Molecular and Clinical Studies of Insulin Resistance

胰岛素抵抗的分子和临床研究

• 批准号: 8148800
• 负责人: PHILLIP GORDEN
• 金额: $ 33.13万
• 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/8148800
• 关键词: Clinical Research; Insulin Resistance; Molecular

We have had a long-standing interest in the etiology of severe insulin resistance. Initially, we 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 resistance. In a collaboration with Dr. Abhimanyhu Garg (University of Texas Southwestern), we have reported mutations in the lamin A/C gene in patients with an autosomal dominant form of familial partial lipodystrophy and also reported a mutation on chromosome 9q34 in a form of congenital generalized lipodystrophy. The gene on chromosome 9q34 codes for an enzyme that is important in triglyceride synthesis. In following patients with lipodystrophy, we have observed that they have a high incidence of proteinuric renal disease. Further, it turns out that the renal abnormality is not diabetic as expected, but most often focal segmental glomerulonephritis or membranoproliferative glomerulonephritis. We are continuing this study in collaboration with Dr. James Balow in an attempt to understand the relationships of these secondary forms of renal disease to lipodystrophy. Another very new observation is that both patients with mutations in their insulin receptors and autoantibodies to the receptor have markedly elevated adiponectin levels in contrast to the low levels that would be expected in this form of extreme insulin resistance. Thus, our longstanding and continued follow-up of patients with syndromic forms of insulin resistance continues to yield new and important information. 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. In a recent study we have described a new and very effective treatment for the syndrome of autoantibodies to the insulin receptor.

我们对严重胰岛素耐药性的病因一直很感兴趣。 最初，我们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抵抗。 在与Abhimanyhu Garg博士（德克萨斯大学西南大学）的合作中，我们报道了层粘连蛋白A/C基因的突变，该基因的患者是家族性部分部分脂质营养不良的常染色体显性型占主导地位，并且还报告了以先行性脂质化脂质化脂质体的形式对9q34染色体的突变。 染色体9q34上的基因代码在甘油三酸酯合成中很重要的酶代码。 在跟随脂肪营养不良的患者中，我们观察到他们的蛋白尿肾脏疾病发生率很高。 此外，事实证明，肾脏异常不是预期的糖尿病性，但最常见的是局灶性节段性肾小球肾炎或膜增生性肾小球肾炎。 我们正在与詹姆斯·巴洛（James Balow）博士合作继续这项研究，以了解这些次要形式的肾脏疾病与脂肪营养不良的关系。 另一个非常新的观察结果是，胰岛素受体中突变的患者和对受体的自身抗体的患者均显着升高脂联素水平，与低水平相比，这种高水平以这种极端胰岛素抵抗的形式可以预期。 因此，我们对综合症胰岛素耐药性综合症患者的长期和持续随访继续产生新的重要信息。 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。 在最近的一项研究中，我们描述了针对胰岛素受体自身抗体综合征的一种新的且非常有效的治疗方法。