Zhejiang University: New mechanism in dietary intervention preserves pancreatic β

The modern lifestyle characterized by excessive nutrition and poverty of exercise contributes to the global epidemic of obesity and type 2 diabetes (T2D). Pancreatic β cell dysfunction, together with insulin resistance, are the main causes for the pathogenesis of T2D. A thorough analysis of the dynamic changes in the number and function of β cells in T2D and the mechanism of β cell dysfunction will provide a theoretical basis and molecular targets for the development of new and more effective individualized therapies for diabetes. It is well known that dietary intervention is an effective measure to prevent and treat diabetes. In recent years, many clinical trials have demonstrated that the recovery potential of pancreatic β cell function is a decisive factor in diet intervention for remission and treatment of T2D. However, how dietary intervention improves β cell function at different stages of obesity and T2D and its underlying molecular mechanisms remain unclear. Because of the unique anatomy of islets, most studies were based on detecting the changes of insulin levels in blood to reflect the function of β cells. The change of insulin level in blood circulation is not only related to the function of islet β cells, but also closely related to the insulin sensitivity of peripheral tissues, so it can not reflect the functional change of β cells accurately. Therefore, it is urgent to establish an appropriate and stable animal model to investigate the aforementioned processes and potential mechanisms.

On June 2, 2022, Prof. MENG Zhuoxian from the Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine and Prof. ZHU Lingyun from the National University of Defense Technology co-published an article entitled “Dietary Intervention Preserves β Cell Function in Mice Through CTCF-mediated Transcriptional Reprogramming” in the Journal of Experimental Medicine.

In this study, the researchers establish a mouse model exhibiting the compensation-to-decompensation adaptation of β cell function in response to increasing duration of high-fat diet (HFD) feeding. Comprehensive islet functional and transcriptome analyses reveal a dynamic orchestration of transcriptional networks featuring temporal alteration of chromatin remodeling. Interestingly, prediabetic dietary intervention completely rescues β cell dysfunction, accompanied by a remarkable reversal of HFD-induced reprogramming of islet chromatin accessibility and transcriptome. Mechanistically, ATAC-based motif analysis identifies CTCF as the top candidate driving dietary intervention–induced preservation of β cell function. CTCF expression is markedly decreased in β cells from obese and diabetic mice and humans. Both dietary intervention and AAV-mediated restoration of CTCF expression ameliorate β cell dysfunction ex vivo and in vivo, through transducing the lipid toxicity and inflammatory signals to transcriptional reprogramming of genes critical for β cell glucose metabolism and stress response.

Overall, this study systematically delineates a dynamic map of β cell function and gene expression profiles during the onset and development of obesity and T2D, revealing that dietary intervention improves β cell function in T2D. On this basis, it provides new molecular insights for the progression and dietary intervention-induced remission of β cell dysfunction in T2D.

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