Exploring novel molecular mechanisms of TSC22D4 action in development of diabetes mellitus

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Type 2 diabetes is the disease of the modern world which is associated with unhealthy eating habits and sedentary life style. Although anti-diabetes medications exist, they all have their own limitations and side effects. Hence, type 2 diabetic patients are in need of novel therapeutics, which requires a better understanding of the disease.We identified TSC22D4 as a novel regulator of insulin sensitivity and glucose metabolism and showed that human type 2 diabetic patients have elevated hepatic TSC22D4 levels that negatively correlate with insulin sensitivity. Yet the molecular mechanism of TSC22D4 action in controlling glucose homeostasis remains elusive. More recently, we could show that TSC22D4 interacts with Akt1 in a regulatory manner. While energy availability weakens the TSC22D4-Akt1 interaction, oxidative stress and mitochondrial inhibition promote it, suggesting that the TSC22D4-Akt1 interaction might inhibit Akt function. Interestingly, JNK signaling also promotes the TSC22D4-Akt1 interaction and introduces phosphorylation(s) on TSC22D4 at yet-to-be identified threonine residues(s). Additionally, we identified S62 as a novel phosphorylation site on TSC22D4 and showed that phospho-defective TSC22D4-S62A mutant impairs insulin stimulated Akt1 phosphorylation.Based on our preliminary data, my proposal will explore the functional implications of TSC22D4-Akt1 interaction in glucose metabolism and its state of regulation in healthy vs. diabetic state both in mice and humans. By employing p-S62 antibodies, we will also investigate the regulation and function of TSC22D4 S62 phosphorylation in maintenance of glucose homeostasis and insulin sensitivity. Importantly, we will examine the JNK-TSC22D4 connection in the context of oxidative stress and insulin resistance and identify JNK regulated threonine phosphorylation(s) on TSC22D4.Overall, this proposal will reveal the novel function of TSC22D4 action in controlling blood glucose levels and insulin sensitivity at the intersection of Akt and JNK signaling pathways, both of which are highly implicated in type 2 diabetes. Our findings will significantly contribute to our understanding of pathogenesis of type 2 diabetes and might promote development of novel therapeutics to treat this modern world disease.