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

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 糖尿病分会长期以来对严重胰岛素抵抗的病因学感兴趣。最初，我们已经确定了胰岛素受体基因的突变，并研究了一组具有胰岛素受体自身抗体的患者。最近，我们专注于脂肪营养不良综合征：一组以脂肪组织缺乏和严重胰岛素抵抗为特征的异质综合征。与 Abhimanyhu Garg 博士（德克萨斯大学西南分校）合作。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核纤层蛋白 A/C 基因突变，还报道了染色体 9q34 上先天性全身性脂肪营养不良形式的突变。该基因编码一种对甘油三酯合成很重要的酶。我们的主要努力是瘦素疗法和脂肪营养不良的临床试验。这些患者的瘦素水平较低，瘦素替代疗法可降低糖化血红蛋白、空腹血糖、甘油三酯值，缩小肝脏大小，并改善肝功能。因此，瘦素治疗似乎对这些患者的代谢异常具有重要的有益作用。此外，在那些具有正常生殖器官的患者中，瘦素治疗会导致 GNRH 后促性腺激素分泌大幅增加，这与这些闭经患者的月经开始有关。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，特别是瘦素对脂肪营养不良的临床效果的跟踪。最近，我们启动了一项新的研究，测试脂肪细胞来源的瘦素激素替代品在改善胰岛素受体突变患者代谢异常方面的功效。这项研究提供了一个独特的机会来研究瘦素对肌肉和肝脏的外周影响，初步结果显示出良好的反应。虽然主要焦点是脂肪营养不良综合征，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史。