Since hyperglucagonemia and/or hyperinsulinemia can augment AMPKα1/2 phosphorylation at S496/491 to impair AMPK activity and regulation of liver glucose production, blocking AMPKα1/2 phosphorylation at S496/491 by our targeting peptides Pa496h or Pa496m (mouse form) could significantly improve hyperglycemia in obese mice (29). This evidence concerns the gene PRKAA1 and hyperinsulinism.