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

基本信息

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
项目类别：
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&apos -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

项目摘要

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.

钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂用于治疗 2 型糖尿病 (T2D) 的高血糖症由于它们能够增加尿葡萄糖排泄；然而，新的证据表明 SGLT2 抑制还可以改善骨骼肌胰岛素作用，作为改善血糖的机制。最近对人类的研究啮齿动物模型报告 SGLT2 抑制剂治疗会增加胰岛素刺激的葡萄糖处理，即使在计算尿葡萄糖损失。尽管这些发现具有临床意义，但其机制解释这一效应仍未解决。当前的项目将测试 SGLT2 抑制剂的假设治疗刺激骨骼肌脂肪代谢的变化，从而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 抑制剂治疗会改变线粒体功能，可以诱导能量应激信号（AMP 激活蛋白激酶），甚至降低已知具有负调节胰岛素信号的生物活性脂质。这些发现支持我们的假设鉴于 SGLT2 抑制作用，强调需要更好地了解 SGLT2 抑制对人类骨骼肌的影响在调节全身葡萄糖代谢中发挥重要作用。当前的项目还将检验以下假设： SGLT2 抑制可能在发病前提供治疗益处（通过改善骨骼肌代谢） T2D 的。考虑到糖尿病前期患者的病情，使用 SGLT2 抑制剂治疗他们是一个特别有吸引力的选择血糖异常、晚期心脏代谢疾病的高风险和当前治疗选择有限（即，生活方式改变和二甲双胍）。总而言之，当前提案的总体目标是确定 SGLT2 抑制如何改善骨骼肌胰岛素作用的机制并测试抑制 SGLT2 可改善糖尿病前期个体的骨骼肌代谢。目前的该项目是一项随机、双盲、为期 13 周的干预措施，对 SGLT2 抑制与安慰剂进行比较患有糖尿病前期的超重和肥胖成年人。参与者将在之前接受强大的代谢表型分析并针对干预措施实现以下具体目标：目标 1：检验假设 SGLT2 抑制可改善糖尿病前期的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 抑制降低骨骼肌二酰基甘油和神经酰胺含量的程度糖尿病前期。拟议的研究有望产生有关机制的新信息 SGLT2 抑制如何改善骨骼肌代谢并提供新的认识使用 SGLT2 抑制剂治疗糖尿病前期的治疗潜力。