Takumi Kitamoto1, Kenichi Sakurai2, Eun Young Lee3, Koutaro Yokote4, Domenico Accili5, Takashi Miki6. 1. Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan; Department of Clinical Cell Biology and Medicine, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan; Division of Endocrinology, Department of Medicine, Columbia University, New York 10032, USA. 2. Center for Preventive Medical Sciences, Chiba University, Chiba 263-8522, Japan. 3. Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan. 4. Department of Clinical Cell Biology and Medicine, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan. 5. Division of Endocrinology, Department of Medicine, Columbia University, New York 10032, USA. 6. Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan. Electronic address: tmiki@faculty.chiba-u.jp.
Abstract
OBJECTIVE: Pancreatic β-cell mass and function are critical in glucose homeostasis. Their regulatory mechanisms have been studied principally under experimental conditions of reduced β-cell numbers, such as β-cell ablation and partial pancreatectomy. In the present study, we generated an opposite mouse model with an excessive amount of ectopic β-cells, and analyzed its consequence on β-cell mass and survival. METHODS: Mice underwent sub-renal transplantation (SRT) of pseudo-islets generated from a pancreatic β-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 β-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 β-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 β-cell survival. In fact, IPT (i.e. transplantation close to endogenous β-cells) resulted in fewer apoptotic Ins+ cells compared with those induced by SRT. On the other hand, β-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 β-cell survival and β-cell mass regulation through its local and systemic actions on β-cells, respectively.
OBJECTIVE: Pancreatic β-cell mass and function are critical in glucose homeostasis. Their regulatory mechanisms have been studied principally under experimental conditions of reduced β-cell numbers, such as β-cell ablation and partial pancreatectomy. In the present study, we generated an opposite mouse model with an excessive amount of ectopic β-cells, and analyzed its consequence on β-cell mass and survival. METHODS:Mice underwent sub-renal transplantation (SRT) of pseudo-islets generated from a pancreatic β-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 β-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 β-cell survival. RESULTS:SRTmice 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 β-cell survival. In fact, IPT (i.e. transplantation close to endogenous β-cells) resulted in fewer apoptotic Ins+ cells compared with those induced by SRT. On the other hand, β-cell mass was decreased in proportion to the decrease in blood glucose levels in both SRT and IPTmice, suggesting a contribution of hypoglycemia induced by systemic hyperinsulinemia. CONCLUSION: Insulin plays distinct roles in β-cell survival and β-cell mass regulation through its local and systemic actions on β-cells, respectively.
Authors: Vivi F H Jensen; Anne-Marie Mølck; Jette Nowak; Johannes J Fels; Jens Lykkesfeldt; Ingrid B Bøgh Journal: Sci Rep Date: 2022-08-18 Impact factor: 4.996