Selective Insulin Resistance- Diabetic Cardiovascular Diseases

选择性胰岛素抵抗-糖尿病心血管疾病

• 批准号: 7654233
• 负责人: GEORGE L KING
• 金额: $ 38.81万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7654233
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acceleration; Affect; Animals; Antiatherogenic; Apolipoprotein E; Arteries; Atherosclerosis; B-insulin; Blood Vessels; Blood capillaries; Breeding; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cause of Death; Cells; Cessation of life; Clinical Research; Crossbreeding; Data; Development; Diabetes Mellitus; Endothelial Cells; Endothelin; Endothelin-1; Endothelium; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Exhibits; Figs - dietary; Gene Deletion; Genes; Glucose; Growth; Heart; Heart Diseases; Hyperglycemia; Hyperlipidemia; Inflammatory; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Intervention; Knockout Mice; Lipids; MAP Kinase Modules; Mediating; Mitogen-Activated Protein Kinases; Morbidity - disease rate; Mus; Muscle; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Pathway interactions; Phosphorylation; Phosphorylation Site; Physiology; Plasminogen Activator Inhibitor 1; Protein Isoforms; Protein Kinase C; Reporting; Resistance; Risk Factors; Rodent; Rodent Model; Role; Severities; Smooth Muscle Myocytes; Testing; Tissues; Vascular Endothelial Growth Factors; Vascular Endothelium; capillary; cardiovascular disorder risk; cardiovascular risk factor; citrate carrier; cytokine; density; diabetic; diabetic cardiomyopathy; diabetic patient; glycemic control; heme oxygenase-1; human NOS3 protein; improved; in vivo; insulin signaling; migration; mortality; non-diabetic; novel; overexpression; prevent; public health relevance

DESCRIPTION (provided by applicant): Cardiovascular pathologies in diabetic patients are caused by the acceleration of atherosclerosis. Abnormalities such as hyperlipidemia, insulin resistance and hyperglycemia are important risk factors for cardiovascular disease (CVD) in diabetes. Clinical studies such as DCCT/EDIC, ACCORD, and ADVANCE showed that intensive glycemic control lowers the risk for CVD in type 1 but not type 2 diabetic patients suggesting that insulin resistance at the vascular wall could be very important in the development of CVD complications in type 2 DM. Previously, we have proposed a novel concept that "selective" inhibition of insulin's anti-atherogenic actions mediated by the activation of IRS/PI3K/Akt pathways could be a major cause of cardiovascular complications in diabetes. We showed that diabetes or insulin resistance will inhibit insulin's signaling via IRS-1/PI3K/Akt pathway but may enhance insulin's actions through MAPK pathways, thus causing "selective insulin resistance". Recently, we have obtained the first definitive in vivo evidence to show that insulin has "anti-atherogenic" actions in the endothelium, since mice with deletion of both insulin receptors in the endothelial cells (EC) and apolipoprotein E (apoE-/-) exhibited significantly more atherosclerosis (2X) than apoE-/- single gene deletion mice in parallel with a 50% reduction in Akt/eNOS activation. We have also reported that hyperglycemia and free fatty acids (FFA) can activate protein kinase C (PKC), specifically the 21/2 and 4 isoforms, and induce "selective insulin resistance" in the microvessels or arteries of diabetic or insulin resistant animals. We also showed that "selective insulin resistance" also exists in the myocardium of diabetic or insulin resistant rodents, which could be responsible for the decreases in VEGF expression and collateral vessel formation in the heart observed in these conditions. Thus, our hypothesis suggests that abnormal metabolites of diabetes, resulting from insulin deficiency or resistance, will activate PKC 2 and 4 isoforms, inhibit the IRS-1/PI3K/Akt pathway of insulin signaling via PI3K and resulting in the loss of insulin's "anti-atherogenic" and angiogenic actions. Thus, we are proposing to: (1) Determine whether enhancing insulin's actions at IRS1/2 step by overexpressing IRS-1 in the endothelium will improve endothelial function and decrease atherosclerosis in apoE-/- mice. (2) Identify the role of phospho-Thr86 of p85/PI3K in causing selective insulin resistance in EC and correlate the changes of phospho-Thr86/p85 with vascular insulin resistance and PKC activation in vivo. Evaluate the effect of PKC22 and 4 activation and changes in phosphorylation and function of PI10/PI3K and Akt1/2 as additional targets of PKC to inhibit insulin's signaling in EC. (3) Evaluate the effect of overexpressing PKC22 and 4 isoforms targeted to endothelial cells to cause "selective insulin resistance" and accelerate atherosclerosis when crossbred with apoE-/- mice. PUBLIC HEALTH RELEVANCE: Heart diseases are the major causes of death among diabetic patients. We have found that insulin normally has several actions that can prevent atherosclerosis, which are lost when diabetes develops. We have proposed studies, which could provide explanations and potential interventions, such as the use of inhibitor of an enzyme, PKC, that can improve insulin's effect on the heart and the blood vessels, and decrease the risk of cardiovascular deaths in diabetic patients.

描述（由申请人提供）：糖尿病患者的心血管病理是由动脉粥样硬化加速引起的。糖尿病中心血管疾病（CVD）等异常，例如高脂血症，胰岛素抵抗和高血糖是心血管疾病（CVD）的重要危险因素。诸如DCCT/EDIC，ACCORD和ADVART的临床研究表明，密集的血糖控制降低了1型CVD的风险，但不建议使用2型糖尿病患者，这表明血管壁的胰岛素抵抗对于2型2型DM中CVD并发症的发展可能非常重要。以前，我们提出了一个新的概念，即通过激活IRS/PI3K/AKT途径介导的胰岛素抗动脉粥样硬化作用“选择性”可能是糖尿病心血管并发症的主要原因。我们表明，糖尿病或胰岛素抵抗会通过IRS-1/PI3K/AKT途径抑制胰岛素的信号传导，但可能会通过MAPK途径增强胰岛素的作用，从而引起“选择性胰岛素抵抗”。最近，我们获得了第一个确定的体内证据，表明胰岛素在内皮中具有“抗毒素”作用，因为内皮细胞中胰岛素受体均缺失的小鼠（EC）和载脂蛋白E（APOE-/ - ）与APOE（2x）的动脉粥样硬化（2X）删除（2x）相比，胰岛素E（EC）和载脂蛋白E（APOE-/ - ）的差异更高。 AKT/ENOS激活。我们还报道说，高血糖和游离脂肪酸（FFA）可以激活蛋白激酶C（PKC），特别是21/2和4同工型，并在糖尿病或耐胰岛素抵抗动物的微型固定剂或动脉中诱导“选择性胰岛素抵抗”。我们还表明，在糖尿病或胰岛素耐药啮齿动物的心肌中也存在“选择性胰岛素抵抗”，这可能导致在这些条件下观察到的心脏中VEGF表达和副血管形成的降低。 Thus, our hypothesis suggests that abnormal metabolites of diabetes, resulting from insulin deficiency or resistance, will activate PKC 2 and 4 isoforms, inhibit the IRS-1/PI3K/Akt pathway of insulin signaling via PI3K and resulting in the loss of insulin's "anti-atherogenic" and angiogenic actions.因此，我们提议：（1）确定通过在内皮中过度表达IRS-1在IRS1/2步骤增强胰岛素的作用是否会改善内皮功能并减少APOE - / - 小鼠的动脉粥样硬化。 （2）确定p85/pI3K的磷酸-THR86在EC中引起选择性胰岛素耐药性中的作用，并将磷酸-THR86/p85的变化与血管胰岛素抵抗和体内PKC激活相关联。评估PKC22和4激活的影响以及PI10/PI3K和AKT1/2的磷酸化和功能的变化，作为PKC的其他靶标，以抑制EC中胰岛素的信号传导。 （3）评估靶向内皮细胞的过度表达PKC22和4同工型引起“选择性胰岛素抵抗”，并在与ApoE - / - 小鼠杂交时加速动脉粥样硬化。公共卫生相关性：心脏病是糖尿病患者死亡的主要原因。我们发现，胰岛素通常有多种可预防动脉粥样硬化的作用，而糖尿病发育时会丢失。我们提出了可以提供解释和潜在干预措施的研究，例如使用酶，PKC的抑制剂，可以改善胰岛素对心脏和血管的影响，并降低糖尿病患者心血管死亡的风险。