Insulin is a hormone regulating glucose storage. Insulin resistance predisposes to diabetes and metabolic diseases. The cell stops responding to instructions from the hormone. Restoring insulin sensitivity is an effective approach to prevent and treat diabetes and to reduce the major vascular complications. However, currently available insulin sensitizers have significant adverse effects, such as weight gain due to triglyceride accumulation, fractures and hemodynamic changes.

       In a new study, researchers found insulin inhibits glucose production in the liver by inhibiting FOXO1 to activate G6pase and inhibit glucokinase to promote fat generation , respectively. FOXO1 as inhibition of glucose production is predicted to increase lipogenesis. they found SIN3A is the insulin-sensitive FOXO1 corepressor of glucokinase. Genetic ablation of SIN3A abolishes nutrient regulation of glucokinase without affecting other FOXO1 target genes and lowers glycemia without concurrent steatosis. To extend this work, we executed a small-molecule screen and discovered selective inhibitors of FOXO-dependent glucose production devoid of lipogenic activity in hepatocytes.

       The next step is to optimize these compounds in animal experiments, and lay a foundation for clinical trials, they are likely to develop a new method for safer diabetes treatment.