Hepatic a Typical PKC: A Novel Target for Newlydevelpoed Inhibitors that Reverse Obesity and Metabolic Syndrome and Diabetic Characteristics and Features in Human Hepatocytes and a Murine Obesity/Diabetes Model

Results: Opposite to PKC-ι deficiency in muscle, which limits glucose transport, PKC-ι was over-expressed/over-active in hepatocytes of T2DM humans, and accompanied by increased expression of sterol receptor element binding protein-1c (SREBP-1), SREBP1c-dependent lipogenic enzymes, and proinflammatory and gluconeogenic enzymes. Moreover, apparently acting via conserved levels and heightened phosphatidylinositol3-kinase activity of insulin receptor substrate(IRS)-2, insulin increased hepatic PKC-ι expression by a PKCι-(i.e., self)-dependent, i.e., feed-forward/positive-feedback, mechanism. In contrast, Akt2 activation was diminished in human T2DM hepatocytes, most likely reflecting diminished IRS-1 levels and activity. Treatment of T2DM hepatocytes with two novel PKC-ι/λ inhibitors diminished aPKC activity and expression of lipogenic, proinflammatory and gluconeogenic enzymes. Also, in a murine obesity/ T2DM model, both agents selectively inhibited hepatic PKC-ι/λ and abnormalities in hepatic expression of lipogenic, proinflammatory and gluconeogenic enzymes, thereby improving insulin signalling in muscle and adipocytes, insulin resistance, glucose intolerance, hepatosteatosis, abdominal obesity, hypertriglyceridemia and hypercholesterolemia.