Increasing glycolysis in the diabetic heart is cardioprotective and improves glucose tolerance

糖尿病心脏中糖酵解的增加具有心脏保护作用并改善葡萄糖耐量

• 批准号: 10676962
• 负责人: Kenneth M Humphries
• 金额: $ 43.7万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676962
• 关键词: 6-Phosphofructo-2-kinase; Adipocytes; Adipose tissue; Adrenergic Agents; Adult; Affect; Bioenergetics; Biological Assay; Cardiac; Cardiac Myocytes; Cause of Death; Chronic; Defect; Diabetes Mellitus; Diet; Echocardiography; Energy Metabolism; Enzymes; Estrogens; Face; Fatty Acids; Female; Free Radicals; Functional disorder; Future; Glycolysis; Goals; Health; Heart; Heart Diseases; Heart Mitochondria; Heart failure; High Fat Diet; Hyperglycemia; Impairment; Insulin-Dependent Diabetes Mellitus; Knockout Mice; Knowledge; Lipids; Measures; Mediating; Metabolic; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Oxidative Stress; Population; Production; Proteomics; Public Health; Pyruvate; Pyruvate Metabolism Pathway; Radiolabeled; Regulation; Resistance; Role; Severities; Stress; Testing; Therapeutic; Work; adipocyte differentiation; blood glucose regulation; cardioprotection; diabetic; diabetic cardiomyopathy; dietary; enzyme activity; fatty acid oxidation; feeding; flexibility; functional improvement; glucose metabolism; glucose tolerance; glucose uptake; heart function; heart metabolism; improved; insulin sensitivity; insulin signaling; metabolic profile; metabolomics; mitochondrial dysfunction; oxidation; prevent; pyruvate dehydrogenase; response; skeletal tissue; sugar; type I and type II diabetes

The goal of this proposal is to identify whether increasing cardiac glycolysis at its rate-limiting step can mitigate diabetic cardiomyopathy (DC) and improve whole body glucose tolerance. DC is a major public health issue that arises in both type 1 and type 2 diabetes and is mediated by numerous factors. Chief amongst them is the loss of metabolic flexibility, which is the capacity of the heart to take up and metabolize available circulating nutrients. The healthy heart primarily uses fatty acids, but it can shift to glucose metabolism in response to feeding. However, with diabetes the heart relies almost exclusively on fatty acid oxidation and if chronic, this leads to mitochondrial dysfunction, oxidative stress, and ultimately DC. While restoring proper cardiac metabolism has therapeutic potential, there are currently no treatments to normalize metabolic inflexibility. We posit that increasing glycolysis can normalize metabolic inflexibility and mitigate DC. We have been testing this hypothesis using mice that have enhanced cardiac glucose metabolism (GlycoHi mice) via the expression of a constitutively active form of the glycolytic regulator, phosphofructokinase-2 (PFK-2). We found that: GlycoHi mice are resistant to diet-induced cardiac diastolic dysfunction; GlycoHi heart mitochondria have an enhanced capacity to use pyruvate, indicative of increased metabolic flexibility; and female GlycoHi mice have improved systemic glucose tolerance and are resistant to HFD effects. This supports our hypothesis that increasing cardiac PFK-2 activity can mitigate DC and have beneficial effects on whole body glucose regulation. Our first Aim is to test the hypothesis that increasing cardiac glycolysis improves metabolic flexibility in response to HFD or type 1 diabetes. Control and GlycoHi mice will be subjected to HFD or induced with type 1 diabetes. We will determine cardiac function and metabolic profile by both proteomics and metabolomics. Metabolic flexibility will be measured in adult cardiomyocytes using a radiolabeled assay. Aim 2 will test the hypothesis that increasing cardiac glycolysis sustains mitochondrial function under diabetic conditions. We will interrogate mitochondrial function in diabetic (T1D and T2D) control GlycoHi, and PFK-2 knockout mice. We will also determine how the increase in glycolysis is able to sustain pyruvate dehydrogenase activity. Aim 3 will determine the mechanisms by which increasing cardiac glycolysis improves whole body glucose tolerance in diabetic GlycoHi mice. We will discern between increased energy expenditure, using metabolic cages, and increased insulin sensitivity in heart, skeletal muscle, and adipose tissue. We will also test the hypothesis that the effects are mediated through changes in adipocyte differentiation and bioenergetics. The occurrence of diabetes continues to increase, and heart disease and heart failure are leading causes of death in this population. It is not known whether increasing cardiac glycolysis has therapeutic potential in mitigating DC. These results will be an impetus for future studies that examine the therapeutic potential of targeting PFK-2 to normalize cardiac metabolic flexibility and glucose homeostasis.

该提案的目标是确定在限速步骤增加心脏糖酵解是否可以 减轻糖尿病性心肌病（DC）和改善全身葡萄糖耐量。华盛顿是一个主要的公共卫生 1型糖尿病和2型糖尿病都存在这种问题，并由许多因素介导。其中的首领 是代谢灵活性的丧失，这是心脏吸收和代谢可用循环的能力， 营养素健康的心脏主要使用脂肪酸，但它可以转移到葡萄糖代谢，以响应 喂食然而，糖尿病患者的心脏几乎完全依赖于脂肪酸氧化，如果是慢性的， 导致线粒体功能障碍，氧化应激，并最终导致DC。在恢复正常心脏功能的同时 尽管代谢具有治疗潜力，但目前没有使代谢耐受性正常化的治疗。我们 证明增加糖酵解可以使代谢平衡正常化并减轻DC。我们一直在测试 使用通过表达一种新的蛋白质来增强心脏葡萄糖代谢的小鼠（GlycoHi小鼠）的假设， 糖酵解调节剂磷酸果糖激酶-2（PFK-2）的组成型活性形式。我们发现：GlycoHi小鼠 对饮食诱导的心脏舒张功能障碍有抵抗力; GlycoHi心脏线粒体具有增强的能力， 使用丙酮酸，这表明代谢灵活性增加;雌性GlycoHi小鼠具有改善的全身性 葡萄糖耐量和抗HFD作用。这支持了我们的假设，增加心脏PFK-2 活动可以减轻DC并对全身葡萄糖调节具有有益的作用。我们的第一个目标是测试 增加心脏糖酵解可以改善对HFD或1型糖尿病的代谢灵活性。 对照和GlycoHi小鼠将经受HFD或诱导1型糖尿病。我们将确定心脏 功能和代谢概况。代谢灵活性将在 使用放射性标记测定的成年心肌细胞。目标2将检验增加心脏糖酵解 在糖尿病条件下维持线粒体功能。我们将询问糖尿病患者的线粒体功能， (T1D和T2 D）对照GlycoHi和PFK-2敲除小鼠。我们还将确定糖酵解的增加 能够维持丙酮酸脱氢酶活性。目标3将确定增加 心脏糖酵解改善糖尿病GlycoHi小鼠的全身葡萄糖耐量。我们将辨别 增加能量消耗，使用代谢笼，以及增加心脏，骨骼肌， 和脂肪组织。我们还将检验这一假设，即这种影响是通过脂肪细胞的变化介导的。 分化和生物能量学。糖尿病的发生率持续增加，心脏病和心脏病 失败是这一人群死亡的主要原因。尚不清楚心脏糖酵解的增加是否 缓解DC的治疗潜力。这些结果将成为未来研究的动力， 靶向PFK-2使心脏代谢灵活性和葡萄糖稳态正常化的治疗潜力。