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

项目摘要 1型和2型糖尿病患者(T1D，T2D)都有更高的骨折风险 糖尿病骨的微结构、材料特性和强度方面的特定缺陷。 钠依赖葡萄糖共转运体2(SGLT2)抑制剂是一类新的FDA- 批准用于T2D患者的血糖调节剂。这些药物(Canagliflazin， 美国和欧洲FDA批准的达帕利福秦和依帕利福秦)增加尿量 通过抑制肾近端小管对葡萄糖的重吸收而排出葡萄糖，从而 改善2型糖尿病患者的血糖控制。他们可能会扮演一个突出的角色 由于这种独特的作用机制，在未来的T2D治疗中扮演着重要的角色，而且因为 它们同时有益于减轻体重和降低血压。然而， 早期的临床研究表明，患者的骨折发生率可能增加约30%。 接受这些药物治疗，骨折最早发生在治疗的12周内。在… 目前，对SGLT2抑制对骨矿物质稳态的影响知之甚少。 骨转换或骨微结构，或这些药物如何特别影响糖尿病骨 疾病。因此，这项建议的目的是利用几种相关的啮齿动物模型 (slc5a2-功能突变、STZ诱导的糖尿病、Tallyho)来研究可能的机制 导致SGLT2抑制剂治疗对骨骼的不良影响。此外，我们 将研究与抗钙尿型噻嗪类利尿剂药物联合治疗的疗效 减轻SGLT2抑制剂治疗对骨骼的负面影响。认识到一个 脆性骨折的终生风险增加现在是糖尿病的一种既定共病，一种更好的 了解SGLT2抑制剂对骨骼健康的影响既及时又高度 关系到糖尿病治疗的未来。

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.