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

作者：Kitamoto Takumi; Sakurai Kenichi; Lee Eun Young; Yokote Koutaro; Accili Domenico; Miki Takashi^*

来源：Metabolism-Clinical and Experimental, 2018, 82: 100-110.

DOI：10.1016/j.metabol.2017.12.017

• beta-Cell survival
• beta-Cell mass regulation
• Hypoglycemia
• Insulin signaling

Objective: Pancreatic beta-cell mass and function are critical in glucose homeostasis. Their regulatory mechanisms have been studied principally under experimental conditions of reduced beta-cell numbers, such as beta-cell ablation and partial pancreatectomy. In the present study, we generated an opposite mouse model with an excessive amount of ectopic beta-cells, and analyzed its consequence on beta-cell mass and survival.
Methods: Mice underwent sub-renal transplantation (SRT) of pseudo-islets generated from a pancreatic beta-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 beta-cells after transplantation was traced using RipCre:Rosa26-tdTomato mice. By using MING cells, we evaluated the roles of extracellular glucose, membrane potential, and insulin signaling on (beta-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 beta-cell survival. In fact, IPT (i.e. transplantation close to endogenous beta-cells) resulted in fewer apoptotic Ins(+) cells compared with those induced by SRT. On the other hand, beta-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 beta-cell survival and beta-cell mass regulation through its local and systemic actions on beta-cells, respectively.

• 出版日期2018-5