Hepatic glycogen cycling contributes to glucose lowering effects of the glucokinase activator LCZ960

Glucokinase (GK) acts as a glucose sensor by facilitating glucose phosphorylation into glucose-6-phosphate (G6P) in the liver and pancreas, the two key target tissues. LCZ960, a glucokinase activator exerts a stimulatory effect on GK activity in hepatocytes in vitro. This study aimed to verify in vivo that LCZ960 stimulates glucose uptake primarily through a mechanism involving hepatic GK activation. Acute and chronic LCZ960 treatment-induced changes in glycemia and hepatic glucose turnover were measured in high fat diet-induced obese (DIO) mice and rats. G6P production and glycogen cycling were quantified by 13C-MR spectroscopy during a [1-13C]glucose infusion, followed by a pulse-chase with [12C]glucose to mimic postprandial conditions in rats. Acute treatment with LCZ960 dose-dependently reduced blood glucose without causing hypoglycemia in DIO mice. Chronic LCZ960 treatment maintained normoglycemia and improved glucose tolerance without increased insulin secretion in DIO mice and rats. In rats, LCZ960 stimulated a 240% increase (P