• G6pc2 deletion lowers fasting blood glucose (FBG) in chow and high fat fed mice. • Elevated FBG increases the risk of cardiovascular-associated mortality (CAM). • G6pc2 deletion results in hypoglycemia in mice on a ketogenic diet. • G6pc2 deletion results in hypoglycemia in mice following prolonged fasting. • G6PC2 inhibitors may prevent CAM but increase risk of hypoglycemia.