Reduced Retinoic Acid Receptor Beta (Rarβ) Affects Pancreatic β-Cell Physiology

Simple Summary Vitamin A is one of the important micronutrients involved in various biological functions. Numerous studies have suggested a link between vitamin A (retinoic acid) and type 2 diabetes (T2D). However, the functional role of vitamin A receptors (RAR alpha, beta, and gamma) in beta-pancreatic cells is not clear yet. In this study, we performed bioinformatics and functional experiments in human islets and INS-1 cells in order to evaluate the potential role of RAR beta on insulin secretion and pancreatic beta-cell function. Various studies have suggested a link between vitamin A (VA), all-trans-retinol, and type 2 diabetes (T2D). However, the functional role/expression of vitamin A receptors (Rar alpha, beta, and gamma) in pancreatic beta-cells is not clear yet. Accordingly, we performed a series of bioinformatics, molecular and functional experiments in human islet and INS-1 cells to evaluate the role of Rar beta on insulin secretion and pancreatic beta-cell function. Microarray and RNA-sequencing (RAN-seq) expression analysis showed that RAR alpha, beta, and gamma are expressed in human pancreatic islets. RNA-seq expression of RAR beta in diabetic/hyperglycemic human islets (HbA1c >= 6.3%) revealed a significant reduction (p = 0.004) compared to nondiabetic/normoglycemic cells (HbA1c < 6%). The expression of RAR beta with INS and PDX1 showed inverse association, while positive correlations were observed with INSR and HbA1c levels. Exploration of the T2D knowledge portal (T2DKP) revealed that several genetic variants in RAR beta are associated with BMI. The most associated variant is rs6804842 (p = 1.2 x 10(-25)). Silencing of Rar beta in INS-1 cells impaired insulin secretion without affecting cell viability or apoptosis. Interestingly, reactive oxygen species (ROS) production levels were elevated and glucose uptake was reduced in Rar beta-silenced cells. mRNA expression of Ins1, Pdx1, NeuroD1, Mafa, Snap25, Vamp2, and Gck were significantly (p < 0.05) downregulated in Rar beta-silenced cells. For protein levels, Pro/Insulin, PDX1, GLUT2, GCK, pAKT/AKT, and INSR expression were downregulated considerably (p < 0.05). The expression of NEUROD and VAMP2 were not affected. In conclusion, our results indicate that Rar beta is an important molecule for beta-cell function. Hence, our data further support the potential role of VA receptors in the development of T2D.