The cell metabolism basis for bone complications in type I diabetes

摘要 令人信服的临床证据表明，糖尿病与骨折风险增加和骨骼愈合受损有关。 骨转换抑制是I型和II型糖尿病的共同特征。因此，使用 双膦酸盐是治疗骨质疏松症的主要药物，但进一步抑制骨转换，可能 从长远来看，会加剧骨骼质量的恶化。然而，目前的骨合成代谢药物有限 用于糖尿病患者，特别是糖尿病儿童，由于黑盒警告。因此，仍然存在 对安全有效的骨合成药物的巨大需求尚未得到满足。对细胞的透彻了解 糖尿病骨骼中的代谢对于合理设计新的骨骼疗法是必不可少的，但这一领域的研究 由于缺乏对骨细胞正常新陈代谢的充分了解，这一研究一直受到阻碍。近几年来 我们和其他人发现了成骨细胞和破骨细胞代谢特征的新细节， 为进一步研究骨细胞代谢异常奠定了坚实的基础。 糖尿病的背景。由于1型糖尿病(T1D)是#年最常见的新诊断糖尿病形式 童年时期，我们目前的研究重点是T1D，我们使用了藏匿自发穴位的秋田小鼠 Ins2基因突变导致胰腺细胞出生后凋亡。我们建议测试中央 假设I型糖尿病扰乱了正常的成骨细胞代谢，并增强了 成骨细胞中的葡萄糖代谢可以减轻糖尿病骨缺损。我们分三个阶段来检验这个假说 明确的目标。目的1从细胞水平描述糖尿病小鼠的骨缺陷。目标2将 详述糖尿病引起的成骨细胞代谢缺陷，并特别研究胰岛素的作用。 最后，在目标3中，我们将从基因上测试糖酵解刺激是否改善了小鼠的骨缺损。 糖尿病小鼠。该提案的成功完成可能会为发展骨骼开辟一条新的途径- 加强药物的使用。

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.