Effects of Intermittent Fasting‐Mimicking Diet on Pancreatic Islet Plasticity: Immunohistochemical, Ultrastructural, and Metabolic Profiles

ABSTRACT Periodic fasting is known to improve metabolic health, but its impact on pancreatic islet plasticity remains unclear. We investigated the effects of intermittent fasting‐mimicking diet (FMD) cycles on islet architecture and function in mice by performing immunohistochemical, ultrastructural, and metabolic analyses after fasting and after refeeding separately. Twelve‐week‐old female C57BL/6J mice were randomized to fasting ( n = 9), refeeding ( n = 10), or control group ( n = 10). FMD was supplied weekly for 3 days (50%, 10%, 10% of daily caloric intake) followed by 4 days of chow food ad libitum (except for pre‐IGTT food withdrawal and the duration of the IGTT). Intraperitoneal glucose tolerance tests (IGTTs) were performed at day 11 (fasting group), day 14 (refeeding group), and day 13 (control group). Mice were sacrificed 7 days after IGTT, and pancreata were subjected to fluorescence immunohistochemistry or scanning electron microscopy (STEM). Bodyweight, blood glucose, proinsulin, and IGF‐1 concentrations were significantly decreased after fasting but rebounded after refeeding. Pancreatic insulin + glucagon + , BRN4 + , and PDX1 + BRN4 + cells increased significantly after fasting and tended to remain high after refeeding, thereby indicating increased pancreatic islet plasticity after fasting. In STEM images, the insulin granule core‐to‐halo ratio increased significantly after fasting. The fasting but not the refeeding group showed impaired glucose tolerance. The more crystallized mature β‐cell granules indicate increased insulin secretory capacity, and the reduced proinsulin‐to‐insulin ratio suggests reduced endoplasmic reticulum stress in ß‐cells after fasting. We propose that this observed plasticity may provide a basis for novel concepts of in vivo β‐cell regeneration. However, further studies to investigate molecular mechanisms of fasting/refeeding in murine type 1 diabetes to evaluate its therapeutic potential are needed.