提供了独特的机会，初步结果表明反应良好。尽管主要重点是脂肪营养综合征，但我们正在继续努力了解其他严重胰岛素耐药态的自然历史。