Distinct roles of systemic and local actions of insulin on pancreatic ?-cells.

ABSTRACT: OBJECTIVE:Pancreatic ?-cell mass and function are critical in glucose homeostasis. Their regulatory mechanisms have been studied principally under experimental conditions of reduced ?-cell numbers, such as ?-cell ablation and partial pancreatectomy. In the present study, we generated an opposite mouse model with an excessive amount of ectopic ?-cells, and analyzed its consequence on ?-cell mass and survival. METHODS:Mice underwent sub-renal transplantation (SRT) of pseudo-islets generated from a pancreatic ?-cell line MIN6 or intra-pancreatic transplantation (IPT) of MIN6 cells, and morphological and functional changes of their endocrine pancreata were analyzed. Cellular fate of pancreatic ?-cells after transplantation was traced using RipCre:Rosa26-tdTomato mice. By using MIN6 cells, we evaluated the roles of extracellular glucose, membrane potential, and insulin signaling on ?-cell survival. RESULTS:SRT mice developed severe, progressive hypoglycemia associated with marked reduction in insulin-positive (Ins+) cell mass and apparent increase in apoptotic Ins+ cells. In in vitro experiments of MIN6 cells, insulin signaling blockade potently induced cell death, suggesting that local insulin action is required for ?-cell survival. In fact, IPT (i.e. transplantation close to endogenous ?-cells) resulted in fewer apoptotic Ins+ cells compared with those induced by SRT. On the other hand, ?-cell mass was decreased in proportion to the decrease in blood glucose levels in both SRT and IPT mice, suggesting a contribution of hypoglycemia induced by systemic hyperinsulinemia. CONCLUSION:Insulin plays distinct roles in ?-cell survival and ?-cell mass regulation through its local and systemic actions on ?-cells, respectively.

SUBMITTER: Kitamoto T 

PROVIDER: S-EPMC7391221 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature