Use of SGLT2 inhibition to improve skeletal muscle metabolism in prediabetes

钠-葡萄糖协同转运蛋白-2（SGLT 2）抑制剂用于治疗2型糖尿病（T2 D）的高血糖症 由于其增加尿糖排泄的能力;然而，新证据表明SGLT 2抑制 还改善骨骼肌胰岛素作用作为改善胰岛素抵抗的机制。最近对人类的研究 啮齿动物模型报告，SGLT 2抑制剂治疗增加了胰岛素刺激的葡萄糖处置，即使在 导致尿糖丢失尽管这些发现具有临床意义， 解释这种影响仍然没有得到解决。本项目将检验SGLT 2抑制剂 治疗刺激骨骼肌脂肪代谢的变化， 行动上我们在模型系统中的初步研究表明，SGLT 2抑制剂治疗可改变线粒体 功能，可以诱导能量应激信号传导（AMP活化蛋白激酶），甚至降低 已知生物活性脂质负调节胰岛素信号传导。这些发现支持了我们的假设， 强调需要更好地了解SGLT 2抑制对人类骨骼肌的影响，因为它 在调节全身葡萄糖代谢中起关键作用。目前的项目还将检验以下假设： SGLT 2抑制可在发作前提供治疗获益（通过改善骨骼肌代谢） 的T2 D。考虑到糖尿病前期患者的健康状况，使用SGLT 2抑制剂治疗糖尿病前期患者是一种特别有吸引力的选择。 心功能不全、晚期心脏代谢疾病的高风险和有限的当前治疗选择（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SGLT 2抑制如何改善骨骼肌胰岛素作用的机制，并测试 SGLT 2抑制改善糖尿病前期个体的骨骼肌代谢。当前 该项目是一项随机、双盲、13周的干预，比较SGLT 2抑制与安慰剂， 超重和肥胖的糖尿病前期成年人。参与者将在之前进行稳健的代谢表型分析。 目标1：检验以下假设： SGLT 2抑制改善糖尿病前期骨骼肌胰岛素作用和胰岛素信号传导;目的2：确定 SGLT 2抑制期间骨骼肌脂肪氧化增加的机制;目的3：确定 SGLT 2抑制降低骨骼肌甘油二酯和神经酰胺含量的程度， 糖尿病前期预计拟议的研究将产生关于 SGLT 2抑制如何改善骨骼肌代谢，并为研究SGLT 2抑制剂的作用提供新的认识。 使用SGLT 2抑制剂治疗前驱糖尿病的治疗潜力。

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.