γ-Oryzanol Protects Pancreatic β-Cells Against Endoplasmic Reticulum Stress in Male Mice

Endoplasmic reticulum (ER) stress is profoundly involved in dysfunction of beta-cells under high-fat diet and hyperglycemia. Our recent study in mice showed that gamma-oryzanol, a unique component of brown rice, acts as a chemical chaperone in the hypothalamus and improves feeding behavior and diet-induced dysmetabolism. However, the entire mechanism whereby gamma-oryzanol improves glucose metabolism throughout the body still remains unclear. In this context, we tested whether gamma-oryzanol reduces ER stress and improves function and survival of pancreatic beta-cells using murine beta-cell line MIN6. In MIN6 cells with augmented ER stress by tunicamycin, gamma-oryzanol decreased exaggerated expression of ER stress-related genes and phosphorylation of eukaryotic initiation factor-2 alpha, resulting in restoration of glucose-stimulated insulin secretion and prevention of apoptosis. In islets from high-fat diet-fed diabetic mice, oral administration of gamma-oryzanol improved glucose-stimulated insulin secretion on following reduction of exaggerated ER stress and apoptosis. Furthermore, we examined the impact of gamma-oryzanol on low-dose streptozotocin-induced diabetic mice, where exaggerated ER stress and resultant apoptosis in beta-cells were observed. Also in this model, gamma-oryzanol attenuated mRNA level of genes involved in ER stress and apoptotic signaling in islets, leading to amelioration of glucose dysmetabolism. Taken together, our findings demonstrate that gamma-oryzanol directly ameliorates ER stress-induced beta-cell dysfunction and subsequent apoptosis, highlighting usefulness of gamma-oryzanol for the treatment of diabetes mellitus.