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

基本信息

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
项目类别：
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

项目摘要

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中增加心肌糖酵解是否可以减轻糖尿病心肌病（DC）并改善全身葡萄糖耐量。 DC是一个重大的公共卫生问题该问题在 1 型和 2 型糖尿病中都会出现，并且由多种因素介导。其中最主要的是是代谢灵活性的丧失，即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，但它可以响应葡萄糖代谢喂养。然而，对于糖尿病，心脏几乎完全依赖于脂肪酸氧化，如果是慢性的，这种情况就会发生。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代谢具有治疗潜力，但目前尚无治疗方法可以使代谢不灵活正常化。我们假设增加糖酵解可以使代谢不灵活正常化并减轻 DC。我们一直在测试这个假设使用通过表达a增强心脏葡萄糖代谢的小鼠（GlycoHi小鼠）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 小鼠对饮食引起的心脏舒张功能障碍有抵抗力； GlycoHi 心脏线粒体能力增强使用丙酮酸盐，表明代谢灵活性增加；雌性 GlycoHi 小鼠的系统性改善葡萄糖耐量和对 HFD 的影响具有抵抗力。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产生有益影响。我们的首要目标是测试假设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。对照小鼠和 GlycoHi 小鼠将接受 HFD 治疗或诱导 1 型糖尿病。我们将确定心脏蛋白质组学和代谢组学的功能和代谢特征。代谢灵活性的衡量标准是使用放射性标记测定法检测成人心肌细胞。目标 2 将检验增加心肌糖酵解的假设在糖尿病条件下维持线粒体功能。我们将研究糖尿病患者的线粒体功能（T1D 和 T2D）对照 GlycoHi 和 PFK-2 敲除小鼠。我们还将确定糖酵解的增加如何能够维持丙酮酸脱氢酶活性。目标 3 将确定增加的机制心脏糖酵解可改善糖尿病 GlycoHi 小鼠的全身葡萄糖耐量。我们将辨别使用代谢笼增加能量消耗，并增加心脏、骨骼肌、和脂肪组织。我们还将检验以下假设：这些影响是通过脂肪细胞的变化介导的分化和生物能学。糖尿病的发病率持续增加，心脏病和心脏疾病失败是该人群死亡的主要原因。目前尚不清楚心肌糖酵解是否增加缓解 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。