METABOLIC CAUSES OF THROMBOSIS IN TYPE 2 DIABETES

2 型糖尿病血栓形成的代谢原因

• 批准号: 8056094
• 负责人: STEPHEN DAVIS
• 金额: $ 45.88万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056094
• 关键词: Adrenal Cortex Hormones; Alteplase; Area; Blood Vessels; Bradykinin; Characteristics; Coronary Arteriosclerosis; Corticosteroid Receptors; Data; Diabetes Mellitus; Disease; Disodium Salt Nitroprusside; Dyslipidemias; Endocrine; Environment; Equilibrium; Euglycemic Clamping; Event; Functional disorder; Glucose; Glucose Clamp; Glucose Clamp Technique; Hormones; Hyperglycemia; Hyperinsulinism; Hypertension; Hypoglycemia; Individual; Insulin; Insulin Resistance; Intra-Arterial Infusions; Measures; Metabolic; Metabolic Diseases; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Pancreas; Patients; Pituitary Gland; Plasma; Plasminogen Activator Inhibitor 1; Play; Prediabetes syndrome; Prevalence; Research; Role; Smoking; Thrombosis; United States; atherothrombosis; basal insulin; clinically relevant; diabetic patient; glycemic control; impaired glucose tolerance; in vivo; mortality; research study

Atherothrombosis is a major cause of morbidity and mortality in patients with type 2 diabetes (T2DM). Although some of the causes responsible for this finding have been determined (e.g. hypertension, smoking, dyslipidemia) many of other putative mechanisms remain ill-defined. Remarkably, limited specific information exists identifying which of the parameters present in the disordered metabolic milieu occurring in T2DM are mechanisms responsible for the increased prothrombotic state and reduced endothelial function characteristic of this condition. The studies outlined in this proposal are focused on determining the in-vivo "metabolic" mechanisms causing the increased prothrombotic state that occurs in T2DM. Studies will determine whether it is insulin, hyperglycemia or insulin resistance that is a mechanism for disordered fibrinolytic balance and decreased endothelial function in T2DM. Additionally, studies aimed at determining the effects of high glucose, high FFA and basal insulin on fibrinolytic balance will also be proposed. We will introduce a new, clinically relevant area of research by determining the effects of hypoglycemia on endothelial function and vascular fibrinolytic balance in T2DM. Experiments will use the glucose clamp and pituitary-pancreatic-glucose clamp techniques, to precisely control glycemic and endocrine environments during our studies. Endothelial and non-endothelial dependent function will be determined by graded intra-arterial infusions of bradykinin and sodium nitroprusside. Vascular fibrinolytic balance will be determined by measuring plasma PAI-1 and arterial t-PA release. The specific aims of this proposal are to determine: 1) To determine the effects of hyperglycemia per se and hyperinsulinemia per se on disordered fibrinolytic balance and endothelial dysfunction in patients with diabetes, 2) To determine the effects of elevated free fatty acids and hyperglycemia on endothelial function and fibrinolytic balance in patients with type 2 diabetes, 3) To determine the effects of hypoglycemia on fibrinolytic balance in patients with diabetes, and 4) To determine the roles played by corticosteroid receptors on hypoglycemia effects on vascular fibrinolytic balance and endothelial function in patients with type 2 diabetes.

动脉粥样硬化是2型糖尿病患者（T2DM）患者发病率和死亡率的主要原因。虽然 负责这一发现的一些原因已经确定（例如高血压，吸烟，血脂异常） 其他许多推定的机制仍然不明显。值得注意的是，存在有限的特定信息识别 T2DM中发生的无序代谢环境中存在的哪些参数是负责机制 为了增加促血栓形成状态并降低了这种情况的内皮功能特征。研究 该提案中概述的重点是确定体内“代谢”机制，导致增加 在T2DM中发生的促血栓性状态。研究将确定它是胰岛素，高血糖还是胰岛素 电阻是纤维蛋白水解平衡和T2DM中内皮功能降低的机制。 此外，旨在确定高葡萄糖，高FFA和基底胰岛素对纤维蛋白水解的影响 还将提出余额。我们将通过确定一个新的，临床上相关的研究领域 低血糖对T2DM中内皮功能和血管纤维蛋白水解平衡的影响。实验将使用 葡萄糖夹和垂体 - 胰葡萄糖夹技术，以精确控制血糖和内分泌 我们研究期间的环境。内皮和非内皮依赖性功能将由分级确定 缓激肽和亚硝基钠的动脉内输注。血管纤维蛋白水解平衡将取决于 测量血浆PAI-1和动脉T-PA释放。该提案的具体目的是确定：1​​） 确定高血糖本身和高胰岛素血症本身对纤维蛋白水解平衡的影响 糖尿病患者的内皮功能障碍，2）确定升高的游离脂肪酸和 2型糖尿病患者的内皮功能和纤维蛋白水解平衡的高血糖，3） 低血糖对糖尿病患者纤维蛋白水解平衡的影响，4）确定由 皮质类固醇受体对低血糖对患者血管纤维蛋白水解平衡和内皮功能的影响 与2型糖尿病。