Use of SGLT2 inhibition to improve skeletal muscle metabolism in prediabetes

利用 SGLT2 抑制改善糖尿病前期的骨骼肌代谢

• 批准号: 10612939
• 负责人: Sean A. Newsom
• 金额: $ 29.7万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612939
• 关键词: 5' -AMP-activated protein kinase; Accounting; Address; Adult; Aftercare; Biological Models; Biopsy; Body Composition; Body Weight decreased; Cardiometabolic Disease; Cardiovascular system; Ceramides; Clinical Trials; Data; Diglycerides; Disease; Disease Progression; Double-Blind Method; Excretory function; Fatty Acids; Fatty acid glycerol esters; Glucose; Glucose Clamp; Health; Human; Hyperglycemia; Hyperinsulinism; Individual; Insulin; Insulin Resistance; Intervention; Kinetics; Life Style Modification; Lipids; Metabolic; Metabolic Diseases; Metformin; Mission; Mitochondria; Modeling; Muscle Cells; Muscle Mitochondria; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Overweight; Participant; Placebos; Prediabetes syndrome; Proteins; Randomized; Reporting; Respiration; Risk; Rodent Model; Role; Signal Transduction; Skeletal Muscle; Sodium; Stress; Testing; Therapeutic; Therapeutic Intervention; Tracer; Treatment Efficacy; United States; Weight Gain; adult obesity; clinically significant; comparison intervention; feasibility testing; glucose disposal; glucose metabolism; high risk; human model; improved; inhibitor; insulin signaling; lipid metabolism; lipidomics; metabolic phenotype; oxidation; pilot test; response; skeletal muscle metabolism; symporter; therapeutically effective; urinary

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are used to treat hyperglycemia in type 2 diabetes (T2D) due to their ability to increase urinary glucose excretion; however, new evidence suggests SGLT2 inhibition also improves skeletal muscle insulin action as a mechanism to improve glycemia. Recent studies in humans and rodent models report SGLT2 inhibitor treatment increases insulin-stimulated glucose disposal, even after accounting for urinary glucose losses. Despite the clinical significance of these findings, mechanisms to explain this effect remain unresolved. The current project will test the hypothesis that SGLT2 inhibitor treatment stimulates changes in skeletal muscle fat metabolism that serve to improve skeletal muscle insulin action. Our preliminary studies in model systems demonstrate SGLT2 inhibitor treatment alters mitochondrial function, can induce energetic stress signaling (AMP-activated protein kinase), and even lower accumulation of bioactive lipids known to negatively regulate insulin signaling. These findings support our hypothesis and highlight the need to better understand the impact of SGLT2 inhibition on human skeletal muscle given its critical role in regulating whole-body glucose metabolism. The current project will also test the hypothesis that SGLT2 inhibition may provide therapeutic benefit (via improved skeletal muscle metabolism) before the onset of T2D. Treating individuals with prediabetes with SGLT2 inhibitors is an especially attractive option given their dysglycemia, high risk for advanced cardiometabolic disease and limited current treatment options (i.e., lifestyle modification and metformin). Taken together, the overall objectives of the current proposal are to identify mechanisms of how SGLT2 inhibition improves skeletal muscle insulin action and test the ability of SGLT2 inhibition to improve skeletal muscle metabolism among individuals with prediabetes. The current project is a randomized, double-blind, 13-week intervention comparing SGLT2 inhibition with placebo among overweight and obese adults with prediabetes. Participants will undergo robust metabolic phenotyping before and in response to the intervention to achieve the following specific aims: Aim 1: Test the hypothesis that SGLT2 inhibition improves skeletal muscle insulin action and insulin signaling in prediabetes; Aim 2: Determine mechanisms responsible for increased skeletal muscle fat oxidation during SGLT2 inhibition; Aim 3: Determine the extent to which SGLT2 inhibition lowers skeletal muscle diacylglycerol and ceramide content in prediabetes. The proposed studies can be expected to generate new information regarding the mechanisms of how SGLT2 inhibition can improve skeletal muscle metabolism and provide new understanding of the therapeutic potential of using SGLT2 inhibitors as a treatment for prediabetes.

葡萄糖共转运蛋白-2（SGLT2）抑制剂用于治疗2型糖尿病（T2D）中的高血糖症（T2D） 由于它们有能力增加尿葡萄糖排泄；但是，新的证据表明SGLT2抑制作用 还可以改善骨骼肌胰岛素作用，作为改善血糖的机制。最近在人类的研究 啮齿动物模型报告SGLT2抑制剂治疗也会增加胰岛素刺激的葡萄糖处置 考虑尿葡萄糖损失。尽管这些发现具有临床意义，但机制 解释这种效果仍未解决。当前项目将检验SGLT2抑制剂的假设 治疗刺激骨骼肌脂肪代谢的变化，这些代谢可改善骨骼肌胰岛素 行动。我们在模型系统中的初步研究表明SGLT2抑制剂治疗改变了线粒体 功能，可以诱导能量应力信号传导（AMP激活的蛋白激酶），甚至较低的积累 已知的生物活性脂质对胰岛素信号传导。这些发现支持我们的假设和 强调有必要更好地了解SGLT2抑制对人骨骼肌的影响 在调节全身葡萄糖代谢中的关键作用。当前项目还将检验以下假设 SGLT2抑制可能会在发作前提供治疗益处（通过改善骨骼肌肉代谢） T2D。鉴于他们 血糖症，晚期心脏代谢疾病的高风险和当前治疗方案有限（即 生活方式修饰和二甲双胍）。综上所述，当前建议的总体目标是 确定SGLT2抑制作用如何改善骨骼肌胰岛素作用并测试能力的机制 SGLT2抑制以改善糖尿病患者的骨骼肌代谢。电流 项目是一个随机，双盲，13周的干预措施，比较SGLT2抑制与安慰剂 超重和肥胖的成年人患有糖尿病前期。参与者将在之前进行强大的代谢表型 并回应干预措施以实现以下特定目的：目标1：检验以下假设： SGLT2抑制可改善糖尿病前期骨骼肌胰岛素作用和胰岛素信号传导；目标2：确定 SGLT2抑制期间骨骼肌脂肪氧化增加的机制；目标3：确定 SGLT2抑制在多大程度上降低了骨骼肌二酰基甘油和神经酰胺的含量 糖尿病。可以期望拟议的研究生成有关机制的新信息 SGLT2抑制如何改善骨骼肌代谢并提供对 使用SGLT2抑制剂作为糖尿病前期的治疗潜力。