Role of glycogenolysis and reduced glucose uptake in AKT inhibitor-induced hyperglycemia

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AKT is a key mediator of insulin signaling and inhibition of PI3K-AKT pathway often leads to elevation in blood glucose and insulin levels. GSK690693, a pan-AKT kinase inhibitor in clinical development, induces transient hyperglycemia and hyperinsulinemia in animals. Anti-diabetic agents, fasting, and diet alteration were used to investigate the likely mechanism(s) of AKT inhibitor-induced hyperglycemia in rodents.
 Administration of approved anti-diabetic agents including insulin infusion, rosiglitazone, metformin, exenatide, and vildagliptin (DPP-4 inhibitor) had no significant effect on GSK690693-induced hyperglycemia in rodents suggesting these agents cannot reverse GSK690693-abrogated insulin functions. GSK690693 potently inhibited phosphorylation of GSK3β in vitro and in vivo indicating an inactivation of glycogen synthase activity. Liver glycogen content was significantly reduced (~90%, p<0.001) at 2h after single intraperitoneal administration of GSK690693 (30 or 40 mg/kg) in mice, further suggesting that GSK690693 may inhibit glycogen synthesis as well as activate glycogenolysis. Fasting for 16-20h to reduce liver glycogen content attenuated the hyperglycemia effect induced by GSK690693 in mice. GSK690693 also inhibited peripheral glucose uptake as measured by glucose tolerance test, implying that a carbohydrate-containing diet may result in blood glucose elevation in individuals treated with AKT inhibitor(s). Introduction of a low (7%) or 0% carbohydrate diet after GSK690693 administration effectively reduced the diet-induced hyperglycemia in mice.
 Insulin promotes glucose uptake and glycogen synthesis. Overall, our data suggests that abrogation of insulin signaling by AKT inhibitor(s) leads to glycogenolysis in the liver as well as a blockade of the peripheral glucose uptake, resulting in an increased blood glucose level. A combination of fasting, prior to drug administration (to reduce liver glycogen content), and a low or no carbohydrate diet after drug administration (to reduce availability of circulating glucose from diet) can successfully manage GSK690693-induced hyperglycemia in mice.