β-Cell compensation concomitant with adaptive endoplasmic reticulum stress and β-cell neogenesis in a diet-induced type 2 diabetes model

Insulin-secreting pancreatic beta-cells adapt to obesity-related insulin resistance via increases in insulin secretion and beta-cell mass. Failed beta-cell compensation predicts the onset of type 2 diabetes (T2D). However, the mechanisms of beta-cell compensation are not fully understood. Our previous study reported changes in beta-cell mass during the progression of T2D in the Nile rat (NR; Arvicanthis niloticus) fed standard chow. In the present study, we measured other beta-cell adaptive responses, including glucose metabolism and beta-cell insulin secretion in NRs at different ages, thus characterizing NR at 2 months as a model of beta-cell compensation followed by decompensation at 6 months. We observed increased proinsulin secretion in the transition from compensation to decompensation, which is indicative of impaired insulin processing. Subsequently, we compared adaptive unfolded protein response in beta-cells and demonstrated a positive role of endoplasmic reticulum (ER) chaperones in insulin secretion. In addition, the incidence of insulin-positive neogenic but not proliferative cells increased during the compensation phase, suggesting nonproliferative beta-cell growth as a mechanism of beta-cell mass adaptation. In contrast, decreased neogenesis and beta-cell dedifferentiation were observed in beta-cell dysfunction. Furthermore, the progression of T2D and pathophysiological changes of beta-cells were prevented by increasing fibre content of the diet. Novelty Our study characterized a novel model for beta-cell compensation with adaptive responses in cell function and mass. The temporal association of adaptive ER chaperones with blood insulin and glucose suggests upregulated chaperone capacity as an adaptive mechanism. beta-Cell neogenesis but not proliferation contributes to beta-cell mass adaptation.