Transcriptome analysis of islets from diabetes‐resistant and diabetes‐prone obese mice reveals novel gene regulatory networks involved in beta‐cell compensation and failure

Abstract The mechanisms underpinning beta‐cell compensation for obesity‐associated insulin resistance and beta‐cell failure in type 2 diabetes remain poorly understood. We used a large‐scale strategy to determine the time‐dependent transcriptomic changes in islets of diabetes‐prone db/db and diabetes‐resistant ob/ob mice at 6 and 16 weeks of age. Differentially expressed genes were subjected to cluster, gene ontology, pathway and gene set enrichment analyses. A distinctive gene expression pattern was observed in 16 week db/db islets in comparison to the other groups with alterations in transcriptional regulators of islet cell identity, upregulation of glucose/lipid metabolism, and various stress response genes, and downregulation of specific amino acid transport and metabolism genes. In contrast, ob/ob islets displayed a coordinated downregulation of metabolic and stress response genes at 6 weeks of age, suggestive of a preemptive reconfiguration in these islets to lower the threshold of metabolic activation in response to increased insulin demand thereby preserving beta‐cell function and preventing cellular stress. In addition, amino acid transport and metabolism genes were upregulated in ob/ob islets, suggesting an important role of glutamate metabolism in beta‐cell compensation. Gene set enrichment analysis of differentially expressed genes identified the enrichment of binding motifs for transcription factors, FOXO4, NFATC1, and MAZ. siRNA‐mediated knockdown of these genes in MIN6 cells altered cell death, insulin secretion, and stress gene expression. In conclusion, these data revealed novel gene regulatory networks involved in beta‐cell compensation and failure. Preemptive metabolic reconfiguration in diabetes‐resistant islets may dampen metabolic activation and cellular stress during obesity.