2型糖尿病发病过程中胰岛炎症的动力学机理

The dynamics mechanism of islet inflammation during type 2 diabetes progress

2型糖尿病是一种以慢性高血糖为主要特征的代谢性疾病,其发病机制复杂.近年来的研究发现,糖脂代谢紊乱造成的慢性炎症可引起机体胰岛损伤,与2型糖尿病发生发展密切相关.但是,由代谢紊乱诱发的胰岛炎症如何发展并最终导致胰岛功能不可逆性损伤的机制尚未完全阐明.本研究,首先选取自发性2型糖尿病GK大鼠和转基因动物IDOL小鼠,建立了胰岛炎症实验模型并对相关炎症因子变化进行检测,结果显示巨噬细胞与胰岛炎症进程相关.随后建立相应的定量数学模型描述胰岛β细胞和巨噬细胞相互作用,理论模型的结果表明,胰岛β细胞和巨噬细胞之间的正反馈回路可能导致IL-1β的激活过程存在不可逆双稳态和磁滞回线效应,并导致胰岛炎症的不可逆性发展.本研究提出了胰岛炎症过程中动力学机理,希望能够为2型糖尿病发病机制的深入研究和治疗药物的研发提供新的思路和有益的帮助.

Type 2 diabetes is a chronic metabolic disease characterized by hyperglycemia, which is mainly caused by insulin resistance and islet β-cells dysfunction. The increasing prevalence of type 2 diabetes worldwide poses a significant threat to human health. Studies showed that chronic inflammation induced by glucotoxicity and lipotoxicity impairs pancreatic islets function, which is associated with the progression of type 2 diabetes. However, the dynamic mechanism underlying dysfunction of pancreatic islets caused by chronic inflammation is still not fully understood.As the systems biology develops, its multidisciplinary, holistic, systematic research approach affect many aspects of disease. Due to the rapid development of systems biology in the research of complex diseases in the past decade, it is considered to be an effective strategy for the study of type 2 diabetes mechanisms. Recent years, the systems biology approach based on bifurcation theory and quantitatively analyzing of multi-level data brings new ideas to highlight the mechanism of type 2 diabetes. Bifurcation theory can be used to explain the state transitions and genetic switches of certain biological processes, such as DNA damage and cell apoptosis. It has been widely accepted that the strong nonlinearity generated by positive feedback results in the bistability of the system. The biochemical switch with bistability and hysteresis, which is mainly caused by saddle-node bifurcation, provides a stable transition, even an irreversible transitions in physiological process.In this study, experimental model of islet inflammation was established using spontaneous type 2 diabetes Goto-Kakizaki(GK) rats and transgene IDOL mice to detect the changes of inflammatory factors. We found that both macrophage infiltration and IL-1β expression accelerates in GK rat islets during the progression of diabetes, especially in mid-and latestage(8-24 weeks). The expression level of CCL2 is upregulated following the increase of glucose and palmitic acid concentration and extension of treatment time. Besides, treatment of glucose and palmitic acid promotes IL-1β expression and activation in islets in vitro.A mathematical model depicting interaction between macrophage and islet β cells was built based on the above observation, where macrophage cells activate IL-1β in islet β cells with positive feedback loop. Our results showed that macrophage could influence the progression of islet inflammation. The positive feedback between pancreatic β cells and macrophages leads to saddle node bifurcation in the system. The bistable and hysteresis effect during the IL-1β activation progress causing by saddle node bifurcation has showed that IL-1β activation may be irreversible bistable, which will result in the irreversible development of islet inflammation. We investigated the IL-1β level with and without the macrophages during the glucose-induced islet inflammation process.We integrated cellular experiment with mathematical model, and analyzed quantitatively the effect of glucose and free fatty acid concentration on macrophage recruitment and islet inflammation. This dynamics mechanism of islet inflammation development will provide new insight on type 2 diabetes pathogenesis and treatment.