Overexpression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in mouse liver lowers blood glucose by suppressing hepatic glucose production

Hepatic 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase is an importan t regulatory enzyme of glucose metabolism. By controlling the level of fruc tose-2,6-bisphosphate, an allosteric activator of the glycolytic enzyme 6-p hosphofructo-1-kinase and an inhibitor of the gluconeogenic enzyme fructose -1,6-bisphosphatase, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase r egulates hepatic glucose output. We studied the effects of adenovirus-media ted overexpression of this enzyme on hepatic glucose metabolism in normal o r diabetic mice. These animals were treated with virus encoding either wild -type or bisphosphatase activity-deficient 6-phosphofructo-2 -kinase/fructo se-2,6-bisphosphatase. Seven days after virus injection, hepatic fructose-2 ,6-bisphosphate levels increased significantly in both normal and diabetic mice, with larger increases observed in animals with overexpression of the mutant enzyme. Blood glucose levels in normal mice overexpressing either en zyme were lowered accompanied by increased plasma lactate, triglycerides, a nd FFAs. Blood glucose levels were markedly reduced in diabetic mice overex pressing the wild-type enzyme, and still more so in mice overexpressing the mutant form of the enzyme. The lower blood glucose levels in diabetic mice were accompanied by partially normalized plasma triglycerides and FFAs, in creased plasma lactate, and increased liver glycogen levels, relative to di abetic mice treated with a control adenovirus. Our findings underscore the critical role played by hepatic 6-phosphofructo-2-kinase/fructose-2,6-bisph osphatase in control of fuel homeostasis and suggest that this enzyme may b e considered as a therapeutic target in diabetes.