基于维生素D调控肌肉因子Irisin对老年人前期糖尿病的防控作用及其机制研究

Human and rodent aging is characterized by the progressive decline of skeletal muscle mass and strength, a condition known as sarcopenia. Prediabetes (intermediate hyperglycaemia) is a high-risk state for diabetes that is defined by glycaemic variables that are higher than normal, but lower than diabetes thresholds. Sarcopenia and prediabetes are interrelated and often coexist in elderly, which can affect their quality of life. Recent studies have shown that irisin which secreted by skeletal muscle could regulate glucose metabolism. Vitamin D deficiency/insufficiency is prevalent in the Chinese population in almost all age groups and areas. Moreover, intracellular vitamin D receptor (VDR) is expressed in human skeletal muscle tissue. To date, several experimental studies have demonstrated the effects of active vitamin D and identify their potential mechanisms of action on myoblast proliferation and differentiation. However, the effects and mechanisms of vitamin D on the secretion of myokines are not as well understood. We found that active vitamin D was closely related to the secretion of irisin. Moreover, the experimental results suggest that active vitamin D treatment can increase the secretion of irisin through activating the signal pathway in muscle cells. The primary objective of the present research is to examine the effects of vitamin D on the progression of sarcopenia and prediabetes in an animal model of aging in vivo and in vitro, and the involvement of the VDR and p38MAPK-PGC1α-irisin-betatrophin signaling pathway. Furthermore, we will conduct a randomized double-blind placebo-controlled trial to investigate the effect of vitamin D supplementation on the progression of sarcopenia and prediabetes in sarcopenia and prediabetes older people with a vitamin D deficiency. This study seeks to establish a rationale for nutritional therapy by targeting the VDR and related signaling pathway and providing a new strategy for the prevention or treatment of sarcopenia and prediabetes.

肌肉衰减综合征（肌衰征）和前期糖尿病常常并存，危害老年人生活质量。近年的研究表明骨骼肌分泌肌肉因子Irisin可调控糖代谢。老年人群普遍缺乏维生素D（VD），而VD受体在骨骼肌组织表达。以往，对VD影响成肌细胞增殖和分化研究较多，而对肌肉因子的调控机制不详。我们在前期研究中发现VD缺乏与肌肉因子分泌密切相关，而肌肉干细胞模型研究表明VD激活了Irisin分泌信号通路。本课题拟采用细胞和小鼠模型、肌衰征/前期糖尿病老年人三个层次探讨VD通过调控肌肉因子防控前期糖尿病的作用。通过检测VD对p38MAPK-PGC1α-irisin-betatrophin轴的作用，阐明VD在调控肌肉因子和糖代谢功能中的机制；进而在VD缺乏肌衰征/前期糖尿病人群中，明确VD补充对肌肉因子和防控前期糖尿病的效果。该研究有助于明确VD缺乏造成肌肉功能下降进而影响糖代谢的关键机制，为以肌肉因子为靶点的药物研发开辟新途径。

肌少症（肌衰征）和前期糖尿病常常并存，危害老年人生活质量。近年的研究表明骨骼肌分泌肌肉因子Irisin可调控糖代谢。老年人群普遍缺乏维生素D（VD），而VD受体在骨骼肌组织表达。我们在前期研究中发现VD缺乏与肌肉因子分泌密切相关，而肌肉干细胞模型研究表明VD激活了Irisin分泌信号通路。本课题拟采用细胞和小鼠模型、肌少症/前期糖尿病老年人三个层次探讨VD通过调控肌肉因子防控前期糖尿病的作用。通过检测VD对p38MAPK-PGC1α-irisin-betatrophin轴的作用，阐明VD在调控肌肉因子和糖代谢功能中的机制；进而在VD缺乏肌少症/前期糖尿病人群中，明确VD补充对肌肉因子和防控糖尿病前期的效果。in vitro，我们分析了VD缺乏和补充对来源于肌少症模型小鼠肌肉干细胞/成肌细胞的作用。结果显示1,25-(OH)2D3 (活性VD3)添加显著增加了肌纤维PGC-1α与P-p38MAPK蛋白的表达水平，与此同时，活性VD3也相应地增加了细胞培养液中Irisin浓度。在此基础上，我们发现Irisin的干预显著增加了脂肪细胞培养液中Betatrophin浓度。此外，我们也发现Betatrophin的干预显著增加了胰岛β细胞培养液中Insulin浓度。in vivo，我们使用肌少症/糖尿病前期小鼠模型, 评估了VD3补充对血清Irisin、Betatrophin及血糖的作用。结果显示VD3补充可显著增加血清Irisin和Betatriphin水平，而降低了血糖水平。与此同时，我们发现3者间存在显著相关关系。最后，我们在VD缺乏肌少症/糖尿病前期老年人群中实施双盲随机化干预试验。结果显示VD3干预明显增加了老年人群血清中Irisin和Betatrophin的浓度。与此同时，VD3干预也降低了血糖水平。该研究不仅有助于明确VD缺乏造成肌肉功能下降进而影响糖代谢的关键机制，也为以肌肉因子为靶点的药物研发开辟新途径。