Glucose-stimulated insulin secretion (GSIS) from pancreatic beta-cell is essential in maintaining blood glucose homeostasis, whereas insufficient insulin secretion upon changes in nutrient level causes Type 2 Diabetes. We have previously shown inhibition of autophagy, which is a cellular catabolic machinery, increased GSIS. Here, we hypothesize that autophagy responses to changes in whole-body nutrient status to regulate the fuel level reserved in beta-cell and plays a role in GSIS.

Mice with beta-cell specific inducible deletion of the autophagy gene ATG7 (βATG7KO) were used in the study. To examine the role of autophagy in GSIS upon high-fat feeding, wild-type or βATG7KO mice were fed with chow or high-fat diet for 5 weeks followed by injection of tamoxifen to induce gene deletion, then, with a further 3-week diet, they were subjected to oral Glucose Tolerance Test (oGTT) and in vivo insulin measurement. Finally, islets were isolated for ex vivo GSIS study. Conversely, mice with the induced gene deletion were starved for 6h or 24h prior to oGTT and insulin measurement for the investigation of the role of autophagy in GSIS during nutrient deprivation.

Glucose tolerance impaired by long-term high-fat feeding was improved by beta-cell specific autophagy deletion, which was due to the enhanced insulin secretion. However, there is no observable change in the chow-fed mice. Compellingly, ex vivo GSIS in islets from high-fat fed mice was augmented by autophagy deficiency in beta-cells, and the increment was blocked by Orlistat (a neutral lipase inhibitor). On the other hand, insulin secretion was suppressed by overnight fasting compared to the 6h fasted mice and, notably, it was completely reversed in the βATG7KO mice. It was also accompanied by a modest improvement in overall glucose tolerance.

Autophagy operates in vivo during long-term high-fat feeding and starvation, which reduces lipid reserve in beta-cells and represses GSIS.