肌醇对2型糖尿病db/db小鼠骨量减少及代谢紊乱的干预作用及其机制

Osteopenia and metabolic syndrome in patients with type 2 diabetes mellitus (T2DM) are getting more and more attention, with an urgent need for new effective and targeted agents. Myo-inositol, already confirmed to be essential in osteogenesis, bone formation and bone mass determination in mice, has also been proved as a protective factor against osteoporosis in postmenopausal women. Moreover, myo-inositol has been shown to be an effective treatment for metabolic disorders in polycystic ovary syndrome patients or postmenopausal women, such as hyperglycemia, hyperinsulinemia, insulin resistance, obesity and dyslipidemia. Its role in osteopenia and dysmetabolism in T2DM nonetheless is unclear and has never been reported. With the T2DM db/db mice model, this study aims to make clear the effect of myo-inositol against decreased bone mineral density, impaired bone structure and abnormal bone turnover in T2DM. To understand the underlining mechanisms, mesenchymal stem cells will be isolated, and their proliferation and differentiation to osteoblasts or adipocytes will be investigated. Meanwhile, the role of myo-inositol in metabolic disorders of T2DM, such as hyperglycemia, hyperinsulinemia, insulin resistance, obesity and dyslipidemia, will be studied by detecting the relative biochemical indices from serum, urine or pancreatic tissues in db/db mice. The possible I(1,4,5)P3-Ca2+ pathway is highly considered and will be demonstrated during the intervention of myo-inositol in pancreatic β cells of db/db mice. Finally, this study will provide evidences for the application of myo-inositol in the treatment of osteopenia and metabolic syndrome in T2DM patients.

2型糖尿病患者的骨量减少及代谢紊乱问题日益受到人们关注，人们试图寻找新的有效治疗方案。肌醇，已被证实在小鼠正常骨形成及发育中起着关键作用，并可有效预防绝经后妇女的骨质流失；此外，还可有效调节多囊卵巢综合症患者及合并代谢综合征的绝经后妇女的代谢紊乱情况。然而，迄今为止，尚无肌醇干预2型糖尿病及其合并症的任何报道。本课题拟以2型糖尿病db/db小鼠为动物模型，探讨：1）肌醇对2型糖尿病db/db小鼠骨密度减低、骨微结构不良及骨更新率的影响，以及其机制是否在于调节小鼠骨髓间质干细胞的增殖及其向成骨细胞或脂肪细胞的分化成熟；2）肌醇对2型糖尿病db/db小鼠高血糖、高血脂、肥胖、高胰岛素血症及胰岛素抵抗的改善作用，以及是否通过I(1,4,5)P3- Ca2+ 信号通路来影响胰岛素分泌。本课题将为肌醇在2型糖尿病及其合并症治疗中的应用提供理论依据。

db/db小鼠是经典的T2DM小鼠模型，表现为肥胖、高血糖、胰岛素抵抗、血脂异常及骨量减少。本课题首次证实肌醇能有效纠正db/db小鼠的骨密度减低、骨微结构不良及骨强度下降的缺陷，机制在于促进MSCs细胞增殖，抑制MSCs向脂肪细胞分化，增强MSCs细胞成骨相关基因RUNX2、Osterix及Osteocalcin的表达，加快db/db小鼠MSCs向成骨细胞的分化，从而增加成骨细胞数及成骨基质蛋白沉积，促进骨生成。此外，尽管对体重影响不大，肌醇有效改善了db/db小鼠的高血糖、高胰岛素血症、胰岛素抵抗及高血脂等糖脂代谢紊乱，并能抑制胰岛β细胞被高糖刺激的高水平胰岛素分泌，提示肌醇主要作用在于减轻胰岛素抵抗，保护胰岛功能。本研究为肌醇在T2DM治疗中的应用提供了理论依据。