Fructose bisphosphatase 2 overexpression increases glucose uptake in skeletal muscle

Skeletal muscle is a major tissue for glucose metabolism and can store glucose as glycogen, convert glucose to lactate via glycolysis and fully oxidise glucose to CO2. Muscle has a limited capacity for gluconeogenesis but can convert lactate and alanine to glycogen. Gluconeogenesis requires FBP2, a muscle-specific form of fructose bisphosphatase that converts fructose-1,6-bisphosphate (F-1,6-bisP) to fructose-6-phosphate (F-6-P) opposing the activity of the ATP-consuming enzyme phosphofructokinase (PFK). In mammalian muscle, the activity of PFK is normally 100 times higher than FBP2 and therefore energy wasting cycling between PFK and FBP2 is low. In an attempt to increase substrate cycling between F-6-P and F-1,6-bisP and alter glucose metabolism, we overexpressed FBP2 using a muscle-specific adeno-associated virus (AAV-tMCK-FBP2). AAV was injected into the right tibialis muscle of rats, while the control contralateral left tibialis received a saline injection. Rats were fed a chow or 45% fat diet (HFD) for 5 weeks after which, hyperinsulinaemic-euglycaemic clamps were performed. Infection of the right tibialis with AAV-tMCK-FBP2 increased FBP2 activity 10 fold on average in chow and HFD rats (P