Hyperinsulinemia induces insulin resistance and immune suppression via Ptpn6/Shp1 in zebrafish

Type 2 diabetes, obesity and metabolic syndrome are pathologies where insulin resistance plays a central role and that have an impact on a large population worldwide. These pathologies are usually associated with a dysregulation of insulin secretion leading to a chronic exposure of the tissues to high insulin levels (i.e. hyperinsulinemia), which diminishes the concentration of key downstream elements causing insulin resistance. The complexity of the study of insulin resistance arises from the heterogeneity of the metabolic states where it is observed. To contribute to the understanding of the mechanisms triggering insulin resistance we have developed a zebrafish model to study insulin metabolism and its associated disorders. Zebrafish larvae appeared to be sensitive to human recombinant insulin, becoming insulin resistant when exposed to a high dose of the hormone. Moreover RNAseq-based transcriptomic profiling of these larvae revealed a strong down regulation of a number of immune relevant genes as a consequence of the exposure to hyperinsulinemia. Interestingly, as an exception, the negative immune modulator ptpn6 appeared to be up regulated in insulin resistant larvae. Knockdown of ptpn6 showed to counteract the observed down regulation of the immune system and insulin signaling pathway caused by hyperinsulinemia. These results show that ptpn6 is a mediator of the metabolic switch between insulin sensitive and insulin resistant states. Our zebrafish model for hyperinsulinemia has therefore demonstrated its suitability to discover novel regulators of insulin resistance. In addition, our data will be very useful to further study the function of immunological determinants in a non-obese model system.