Grb10 is an intracellular adaptor protein that is highly expressed in insulin-target tissues, such as muscle and adipose tissue. It binds to, and negatively regulates, receptor tyrosine kinases including the insulin receptor (IR). Previously we have shown that whole body knockouts of Grb10 are bigger than their WT littler-mates with larger muscles (increased fibre number), smaller fat pads and improved glucose tolerance¹. To elucidate the muscle contribution to this phenotype, we generated muscle specific Grb10 knockouts (mGrb10).

Skeletal muscle specific Grb10 knockout mice were generated by mating mice harbouring loxP sites flanking exon 4 of Grb10, with mice expressing Cre recombinase under the control of the skeletal actin promoter. Floxed litter-mates served as controls (WT). At 1 year of age, mice underwent a glucose tolerance test (2g/kg) or underwent cannulation surgery to insert catheters into the carotid artery and jugular vein. Approximately 1 week later, cannulated animals underwent a hyperinsulinaemic-euglycaemic clamp (5mU/kg/min insulin; variable 25% glucose rate) with radioactive tracer administration to determine whole body and tissue specific glucose metabolism.

At 1 year of age, mGrb10 mice were slightly, but significantly, heavier (~8%) but had identical glucose tolerance to that of WT mice. Clamp studies showed that the glucose infusion rate (GIR) needed to maintain euglycaemia was increased in mGrb10 mice compared to WT (48.2 ± 22.9 v 40.5 ± 1.5 mg/kg/min, respectively). This was associated with an increase in glucose uptake into skeletal muscle (~2-fold). Muscle mass was increased, but fat pad weight was not altered in mGrb10 mice. mGrb10 mice had increased Akt phosphorylation in muscle after the clamp, suggesting increased insulin signalling.

This study demonstrates that deletion of Grb10 specifically in muscle causes increased glucose uptake into muscle and this is sufficient to increase in whole body insulin sensitivity.