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

钠依赖性葡萄糖协同转运蛋白 2 抑制对骨的影响。

• 批准号: 9193426
• 负责人: Jeffry Stephen Nyman
• 金额: $ 21.97万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9193426
• 关键词: Adverse effects; Affect; Age; Attenuated; Blood Glucose; Blood Pressure; Body Weight; Bone Density; Bone Diseases; Bone Resorption; Caring; Clinical; Clinical Research; Clinical Trials; Communication; Comorbidity; Diabetes Mellitus; Diabetic mouse; Disease; Europe; Excretory function; Exhibits; FDA approved; Fracture; Functional disorder; Future; Genes; Glucose; Homeostasis; Human; Hydrochlorothiazide; Incidence; Insulin-Dependent Diabetes Mellitus; Kidney; Laboratories; Link; Measures; Mediating; Minerals; Modeling; Mus; Mutate; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nonsense Mutation; Obesity; Patients; Persons; Pharmaceutical Preparations; Phenotype; Physiology; Play; Population; Positioning Attribute; Pre-Clinical Model; Prevention; Property; Proximal Kidney Tubules; Reporting; Resistance; Risk; Rodent; Rodent Model; Role; Safety; Skeleton; Sodium; Streptozocin; Structure; Testing; Thiazide Diuretics; Time; Urine; blood glucose regulation; bone; bone health; bone turnover; clinically relevant; diabetic; diabetic patient; early onset; experience; glycemic control; hypercalciuria; improved; inhibitor/antagonist; innovation; mouse model; mutant; non-diabetic; preclinical study; prevent; skeletal; substantia spongiosa; symporter; type I and type II diabetes; urinary

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.

项目概要 1 型和 2 型糖尿病（T1D、T2D）患者骨折风险均增加，归因于 糖尿病骨骼的微结构、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 (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（卡格列净、 达格列净和恩格列净已在美国和欧洲获得 FDA 批准） 通过抑制肾近曲小管的葡萄糖重吸收来排泄葡萄糖，从而 改善 2 型糖尿病患者的血糖控制。他们很可能扮演重要角色 由于这种独特的作用机制，并且因为 它们同时有益地降低体重和血压。然而， 早期临床研究表明，患者骨折的发生率可能增加约 30% 接受这些药物治疗后，最早在治疗 12 周时就会发生骨折。在 目前，关于 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，或者这些药物如何具体影响糖尿病骨骼 疾病。因此，本提案的目标是利用几种相关的啮齿动物模型 （slc5a2 功能突变体、STZ 诱导的糖尿病、TallyHo）研究潜在机制 导致 SGLT2 抑制剂治疗对骨骼产生不良影响。此外，我们 将研究与抗钙尿噻嗪类利尿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 终生脆性骨折的风险增加现已成为糖尿病的一种既定合并症，更好的方法 对 SGLT2 抑制剂对骨骼健康影响的了解既及时又高度 与糖尿病治疗的未来相关。