Use of SGLT2 inhibition to improve skeletal muscle metabolism in prediabetes

钠-葡萄糖共转运体-2(SGLT2)抑制剂用于治疗2型糖尿病(T2D)的高血糖 由于它们有增加尿糖排泄的能力；然而，新的证据表明SGLT2抑制 还可以改善骨骼肌胰岛素的作用，作为改善血糖的机制。最近对人类的研究 啮齿动物模型报告说，SGLT2抑制剂治疗增加了胰岛素刺激的葡萄糖处置，即使在 说明了尿液中葡萄糖的损失。尽管这些发现具有临床意义，但其发病机制 解释这一影响仍未解决。目前的项目将检验SGLT2抑制剂的假设 治疗刺激骨骼肌脂肪代谢的变化，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抑制剂治疗改变了线粒体 功能，可以诱导能量应激信号(AMP激活的蛋白激酶)，甚至更低的蓄积 已知的生物活性脂质对胰岛素信号有负面调节作用。这些发现支持我们的假设，并且 强调需要更好地了解SGLT2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的关键作用。目前的项目还将检验这一假设 抑制SGLT2可能在发病前提供治疗益处(通过改善骨骼肌代谢) T2D。使用SGLT2抑制剂治疗糖尿病前期患者是一个特别有吸引力的选择，因为他们 血糖异常、晚期心脏代谢性疾病的高风险以及当前治疗选择有限(即， 生活方式改变和二甲双胍)。综上所述，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其能力 抑制SGLT2以改善糖尿病前期患者的骨骼肌代谢。海流 该项目是一项随机、双盲、为期13周的干预措施，比较了SGLT2抑制和安慰剂在 超重和肥胖的糖尿病前期成年人。参与者将接受强健的代谢表型鉴定 作为对干预的回应，以实现以下具体目标：目标1：检验假设 抑制SGLT2可改善糖尿病前期患者骨骼肌的胰岛素作用和胰岛素信号；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小鼠骨骼肌二酰甘油和神经酰胺的含量 糖尿病前期。拟议的研究有望产生关于心力衰竭发病机制的新信息。 SGLT2抑制如何改善骨骼肌代谢并提供新的理解 使用SGLT2抑制剂作为糖尿病前期治疗的治疗潜力。

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.