Molecular and Clinical Studies of Insulin Resistance

胰岛素抵抗的分子和临床研究

• 批准号: 7734160
• 负责人: PHILLIP GORDEN
• 金额: $ 34.85万
• 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/7734160
• 关键词: 9q34; Adipocytes; Adipose tissue; Autoantibodies; Chromosomes; Clinical Research; Code; Collaborations; Condition; Disease; Enzymes; Etiology; Familial generalized lipodystrophy; Familial partial lipodystrophy; Genes; HIV-Associated Lipodystrophy Syndrome; Hormones; IGA Glomerulonephritis; Incidence; Insulin Receptor; Insulin Resistance; Kidney; Kidney Diseases; Lamin Type A; Leptin; Lipodystrophy; Liver; Membranoproliferative Glomerulonephritis; Metabolic; Molecular; Muscle; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Patients; Peripheral; Phenotype; Published Comment; Receptor Gene; Reporting; Syndrome; Testing; Texas; Triglycerides; Universities; adiponectin; base; diabetic; follow-up; interest; novel; receptor; research study; response

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.

我们长期以来对严重胰岛素抵抗的病因学很感兴趣。 最初，我们鉴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。 在与 Abhimanyhu Garg 博士（德克萨斯大学西南分校）的合作中，我们报告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，还报告了先天性遗传性染色体 9q34 上的突变。全身性脂肪营养不良。 染色体 9q34 上的基因编码一种对甘油三酯合成很重要的酶。 在以下脂肪代谢障碍患者中，我们观察到他们蛋白尿性肾病的发病率很高。 此外，事实证明，肾脏异常并不像预期的那样是糖尿病，而是最常见的局灶节段性肾小球肾炎或膜增生性肾小球肾炎。 我们正在与 James Balow 博士合作继续进行这项研究，试图了解这些继发性肾脏疾病与脂肪营养不良之间的关系。 另一个非常新的观察结果是，胰岛素受体突变和受体自身抗体的患者脂联素水平显着升高，而这种极端胰岛素抵抗形式的脂联素水平却较低。 因此，我们对胰岛素抵抗综合征患者的长期持续随访不断产生新的重要信息。 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。