Skeletal Fragility in Type 1 Diabetes: Glycemic Control and Bone Strength

1 型糖尿病的骨骼脆弱性：血糖控制和骨强度

• 批准号: 10693825
• 负责人: MISHAELA R RUBIN
• 金额: $ 27.93万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-12 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10693825
• 关键词: Adolescent; Adult; Advanced Glycosylation End Products; Age; Area; Biomechanics; Blood Glucose; Bone Density; Bone Diseases; Child; Childhood; Clinical; Clinical Data; Complications of Diabetes Mellitus; Continuous Glucose Monitor; Control Groups; Data; Devices; Diabetes Mellitus; Elements; Finite Element Analysis; Follow-Up Studies; Foundations; Fracture; Functional disorder; General Population; Goals; Hyperglycemia; Individual; Insulin-Dependent Diabetes Mellitus; Measures; Minerals; Morbidity - disease rate; Morphology; Natural History; Non-Insulin-Dependent Diabetes Mellitus; Organ; Osteogenesis; Pathogenesis; Patients; Peripheral; Population; Postmenopause; Property; Protocols documentation; Puberty; Research; Resistance; Resolution; Skeleton; Skin; Testing; Thick; Time; Tissues; Vulnerable Populations; Woman; X-Ray Computed Tomography; bone; bone mass; bone quality; bone strength; bone turnover; boys; cohort; diabetic; fracture risk; fragility fracture; girls; glycemic control; high risk; indexing; insulin dependent diabetes mellitus onset; men; mortality; novel; prevent; prospective; sex; skeletal; skeletal disorder; type I and type II diabetes

Patients with type 1 diabetes (T1D) display a high risk of fragility fractures, yet the skeletal pathophysiology of T1D is incompletely understood. Decreases in areal BMD (aBMD) are well-established, but the magnitude of the aBMD deficit explains only 20% of the observed increase in T1D fracture risk. Rather, deficits in bone microarchitecture, turnover and material composition likely predispose to the high fracture risk. In type 2 diabetes (T2D), we have shown reduced bone material strength index (BMSi) using a novel impact microindentation device, which, we found, also correlated with long-term glycemia as reflected by a skin autofluorescence measure of tissue advanced glycation endproduct (AGE) levels. Despite reduced BMSi in T2D, skeletal microarchitecture was found to be intact, as assessed by high resolution peripheral quantitative computed tomography (HR-pQCT). In contrast, in T1D, primary deficits reside in altered microarchitecture and we find reduced trabecular thickness. However, we have little information on effects of T1D on trabecular morphology, biomechanical properties and bone material strength. Importantly, the onset of T1D is generally before attainment of peak bone mass, yet there is little natural history data to demonstrate how bone accrual is impacted. It is also unknown whether glycemic control and variability predict bone deficits. In order to understand the pathogenesis of T1D bone disease, it is thus imperative that we understand the time course of skeletal deficits in T1D, and specifically, how they might progress as a function of glycemic control. Together, these observations underscore our central hypothesis: T1D, in contrast to T2D, is primarily associated with decrements in bone strength due to disrupted microarchitecture occurring during peak bone mass accrual, and that this disruption arises from hyperglycemia and glycemic variability. Thus, the overall goals of this application are: 1) to understand the relationship between glycemic control and bone strength in long-standing T1D adults versus controls using HR-pQCT-based estimates of bone strength (including trabecular and cortical components and trabecular morphology); 2) to elucidate the effects of T1D (including glycemic control and variability by continuous glucose monitoring) on the peak accrual of bone mass by following HR-pQCT-based estimates of bone strength over 2 years in T1D children versus controls; and 3) to examine the relationship between bone material strength by microindentation and AGE accumulation by skin autofluorescence in long- standing T1D adults versus controls. The research will provide comprehensive data about the effects of T1D on the elements of bone that contribute to strength and fracture resistance. The effects of glycemic control on cross-sectional measures and prospective bone acquisition will determine whether skeletal fragility, like other complications of T1D, is associated with poor glycemic control. The results should help unravel the pathogenesis of diabetic skeletal fragility and become a foundation for follow-up studies to develop strategies to mitigate and ideally prevent fractures in this vulnerable population.

1型糖尿病（T1D）患者易碎性骨折的风险较高，但其骨骼病理生理机制却存在差异