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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

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

Kitamoto Takumi T Sakurai Kenichi K Lee Eun Young EY Yokote Koutaro K Accili Domenico D Miki Takashi T

Metabolism: clinical and experimental 20180107

<h4>Objective</h4>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.<h4>Methods</h4>Mice underwent sub-renal transplantation (SRT) of pseudo-islets g ...[more]

PMID: 29320716

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Project description:Expansion of beta cells from the limited number of adult human islet donors is an attractive prospect for increasing cell availability for cell therapy of diabetes. However, attempts at expanding human islet cells in tissue culture result in loss of beta-cell phenotype. Using a lineage-tracing approach we provided evidence for massive proliferation of beta-cell-derived (BCD) cells within these cultures. Expansion involves dedifferentiation resembling epithelial-mesenchymal transition (EMT). Epigenetic analyses indicate that key beta-cell genes maintain open chromatin structure in expanded BCD cells, although they are not transcribed. Here we investigated whether BCD cells can be redifferentiated into beta-like cells.Redifferentiation conditions were screened by following activation of an insulin-DsRed2 reporter gene. Redifferentiated cells were characterized for gene expression, insulin content and secretion assays, and presence of secretory vesicles by electron microscopy. BCD cells were induced to redifferentiate by a combination of soluble factors. The redifferentiated cells expressed beta-cell genes, stored insulin in typical secretory vesicles, and released it in response to glucose. The redifferentiation process involved mesenchymal-epithelial transition, as judged by changes in gene expression. Moreover, inhibition of the EMT effector SLUG (SNAI2) using shRNA resulted in stimulation of redifferentiation. Lineage-traced cells also gave rise at a low rate to cells expressing other islet hormones, suggesting transition of BCD cells through an islet progenitor-like stage during redifferentiation.These findings demonstrate for the first time that expanded dedifferentiated beta cells can be induced to redifferentiate in culture. The findings suggest that ex-vivo expansion of adult human islet cells is a promising approach for generation of insulin-producing cells for transplantation, as well as basic research, toxicology studies, and drug screening.

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

Publications

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

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