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

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.