Moderate calorie restriction to achieve normal weight reverses β-cell dysfunction in diet-induced obese mice: involvement of autophagy

Background: Severe calorie restriction (CR) is shown to improve or even reverse beta-cell dysfunction in patients with obesity and type 2 diabetes mellitus. However, whether mild to moderate CR can reverse beta-cell dysfunction induced by obesity and the underlying mechanism remain unclear. Autophagy plays an important role in maintaining mass, architecture and function of beta-cells. While the impact of CR on beta-cell autophagy is unknown. This study aims to investigate the effects of moderate CR on beta-cell function and autophagy activity in diet-induced obese (DIO) mice. Methods: DIO C57BL/6 mice were subjected to 3 weeks of switching to normal chow (HF -> NC group) or normal chow with 40 % CR (HF -> NC CR group). Then hematoxylin-eosin and immunohistochemistry staining were performed to observe beta-cell morphology. beta-cell function was evaluated by intraperitoneal glucose tolerance test in vivo and static GSIS (glucose-stimulated insulin secretion) in isolated islets. beta-cell autophagy activity was determined by transmission electron microscope and western blot. Results: In the HF -> NC CR group, CR normalized body weights, completely restored glucose tolerance, earlyphase and second-phase insulin secretion, insulin sensitivity, and islet size. CR also normalized insulin content and glucose-stimulated insulin secretion in isolated islets in vitro. Furthermore, beta-cell autophagy level was increased in the HF -> NC CR group, but AMPK phosphorylation remained unchanged. Although HF -> NC mice achieved moderate weight loss and normal glucose tolerance, their insulin secretion was not improved compared with obese control mice, and additionally, beta-cell autophagy was not activated in these mice. Conclusions: Moderate (40 %) CR to achieve normal weight reversed beta-cell dysfunction and insulin resistance, and restored glucose homeostasis in DIO mice. Furthermore, the up-regulation of beta-cell autophagy may play a role in this process, independent of AMPK activation.