Glucoregulatory Hormone Interactions in Diabetes

糖尿病中的葡萄糖调节激素相互作用

• 批准号: 8038031
• 负责人: ROBERT S SHERWIN
• 金额: $ 16.55万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8038031
• 关键词: Acute; Affect; Age; Anatomy; Biochemical; Blood - brain barrier anatomy; Blood flow; Brain; Brain region; CRF receptor type 2; Cells; Chronic; Clinical; Cognition; Cognitive; Cognitive deficits; Conflict (Psychology); Corticotropin-Releasing Hormone; Data; Development; Diabetes Mellitus; Dialysis procedure; Diazoxide; Drops; Enzymes; Experimental Models; Exposure to; Failure; Functional Magnetic Resonance Imaging; Funding; GLUT-3 protein; Gene Expression; Gene Proteins; Genomics; Glucagon; Glucocorticoids; Glucokinase; Glucose; Goals; Hippocampus (Brain); Hormonal; Hormones; Human; Hydrocortisone; Hyperglycemia; Hypoglycemia; Hypothalamic structure; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Investigation; Islets of Langerhans Transplantation; Knock-out; Knockout Mice; Lead; Link; Long-Term Effects; Longevity; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Medium chain fatty acid; Memory; Metyrapone; Modeling; Molecular; Mus; Neurons; Pathway interactions; Patients; Pattern; Performance; Peripheral; Play; Proteomics; Protocols documentation; Rattus; Recurrence; Risk; Rodent; Rodent Model; Role; SLC2A1 gene; Saline; Short-Term Memory; Signal Transduction; Site; Structure of beta Cell of islet; Task Performances; Testing; Therapeutic; Transgenic Mice; Transplantation; Visual; adenylate kinase; arm; awake; base; blood oxygenation level dependent response; cognitive function; counterregulation; diabetic; diabetic rat; enzyme activity; gamma-Aminobutyric Acid; glucose metabolism; glucose transport; human subject; hypoglycemia unawareness; improved; non-diabetic; novel; prevent; protein expression; research study; response; restoration; sex

Hypoglycemia remains the major factor limiting the use of intensified insulin therapy that has been shown to prevent complications in type 1 diabetes (T1DM). This MERIT extension proposal continues studies focused on the mechanisms that trigger glucose counterregulation and lead to the development of hypoglycemiaassociated autonomic failure (HAAF) and hypoglycemia unawareness. The protocols utilize unique rodent models to test specific hypotheses, and where possible include studies in patients with T1DM. We will evaluate the molecular mechanisms used by glucose-sensing neurons in the ventromedial hypothalamus (VMM) to activate counterregulatory responses. Specifically, we test the hypothesis that hypoglycemia activates a coordinated VMH signal that results from the opening of KATP channels in glucose-sensing neurons causing a drop in GABAergic inhibitory tone that promotes the activation of VMH glucose-inhibited neurons by the fuel sensing enzyme, AMP-kinase. This model of VMH glucose sensing will serve as a starting point for studies directed at altering VMH gene expression in rodents to evaluate putative mechanisms responsible for HAAF, including the role of increased GABA or CRF2 receptor inhibitory input or decreased AMP-kinase activity within the VMH. The potential therapeutic value of diazoxide will also be tested in intensively treated T1DM patients with suppressed glucose counterregulation. The influence of insulin per se on VMH glucose sensing will be determined. We will test the hypothesis that insulin acts within the VMH to tonically suppress glucagon secretion in the postaborptive state and to diminish the release of glucagon during hypoglycemia. In addition, we will continue study insulin's effect on hippocampus function, specifically whether its beneficial effect on memory function is altered by chronic hyperglycemia. We will also examine the mechanisms for improved cognitive performance in rats after long-term exposure to recurrent hypoglycemia using MR spectroscopy as well as genomic and proteomic analyses. Finally, we will evaluate how brain activation patterns assessed by fMRI and hypothalamic blood flow are affected by acute hypoglycemia in T1DM patients with severe hypoglycemia unawareness as compared to controls and if such changes are reduced by medium chain fatty acids. The long-term goal is to develop novel clinical strategies aimed at minimizing the risk of insulin-induced hypoglycemia in patients with T1DM.

低血糖仍然是限制强化胰岛素治疗的主要因素， 预防1型糖尿病（T1 DM）并发症。这项MERIT扩展提案继续研究重点 关于触发葡萄糖反调节并导致低血糖相关发展的机制 自主神经功能衰竭（HAAF）和低血糖无意识。方案利用了独特的啮齿动物 用于检验特定假设的模型，并在可能的情况下纳入T1 DM患者的研究。我们将 评估下丘脑腹内侧区葡萄糖敏感神经元的分子机制 (VMM)激活反调节反应。具体来说，我们检验了低血糖 激活葡萄糖敏感中KATP通道开放引起的协调VMH信号 神经元引起GABA能抑制性音调下降，促进葡萄糖抑制的VMH激活 神经元的燃料传感酶，AMP-激酶。这种VMH葡萄糖传感模型将作为 研究的起点是改变啮齿动物中VMH基因的表达， 导致HAAF的机制，包括GABA或CRF 2受体抑制性输入增加的作用 或VMH内AMP激酶活性降低。二氮嗪的潜在治疗价值也将是 在接受强化治疗的葡萄糖反调节受抑制的T1 DM患者中进行了测试。的影响 将确定胰岛素本身对VMH葡萄糖感测的影响。我们将检验胰岛素在体内起作用的假设， VMH在流产后状态下紧张性抑制胰高血糖素分泌，并减少 低血糖时的胰高血糖素。此外，我们将继续研究胰岛素对海马功能的影响， 特别是它对记忆功能的有益作用是否被慢性高血糖症改变。我们还将 研究长期暴露于反复发作的药物后大鼠认知能力改善的机制。 使用MR光谱以及基因组和蛋白质组学分析来评估低血糖。最后，我们将评估 脑激活模式评估功能磁共振成像和下丘脑血流是如何影响急性 与对照组相比，患有严重低血糖无意识的T1 DM患者的低血糖，如果存在这种情况 中链脂肪酸减少了这种变化。长期目标是开发新的临床策略 旨在最大限度地降低T1 DM患者中胰岛素诱导的低血糖风险。