Radiographic and proteomic characterization of bone health in patients with type 2 diabetes and type 1 diabetes of extreme duration
Decreased bone health and subsequent fracture is one of the less considered complications of both type 1 (T1DM) and type 2 (T2DM) diabetes, but has significant impact on quality of life and mortality. Studies have shown that in 30% of hip fracture cases, death occurs within one year of the event. This is of significant concern, with fracture rates increasing among both those with T1DM and T2DM due to the aging population. Individuals with T1DM are most at risk with up to a 12-fold increased risk of hip, wrist or vertebral fractures. Studies on the structural defects resulting from T2DM cite not only the toxic effects of hyperglycemia but also hyperinsulinemia, implicated in osteoblast proliferation. In addition, excess adiposity characteristic of T2DM contributes to increased levels of adipokines, such as leptin, which inhibit osteoclast formation, unbalancing bone formation and resorption. The culmination of these T2DM characteristics are hypothesized to lead to overall decreased bone turnover, increasing bone mineral density, yet there is greater cortical porosity and poorer bone quality, increasing fracture risk. Much less is understood regarding the structural and biochemical profile of bone pathology in T1DM, where resorption appears to be at the crux of the imbalance. Little is understood regarding how the pathways of hyperglycemic toxicity, the differing phenotypes of T1DM and T2DM, and aging related factors affect bone health. The Joslin 50-Year Medalist Study has extensively characterized a cohort (n=1,000) with over 50 years of T1DM, with mean duration of 55 years and age of 69 years. In preliminary data from dual energy X-ray absorptiometry (DEXA) scans of 65 Medalists, the prevalence of osteoporosis (T-score < -2.5SD) was only 4.6% across sites including lumbar spine, total hip and femoral neck, while the prevalence of osteopenia (T-score < -1.0SD) was 70.8%. Diabetes duration, age at onset and glycemic control did not differ for osteoporosis or osteopenia. Among four female Medalists who received high resolution peripheral computed tomography (HR-pQCT), differences from normative data were not only in the cortical but also in the trabecular aspects of the distal radius and tibia. This contrasts literature reports of T2DM post-menopausal women showing increases in radial cortical porosity, but no defects in other bone morphology. These hypotheses as to mechanisms and early data regarding morphologic changes suggest further work is needed to characterize the differences of type 1 and type 2 diabetic osteoporosis to identify possible therapies and interventions. To do this we propose to 1.) Characterize bone health by DEXA and HR-pQCT in those with extreme duration type 1 diabetes (Medalists); 2.) Characterize bone health by DEXA and HR-pQCT in a matched group of individuals with type 2 diabetes and nondiabetic controls, and compare to those with extreme duration type 1 diabetes; 3.) Characterize and compare the plasma protein profiles associated with morphologic features of type 1 diabetes, type 2 diabetes and non-diabetic controls.

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