This difference in levels of PKC-ι in muscle and liver most likely reflects that: (a) expression (i.e., mRNA production) of PKC-ι, but not other aPKCs, is stimulated by insulin-induced increases in aPKC enzyme activity [1], i.e., there is a forward-feed, positive feedback mechanism that is operative and excessive in hyperinsulinemic conditions; and (b) whereas IRS-1/PI3K and thus aPKC activities in muscle are diminished in type 2 diabetes, IRS-2/PI3K and aPKC activities are elevated in hepatocytes of type 2 diabetic humans [1]. Here, IRS2 is linked to type 2 diabetes mellitus.