Adipocyte insulin signaling and circulating adiponectin levels

脂肪细胞胰岛素信号传导和循环脂联素水平

• 批准号: 7018145
• 负责人: ROCIO Ines PEREIRA
• 金额: $ 15.23万
• 依托单位: DENVER HEALTH AND HOSPITAL AUTHORITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7018145
• 关键词: adipocytes; adiponectin; clinical research; insulin; insulin sensitivity /resistance

DESCRIPTION (provided by applicant): Insulin resistant states such as obesity, Type 2 diabetes (T2DM), and the Metabolic Syndrome (MetS) are associated with low circulating levels of adiponectin, a protein produced exclusively by adipocytes. Adiponectin has insulin sensitizing actions in muscle and liver, and anti-atherogenic properties in the vasculature. Thiazolidinediones (TZDs), an insulin sensitizing class of drugs, increase adiponectin levels independently of their actions on glucose metabolism. The mechanisms for this response and for decreased adiponectin in insulin resistant states are not yet understood. The proposed study will test the hypothesis that the mechanism underlying decreased adiponectin in insulin resistant states involves impaired insulin signaling in adipocytes and that therapeutic interventions that raise plasma adiponectin do so by reversing this impairment. This study will aim to establish a correlation between circulating adiponectin levels and adipocyte insulin signaling in controls, T2DM first-degree relatives, and obese subjects with and without T2DM. We plan to assess adiponectin production using RT-PCR and protein analysis methods. Adiponectin rate of production and secretion will be examined with pulse chase experiments in isolated adipocytes, and plasma adiponectin will be measured by radioimmunoassay. Adipocyte insulin sensitivity (anti-lipolytic effect of insulin) will be evaluated in vivo using isotope-labeled metabolites during hyperinsulinemic euglycemic clamp. The activity of the PI3-kinase signaling pathway, known to be impaired in insulin resistance, will be measured in biopsied adipose tissue. We will then attempt to demonstrate that therapeutic interventions which increase adiponectin levels do so by improving adipocyte insulin signaling though the PI 3-kinase pathway. T2DM subjects will be treated for two months with calorie restriction, metformin, or a thiazolidinedione. After treatment, adiponectin, insulin sensitivity, and insulin signaling measures will be repeated. The prevention of complications in patients with obesity, T2DM, and MetS continues to be a public health priority. The anticipated results of this clinical study may provide new insight into potential therapeutic targets in patients with T2DM, obesity, and MetS.

描述（由申请人提供）： 胰岛素抵抗状态如肥胖、2型糖尿病（T2 DM）和代谢综合征（MetS）与脂联素（一种仅由脂肪细胞产生的蛋白质）的低循环水平相关。脂联素在肌肉和肝脏中具有胰岛素增敏作用，在血管中具有抗动脉粥样硬化性质。噻唑烷二酮类（TZDs）是一类胰岛素增敏药物，可增加脂联素水平，与其对葡萄糖代谢的作用无关。这种反应和胰岛素抵抗状态下脂联素降低的机制尚不清楚。该研究将验证以下假设：胰岛素抵抗状态下脂联素降低的潜在机制涉及脂肪细胞中胰岛素信号传导受损，以及通过逆转这种损伤来提高血浆脂联素水平的治疗干预。本研究旨在确定对照组、T2 DM一级亲属和肥胖伴或不伴T2 DM受试者中循环脂联素水平与脂肪细胞胰岛素信号传导之间的相关性。我们计划使用RT-PCR和蛋白质分析方法来评估脂联素的产生。将在分离的脂肪细胞中通过脉冲追踪实验检查脂联素的产生和分泌速率，并将通过放射免疫测定法测量血浆脂联素。将在高胰岛素-正葡萄糖钳夹期间使用同位素标记的代谢物在体内评价脂肪细胞胰岛素敏感性（胰岛素的抗脂解作用）。将在活检的脂肪组织中测量已知在胰岛素抵抗中受损的PI 3-激酶信号传导途径的活性。然后，我们将试图证明，增加脂联素水平的治疗干预，通过改善脂肪细胞胰岛素信号通过PI 3-激酶途径。T2 DM受试者将接受2个月的热量限制、二甲双胍或噻唑烷二酮治疗。治疗后，将重复进行脂联素、胰岛素敏感性和胰岛素信号传导测量。预防肥胖、T2 DM和MetS患者的并发症仍然是公共卫生的优先事项。本临床研究的预期结果可能为T2 DM、肥胖和MetS患者的潜在治疗靶点提供新的见解。