The fed state is frequently described with a glucose-centric focus, where increased glycemia stimulates insulin and decreases glucagon secretion. But, protein-containing meals that better indicate normal nutrition elevate glucagon secretion, generating rise in both hormones. Glucagon and insulin have contradictory impacts on hepatic glycogen; glucagon helps glycogenolysis while insulin promotes storage. Still, most effort in this area has centred on the individual rather than combined actions of these hormones. Megan Capozzi & team aimed to assess the impact of combined insulin and glucagon on postprandial hepatic glycogen metabolism. The team hypothesized that their combined actions elevate glycogen flux to entitle storage of meal nutrients. The findings were presented at the 84^th Scientific Sessions of the ADA Congress 2024, held in Orlando from 21^st – 24^th June 2024.

To evaluate the individual versus combined actions on hepatic glycogen content, Glucagon and/or insulin were injected into 5-hr fasted wild-type mice. Next, glucose alone versus a mixed-nutrient meal was forcibly feeded with matching carbohydrate loads, by a 13C6-glucose tracer to examine inclusion of meal-derived glucose into glycogen. Eventually, to analyse the impact on glycogen metabolism, a mixed-nutrient meal with tracer was given to proglucagon null mice (Gcg-/-).

Glucagon or insulin alone did not modify hepatic glycogen levels, but the combination of both hormones improved glycogenolysis. Meal-derived glucose included into hepatic glycogen was greater following a mixed-nutrient meal than oral glucose alone. Gcg-/- mice stored substantially less meal-derived glucose as glycogen as compared to controls.

The authors concluded that the combined actions of glucagon and insulin improve hepatic glycogen movement because of both improved glycogenolysis and storage of meal-derived glucose as glycogen. These actions qualify the liver to have higher metabolic flexibility for nutrient storage in the postprandial state. This may have consequence for disorder conditions such as diabetes or metabolic-associated steatotic liver disease, where hormone action is modified.