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

• Published in: Applied physiology, nutrition, and metabolism nutrition, and metabolism, 2019-12, Vol.44 (12), p.1355-1366
• Main Authors: Huang, Hui, Yang, Kaiyuan, Wang, Rennian, Han, Woo Hyun, Kuny, Sharee, Zelmanovitz, Paula Horn, Sauvé, Yves, Chan, Catherine B
• Format: Article
• Language: English
• Subjects: Adaptation; animal model; Animals; Compensation; compensation des cellules β; Diabetes; Diabetes Mellitus, Type 2 - chemically induced; Diabetes Mellitus, Type 2 - physiopathology; diabète de type 2; Diet - adverse effects; Dietary Fiber; Endoplasmic reticulum; Endoplasmic Reticulum Stress; ER stress; Glucose - metabolism; Insulin - metabolism; Insulin resistance; Insulin-Secreting Cells - physiology; Male; Metabolism; modèle animal; Murinae; neogenesis; néogenèse; Physiology; proliferation; prolifération; stress ER; type 2 diabetes; Unfolded Protein Response; β-cell compensation
• ISSN: 1715-5312; 1715-5320
• DOI: 10.1139/apnm-2019-0144

Insulin-secreting pancreatic β-cells adapt to obesity-related insulin resistance via increases in insulin secretion and β-cell mass. Failed β-cell compensation predicts the onset of type 2 diabetes (T2D). However, the mechanisms of β-cell compensation are not fully understood. Our previous study reported changes in β-cell mass during the progression of T2D in the Nile rat (NR; Arvicanthis niloticus) fed standard chow. In the present study, we measured other β-cell adaptive responses, including glucose metabolism and β-cell insulin secretion in NRs at different ages, thus characterizing NR at 2 months as a model of β-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 β-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 β-cell growth as a mechanism of β-cell mass adaptation. In contrast, decreased neogenesis and β-cell dedifferentiation were observed in β-cell dysfunction. Furthermore, the progression of T2D and pathophysiological changes of β-cells were prevented by increasing fibre content of the diet. Novelty Our study characterized a novel model for β-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. β-Cell neogenesis but not proliferation contributes to β-cell mass adaptation.