296-OR: Glucagon and Insulin Cross Talk Regulates Hepatic Glycogen Metabolism

The fed state is often defined with a glucose-centric focus, where elevated glycemia stimulates insulin and reduces glucagon secretion. However, protein-containing meals that better reflect normal nutrition increase glucagon secretion, producing elevations in both hormones. Glucagon and insulin have opposing effects on hepatic glycogen; glucagon promotes glycogenolysis while insulin promotes storage. Yet, most work in this area has focused on the individual rather than combined actions of these hormones. The purpose of this study was to determine the effect of combined insulin and glucagon on postprandial hepatic glycogen metabolism. We hypothesized that their combined actions increase glycogen flux to enable storage of meal nutrients.

Glucagon and/or insulin were injected into 5-hr fasted wild-type mice to determine the individual versus combined actions on hepatic glycogen content. Next, glucose alone versus a mixed-nutrient meal was gavaged with matching carbohydrate loads, using a 13C6-glucose tracer to assess incorporation of meal-derived glucose into glycogen. Finally, a mixed-nutrient meal with tracer was given to proglucagon null mice (Gcg^-/-) to determine the effect on glycogen metabolism.

Glucagon or insulin alone did not alter hepatic glycogen levels, however the combination of both hormones enhanced glycogenolysis. Meal-derived glucose incorporated into hepatic glycogen was higher after a mixed-nutrient meal compared to oral glucose alone. Gcg^-/- mice stored significantly less meal-derived glucose as glycogen versus controls.

Our results suggest that the combined actions of glucagon and insulin enhance hepatic glycogen turnover due to both enhanced glycogenolysis and storage of meal-derived glucose as glycogen. These actions enable the liver to have greater metabolic flexibility for nutrient storage in the postprandial state. This may have implications for disease states such as diabetes or metabolic-associated steatotic liver disease, where hormone action is altered.