Increased insulin sensitivity in G(s)alpha knockout mice

The stimulatory guanine nucleotide-binding protein (G(s)) is required for h ormone-stimulated cAMP generation. Gnas, the gene encoding the G(s) alpha - subunit, is imprinted, and targeted disruption of this gene in mice leads t o distinct phenotypes in heterozygotes depending on whether the maternal (m -/f+) or paternal (+/p-) allele is mutated. Notably m-/+ mice become obese, whereas +/p- mice are thinner than normal. In this study we show that desp ite these opposite changes in energy metabolism, both m-/+ and +/p- mice ha ve greater sensitivity to insulin, with low to normal fasting glucose level s, low fasting insulin levels, improved glucose tolerance, and exaggerated hypoglycemic response to administered insulin. The combination of increased insulin sensitivity with obesity in m-/+ mice is unusual, because obesity is typically associated with insulin resistance. In skeletal: muscles isola ted hom both m-/+ and +/p- mice, the basal rate of 8-deoxyglucose uptake wa s normal, whereas the rate of 8-deoxyglucose uptake in response to maximal insulin stimulation was significantly increased. The similar changes in mus cle sensitivity to insulin in m-/+ and +/p- mice may reflect the fact that muscle G(s)alpha expression is reduced by similar to 50% in both groups of mice; GLUT4 expression is unaffected in muscles from +/p- mice. Increased r esponsiveness to insulin is therefore the result of altered insulin signali ng and/or GLUT4 translocation, This is the first direct demonstration in a genetically altered in vivo model that G(s)-coupled pathways negatively reg ulate insulin signaling.