Effects of Sodium-dependent Glucose Co-transporter 2 Inhibition on Bone.

项目摘要 1型和2型糖尿病（T1D，T2D）患者的骨折风险增加，归因于 糖尿病骨的微结构、材料特性和强度的特定缺陷。 钠依赖性葡萄糖协同转运蛋白2（SGLT 2）抑制剂是FDA- 批准用于T2D患者的葡萄糖调节剂。这些药物（卡格列净， 达格列净和恩格列净在美国和欧洲获得FDA批准）增加尿 通过抑制葡萄糖在肾近端小管中的重吸收来促进葡萄糖排泄，从而 改善2型糖尿病患者血糖控制。他们很可能扮演一个突出的角色， 由于这种独特的作用机制， 它们同时提供有益的体重和血压降低。然而，在这方面， 早期的临床研究表明， 接受这些药物治疗的患者，骨折早在治疗12周时就发生了。在 目前，关于SGLT 2抑制对骨矿物质稳态的影响知之甚少， 骨转换或骨微结构，或这些药物如何专门影响糖尿病骨 疾病因此，本提案的目的是利用几种相关啮齿动物模型 （slc5a2功能突变体，STZ诱导的糖尿病，TallyHo），以研究潜在的机制 导致SGLT 2抑制剂治疗对骨骼的不良影响。而且我们 将研究与抗尿钙噻嗪类利尿药联合治疗的疗效， 减轻SGLT 2抑制剂治疗对骨骼的负面影响。认识到一个 脆性骨折的终身风险增加现在是糖尿病的一种确定的合并症， 了解SGLT 2抑制剂对骨骼健康的影响是及时的， 与糖尿病治疗的未来有关。

Project Summary Persons with type 1 and type 2 diabetes (T1D, T2D) both have increased fracture risk, attributed to specific deficits in the microarchitecture, material properties and strength of diabetic bone. Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors are a new class of FDA- approved glucose-regulating agents for use in persons with T2D. These drugs (canagliflozin, dapagliflozin and empagliflozin are FDA-approved in the USA and Europe) increase urinary glucose excretion by inhibiting glucose reabsorption in the renal proximal tubule, and thereby improve glycemic control in persons with type 2 diabetes. They are likely to play a prominent role in the future treatment of T2D because of this unique mechanism of action, and because they provide concurrent beneficial reductions in body weight and blood pressure. However, early clinical studies have demonstrated a possible ~30% increase in bone fractures in patients receiving these medications, with fractures occurring as early as 12 weeks of therapy. At present, very little is known about the effects of SGLT2 inhibition on bone mineral homeostasis, bone turnover or bone microarchitecture, or how these drugs specifically impact diabetic bone disease. Therefore, the objective of this proposal is to utilize several relevant rodent models (slc5a2-functional mutants, STZ-induced diabetes, TallyHo) to investigate potential mechanisms contributing to the adverse effects of SGLT2-inhibitor therapy on the skeleton. Furthermore, we will investigate the efficacy of co-therapy with anti-calciuric thiazide diuretic drugs to potentially mitigate the negative effects of SGLT2-inhibitor therapy on the skeleton. Recognizing that a lifelong increased risk for fragility fracture is now an established comorbidity of diabetes, a better understanding of the effects of SGLT2 inhibitors on bone health is both timely and highly relevant to the future of diabetes treatment.