The cell metabolism basis for bone complications in type I diabetes

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Abstract Compelling clinical evidence has linked diabetes with increased fracture risks and impaired bone healing. Suppressed bone turnover is a common feature in both type I and type II diabetes. Therefore, use of bisphosphonates, which are the main stay of osteoporosis treatment but further suppress bone turnover, may exacerbate bone quality deterioration in the long term. The current bone anabolic drugs however have limited use in diabetic patients, particularly diabetic children, due to black box warnings. Thus, there remain tremendous unmet needs for safe and effective bone anabolic drugs. A thorough understanding of cellular metabolism in diabetic bone is essential for rational designs of novel bone therapies, but research in this area has been hampered by the lack of adequate knowledge about normal metabolism in bone cells. In recent years we and others have uncovered new details about the metabolic signatures of osteoblasts and osteoclasts, therefore providing a solid foundation for investigating the potential dysregulation of bone cell metabolism in the context of diabetes. As type 1 diabetes (T1D) is the most common form of newly diagnosed diabetes in childhood, we focus our present study on T1D by employing the Akita mouse that harbors a spontaneous point mutation in the Ins2 gene causing postnatal apoptosis of pancreatic ß cells. We propose to test the central hypothesis that type I diabetes disrupts normal osteoblast metabolism and that enhancement of glucose metabolism in osteoblasts can mitigate diabetic bone defects. We test the hypothesis in three specific aims. Aim 1 will characterize the bone defects at the cellular level in the diabetic mouse. Aim 2 will detail the metabolic defects in osteoblasts caused by diabetes, and specifically investigate the role of insulin. Finally, in Aim 3 we will test genetically whether stimulation of glycolysis ameliorates the bone defect in the diabetic mouse. Successful completion of the proposal is likely to open a new avenue for developing bone- enhancing drugs.