Restoring Central Regulation of Glucose Production in Type 2 Diabetes

恢复 2 型糖尿病中葡萄糖生成的中央调节

• 批准号: 10652264
• 负责人: MEREDITH A HAWKINS
• 金额: $ 69.93万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652264
• 关键词: ATP sensitive potassium channel complex; Address; Beta Cell; Blood Glucose; Brain; Cells; Central Nervous System; Chronic; Closure by clamp; Complications of Diabetes Mellitus; Data; Defect; Diabetes Mellitus; Diazoxide; Fasting; Fatty Acids; Glucose; Goals; Hepatic; Human; Hyperglycemia; Hypothalamic structure; Impairment; Individual; Infusion procedures; Insulin; Lead; Lipids; Liver; Mediating; Mitochondria; Neurons; Nicotinic Acids; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutritional status; Obesity; Organ; Pancreas; Patients; Play; Population; Potassium; Prevalence; Process; Public Health; Rattus; Regulation; Regulatory Pathway; Rodent; Role; Signal Pathway; Signal Transduction; Somatostatin; Source; TXN gene; Testing; Therapeutic; Transplant Recipients; Work; antioxidant enzyme; blood glucose regulation; diabetic; diabetic rat; endoplasmic reticulum stress; euglycemia; extracellular; glucose production; glycemic control; liver transplantation; mind control; nerve supply; new therapeutic target; non-diabetic; novel therapeutics; overexpression; patch clamp; prevent; restoration; restraint

Project Summary/Abstract Endogenous glucose production (EGP) is a crucial process that maintains blood glucose levels under fasting conditions and is normally inhibited by both glucose and insulin. Inappropriately high EGP is the major source of hyperglycemia in individuals with type 2 diabetes (T2D) and contributes significantly to diabetes complications. Our groups’ ongoing work suggests that central nervous system (CNS) signals play an important role in regulating EGP. ATP-sensitive potassium (KATP) channels in the ventromedial hypothalamus (VMH) appear to mediate some of the suppressive effects of circulating insulin and glucose on EGP, but this regulation is impaired in T2D and diabetic rodents. We have observed that lowering free fatty acid (FFA) levels completely restored the regulation of EGP by central KATP channel activation. Therefore, we hypothesize that chronic lipid overload may contribute to the central signaling defects in T2D. Thus, through complementary human and rodent studies we propose to expand our understanding of how specific CNS signaling pathways regulate EGP through the following specific aims: 1) To establish whether central regulation of EGP can be restored by lowering FFA levels in patients with T2D, 2) To determine whether intact hepatic innervation is required for restoration of central regulation of EGP upon lowering FFA in individuals with T2D, and 3) To establish whether the impaired central regulation of EGP in T2D is mediated by neuron-specific defects in KATP channel activation within the VMH. Furthermore, we will determine whether lowering FFA levels contributes to restoring central regulation of glucose production by reducing endoplasmic reticulum (ER) stress in specific glucose-sensing neurons. Collectively, these studies should provide mechanistic explanation(s) for the impaired central regulation of EGP in T2D and help point toward novel therapeutic targets.

项目总结/摘要 内源性葡萄糖生成（EGP）是维持血液循环的重要过程， 在空腹条件下的葡萄糖水平，并且通常被葡萄糖和 胰岛素不适当的高EGP是个体高血糖的主要来源 2型糖尿病（T2 D）患者，并对糖尿病并发症有显著影响。我们 研究小组正在进行的工作表明，中枢神经系统（CNS）信号在中枢神经系统中起着重要作用。 在调节EGP中的重要作用。ATP敏感性钾（KATP）通道在 腹内侧下丘脑（VMH）似乎介导了一些抑制作用 循环胰岛素和葡萄糖对EGP的影响，但这种调节在T2 D中受损， 糖尿病啮齿动物我们观察到完全降低游离脂肪酸（FFA）水平 通过激活中枢KATP通道恢复EGP的调节。所以我们 假设慢性脂质超负荷可能导致中枢信号传导缺陷， 2型糖尿病因此，通过补充人类和啮齿动物的研究，我们建议扩大 我们了解特定的中枢神经系统信号通路如何通过 以下具体目标：1）确定中央监管EGP是否可以 通过降低T2 D患者的FFA水平恢复，2）为了确定是否完整 肝神经支配是EGP降低后恢复中枢调节所必需的 FFA在T2 D患者中的作用，以及3）确定受损的中枢调节是否 T2 D中EGP的表达是由KATP通道激活中的神经元特异性缺陷介导的， VMH。此外，我们将确定降低FFA水平是否有助于 通过减少内质网来恢复葡萄糖产生的中枢调节 (ER)特定葡萄糖敏感神经元的应激。总的来说，这些研究应该 为2型糖尿病患者EGP中枢调节受损提供机制解释 并帮助指向新的治疗靶点。