间充质干细胞通过WNT-GSK3β-生物钟调控胰岛α细胞功能的机制研究

Pancreatic α cell dysfunction is frequently observed in diabetic patients, but the regulatory mechanism is still vague. The recent studies showed glucagon, one of the most important hyperglycemic hormones, its secretion exhibited a distinct oscillatory profile and therefore suggested that the function of pancreatic α cell might be regulated by the circadian clock. Mesenchymal stromal cells (MSCs) can regulate glucose metabolism and pancreatic islet function through secreting various of cytokines, including the WNT proteins. However, whether MSCs could participate in regulating α cell function and its mechanism remains unclear. Our previous studies showed that MSCs could ameliorate both the hypersecretion of glucagon and the circadian rhythm disorders of α cells induced by oxidative stress. Meanwhile, WNT proteins secreted by MSCs could regulate the activity of GSK3β, and GSK3β is an important regulatory target of the circadian oscillators. Therefore, we proposed a hypothesis that via secreting WNTs and inactivation of GSK3β, MSCs can regulate the circadian rhythms in the pancreatic α cells and improve the disorder of glucagon secretion. In order to test the hypothesis, we used Rev-erb alpha flox/flox Glucagon-Cre mice and a GSK3β phosphorylation inhibition model to observe the effects of MSCs intervention to glucagon secretion. By exploring new mechanism and interventions to pancreatic α cell function, our aim is to provide a view of new intervention targets, and open up new perspectives and ideas for the clinical treatment of diabetes.

胰岛α细胞功能在糖尿病中出现明显紊乱，调控机制尚不清楚。最新研究显示，胰高糖素作为最重要的升糖激素之一，分泌具明显生物钟节律，提示胰岛α细胞功能可能受生物钟调控。间充质干细胞（MSCs）可通过旁分泌调节糖代谢，但其否参与调节胰岛α细胞功能及其机制，目前尚未明了。我们前期研究表明，MSCs能改善氧化应激所致的α细胞分泌亢进及生物钟节律紊乱；同时MSCs分泌的WNT蛋白可调控GSK3β——生物钟节律的重要调节靶点——的活性。因此我们将GSK3β及生物钟基因作为研究靶点，提出MSCs可通过分泌WNT调节胰岛α细胞生物钟节律，从而改善胰高糖素分泌紊乱的科学假说。为证明假说，本课题应用胰岛α细胞特异性生物钟基因敲除小鼠或化学抑制剂构造生物钟/GSK3β磷酸化缺陷模型，多层次观察MSCs对胰高糖素分泌的调节情况，以期为α细胞的功能调控寻找新的干预靶点及手段，为糖尿病的临床治疗开辟新视角和思路。

胰岛α细胞功能在糖尿病中出现明显紊乱，调控机制尚不清楚。间充质干细胞（MSCs）可通过旁分泌调节糖代谢，但其否参与调节胰岛α细胞功能及其机制，目前尚未明了。我们的研究发现，MSCs不仅可通过分泌miR-181a并作用于α细胞中的靶点PTEN，恢复AKT信号的磷酸化，防止胰高血糖素分泌亢进，还可通过SIRT1/FoxO3a信号通路，促进胰岛α细胞对葡萄糖的摄取及活化，增强线粒体OXPHOS以及ATP合成能力，从而改善α细胞能量代谢、减少胰高糖素分泌，延缓T2DM高胰高糖素血症的发生发展。我们的研究进一步证实了MSCs改善糖代谢、缓解糖尿病的有效性，揭示了MSCs调节a细胞功能的新机制，并为下一步MSCs通过调节生物钟改善α细胞能量代谢的研究打下了基础。