The modern lifestyle characterized by overeating and poor exercise contributes to the global epidemic of obesity and type 2 diabetes (T2D). Dysfunction of pancreatic β cells, together with insulin resistance, are the main causes of the pathogenesis of T2DM. Further analysis of the dynamic changes in β-cell number and function in T2DM and the mechanism of β-cell dysfunction will provide a theoretical basis and molecular targets for the development of new, 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, numerous clinical trials have demonstrated that the potential for recovery of pancreatic β-cell function is a decisive factor in dietary intervention for the remission and treatment of T2DM. However, how dietary intervention improves β-cell function in different stages of obesity and T2D and its underlying molecular mechanisms remain unclear. Due to the unique anatomy of the islets, most studies have been based on detecting changes in blood insulin levels to reflect β cell function. The change in the level of insulin in the bloodstream is not only related to the function of islet β cells, but also closely related to the insulin sensitivity of peripheral tissues, so it cannot reflect accurately the functional change of β cells. Therefore, there is an urgent need to establish a suitable and stable animal model to study the above-mentioned processes and potential mechanisms.
On June 2, 2022, Professor MENG Zhuoxian of the Department of Pathology and Pathophysiology and the Department of Cardiology of the Second Affiliated Hospital of the Faculty of Medicine of Zhejiang University and Professor ZHU Lingyun of the National University of Technology of the defense co-published a paper titled “Dietary intervention preserves β-cell function in mice through CTCF-mediated transcriptional reprogramming” in the Journal of Experimental Medicine.
In this study, researchers establish a mouse model exhibiting the adaptation of compensation to decompensation of β-cell function in response to increasing duration of high-fat diet (HFD). Comprehensive analyzes of islet function and transcriptome reveal dynamic orchestration of transcriptional networks exhibiting temporally altered chromatin remodeling. Interestingly, prediabetic dietary intervention completely rescues β-cell dysfunction, accompanied by a remarkable reversal of HFD-induced reprogramming of islet chromatin and transcriptome accessibility. Mechanistically, ATAC-based pattern analysis identifies CTCF as the best candidate for preservation of dietary intervention-induced β-cell function. CTCF expression is markedly decreased in β cells from obese and diabetic mice and humans. Dietary intervention and AAV-mediated restoration of CTCF expression ameliorates β-cell dysfunction ex vivo and in vivo, by transducing lipid toxicity and inflammatory signals into transcriptional reprogramming of genes essential for glucose metabolism in β cells and the stress response.
Taken together, 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 function. β cells in T2D. Based on this, it provides new molecular insights for the progression and dietary intervention-induced remission of β-cell dysfunction in T2DM.