Adrenomedullin has a cytoprotective role against endoplasmic reticulum stress for pancreatic β-cells in autocrine and paracrine manners.

Pancreatic β-cells are sensitive to endoplasmic reticulum (ER) stress, which has a major role in the context of β-cell death. Adrenomedullin (ADM) has been shown to exert a cytoprotective effect under various pathophysiological conditions. Several studies have suggested that thiazolidinediones have protective effects on β-cells. During the course to elucidate the molecular mechanisms by which pioglitazone prevents β-cell death, ADM emerged as a candidate. Here, we studied the regulation of ADM expression, including the effects of pioglitazone, and its role in pancreatic islets. We analyzed ADM expression in islet cell lines treated with pioglitazone. The effects of ER stress on ADM and ADM receptor expressions were investigated by analyzing thapsigargin-treated MIN6 cells and islets isolated from Wfs1 Pioglitazone increased the production and secretion of ADM in islets through peroxisome-proliferator activated receptor-γ-dependent mechanisms. Thapsigargin treatment increased expressions of both ADM and ADM receptor, composed of Ramp2, Ramp3 and Crlr, in MIN6 cells. ADM and ADM receptor expressions were also increased in isolated islets from Wfs1 ER stress stimulates ADM production and secretion in islets. ADM signaling might protect β-cells from ER stress-induced apoptosis, and might be one of the self-protective mechanisms. β-Cell protection by pioglitazone is partly through induction of ADM. ADM-based therapy could be a novel strategy for treating diabetes.

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© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.