In later phases of diet-induced obesity and early phases of type 2 diabetes, increases in hepatic aPKC activity are further heightened, and defects in activation of hepatic IRS-1/PI3K and Akt develop, further diminishing FoxO1 phosphorylation, and further increasing expression of gluconeogenic enzymes. This evidence concerns the gene IRS1 and obesity due to melanocortin 4 receptor deficiency.