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Rescue of insulin receptor condensates in insulin resistant cells

ABSTRACT: Insulin resistance is accompanied by chronic hyperinsulinemia and is associated with type 2 diabetes and other metabolic syndromes in a substantial portion of the population. The risk factors and features of insulin resistance have been thoroughly described but its mechanistic triggers are still under study. Here we consider a condensate model for insulin receptor (IR) function in normal conditions and when dysregulated in chronic hyperinsulinemia-induced insulin resistance. We find that IR is incorporated into liquid-like condensates at the plasma membrane, in the cytoplasm and in the nucleus of liver cells, and provide evidence for insulin-dependent IR function in condensates. Insulin stimulation promotes further incorporation of IR into these dynamic condensates in insulin sensitive cells, which form and dissolve on short, sub-minute time-scales. In contrast, insulin stimulation does not promote further incorporation of IR into condensates in insulin resistant cells, where IR molecules within condensates exhibit less dynamic behavior. Metformin treatment of insulin resistant cells rescues IR condensate dynamics and insulin responsiveness. Insulin resistant cells experience high levels of oxidative stress, which causes reduced condensate dynamics, and treatment of these cells with metformin reduces ROS levels and returns condensates to their normal dynamic behavior. The condensate model we propose can account for features of normal and dysregulated insulin response and has implications for improved therapeutic approaches to insulin resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE181096 | GEO | 2023/07/28

REPOSITORIES: GEO

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Project description:Type 2 Diabetes, obesity and metabolic syndrome are pathologies impacting a large population worldwide where insulin resistance plays a central role. These pathologies are usually associated to a dysregulation of insulin secretion leading to a chronic exposure of the tissues to high insulin levels (i.e. hyperinsulinemia) what diminishes the concentration of key downstream elements causing insulin resistance. The complexity of the study of insulin resistance relies on the heterogeneity of the metabolic states where itM-bM-^@M-^Ys observed. In consequence, animal models for the study of insulin resistance, can not completely recapitulate the metabolic status of insulin resistant humans, what is translated in contradictory observations. 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 embryos appeared to be sensitive to human recombinant insulin, becoming insulin resistant when exposed to a high dose of the hormone, as confirmed by glucose measurements. Moreover RNAseq-based transcriptomic profiling of these embryos revealed a strong down regulation of a number of immune relevant genes as a consequences of the exposure to hyperinsulinemia. Interestingly, as an exception, the negative immune modulator ptpn6 appeared to be up regulated in insulin resistant embryos. Knockdown of ptpn6 showed to counteract the observed down regulation of the immune system and insulin signalling pathways effects at the transcriptional level 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 it 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. 16 samples in total were analyzed. 4 replicates from control samples (injected with PBS) and 4 replicates of insulin injected samples at 0.5 hpi and 4 hpi. In each sample 10 embryos were pooled.

Project description:Type 2 Diabetes, obesity and metabolic syndrome are pathologies impacting a large population worldwide where insulin resistance plays a central role. These pathologies are usually associated to a dysregulation of insulin secretion leading to a chronic exposure of the tissues to high insulin levels (i.e. hyperinsulinemia) what diminishes the concentration of key downstream elements causing insulin resistance. The complexity of the study of insulin resistance relies on the heterogeneity of the metabolic states where it’s observed. In consequence, animal models for the study of insulin resistance, can not completely recapitulate the metabolic status of insulin resistant humans, what is translated in contradictory observations. 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 embryos appeared to be sensitive to human recombinant insulin, becoming insulin resistant when exposed to a high dose of the hormone, as confirmed by glucose measurements. Moreover RNAseq-based transcriptomic profiling of these embryos revealed a strong down regulation of a number of immune relevant genes as a consequences of the exposure to hyperinsulinemia. Interestingly, as an exception, the negative immune modulator ptpn6 appeared to be up regulated in insulin resistant embryos. Knockdown of ptpn6 showed to counteract the observed down regulation of the immune system and insulin signalling pathways effects at the transcriptional level 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 it 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.

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Rescue of insulin receptor condensates in insulin resistant cells

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