Elevation of circulating fatty acids (FA) during fasting supports postprandial (PP) insulin secretion that is critical for glucose homeostasis and impaired in diabetes. We tested our hypothesis that lipid droplet (LD) protein perilipin 5 (PLIN5) in beta cells aids PP insulin secretion by regulating intracellular lipid metabolism. We demonstrated that PLIN5 serves as a LD protein in human islets. In vivo, Plin5 and triglycerides were increased by fasting in mouse islets. MIN6 expressing PLIN5 (Ad-PLIN5) and those expressing perilipin 2 (PLIN2) (Ad-PLIN2) had higher [3H]FA incorporation into triglycerides than Ad-GFP control, which support their roles as LD proteins. However, AD-PLIN5 cells had higher lipolysis than Ad-PLIN2 cells, which increased further by 8-Br-cAMP, indicating that PLIN5 facilitates FA mobilization upon cAMP stimulation as seen postprandially. Ad-PLIN5 in islets enhanced the augmentation of glucose stimulated insulin secretion by FA and 8-Br-cAMP in G-protein-coupled receptor 40 (GPR40) and cAMP activated protein kinase dependent manners respectively. When PLIN5 was increased in mouse beta cells in vivo, glucose tolerance following acute exenatide challenge was improved. Therefore, the elevation of islet PLIN5 during fasting allows partitioning of FA into LD that is released upon re-feeding to support PP insulin secretion in cAMP and GPR40 dependent manners.

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