Delineating mechanisms of skeletal fragility in older adults with Type 1 Diabetes

Massachusetts General Hospital, Boston MA

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Abstract

PROJECT SUMMARY The current proposal is a competitive revision for the recently funded R01DK124710 that will expand the scope and potential impact of the parent grant. Skeletal fragility is a recognized complication of Type 1 diabetes (T1D) and is of particular concern among older adults. However, the mechanisms underlying skeletal fragility are poorly understood. While vascular deficits are a well-known complication of diabetes, their effect on bone blood flow regulation has not been explored. Thus, this proposal seeks to investigate the contribution of diabetes-induced vascular deficits on bone circulation and skeletal fragility within the cohort of older adults of the parent grant. Using a novel approach, near infrared spectroscopy (NIRS), we will non-invasively assess tibial blood flow in humans and on a moment-by-moment basis. Employing NIRS, Aim 1 will investigate whether older adults with T1D have lesser myogenic vasodilation and greater myogenic vasoconstriction in the tibial vasculature compared to nondiabetic controls. Aim 2 will explore whether older adults with T1D have blunted nitric oxide (NO)-mediated vasodilation in the tibial vasculature compared to nondiabetic controls. Furthermore, Aim 3 will explore the relationship of tibial vascular responses (myogenic vasodilation, myogenic vasoconstriction, NO-mediated vasodilation) to microvascular disease burden, peripheral vascular calcification, and glycemic control in older adults with T1D. Lastly, Aim 4 will investigate the relationship between tibial vascular responses and tibial microarchitecture among older adults with T1D. We have assembled a highly interdisciplinary team with complementary expertise to perform this study and we will leverage the existing study cohort of the parent grant in a highly cost-efficient manner; several assessments of the parent grant will be utilized in the current proposal and the patient burden will be minimal, requiring a single study visit. The proposed research will provide the first ever characterization of in vivo bone blood flow regulation among adults with T1D and will add invaluable insight into how vascular complications may compromise bone structure and strength in older adults with T1D. Successful completion of this project will provide the foundation for future work towards novel treatments for bone health in older adults with diabetes.