Importance of oestrogen receptors to preserve functional β-cell mass in diabetes

Protecting the functional mass of insulin-producing beta cells of the pancreas is a major therapeutic challenge in patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM). The gonadal hormone 17 beta-oestradiol (E2) is involved in reproductive, bone, cardiovascular and neuronal physiology. In rodent models of T1DM and T2DM, treatment with E2 protects pancreatic beta cells against oxidative stress, amyloid polypeptide toxicity, lipotoxicity and apoptosis. Three oestrogen receptors (ERs)-ER alpha, ER beta and the G protein-coupled ER (GPER)-have been identified in rodent and human beta cells. Whereas activation of ER alpha enhances glucose-stimulated insulin biosynthesis, reduces islet toxic lipid accumulation and promotes beta-cell survival from proapoptotic stimuli, activation of ER beta increases glucose-stimulated insulin secretion. However, activation of GPER protects beta cells from apoptosis, raises glucose-stimulated insulin secretion and lipid homeostasis without affecting insulin biosynthesis. Oestrogens are also improving islet engraftment in rodent models of pancreatic islet transplantation. This Review describes developments in the role of ERs in islet insulin biosynthesis and secretion, lipid homeostasis and survival. Moreover, we discuss why and how enhancing ER action in beta cells without the undesirable effect of general oestrogen therapy is a therapeutic avenue to preserve functional beta-cell mass in patients with diabetes mellitus.