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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 | 3023
ISSN : 2153-2435

Pharmaceutica Analytica Acta
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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

2nd International Conference on Pharmaceutics & Novel Drug Delivery Systems

Robert V. Farese

Key Note Forum: Pharm Anal Acta

DOI: 10.4172/2153-2435.S1.01

Aims/Hypothesis:We tested the role of the hepatic protein kinase C- ι (PKC- ι ) in mediating metabolic abnormalities in type 2 diabetes mellitus (T2DM) with novel PKC- ι inhibitors. Methods: We examined insulin signalling in hepatocytes of non-diabetic and T2DM humans, and effects of two newly developed small molecule PKC- ι/λ inhibitors in both human hepatocytes and a murine obesity/T2DM 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), SREBP- 1c-dependent lipogenic enzymes, and proinflammatory and gluconeogenic enzymes. Moreover, apparently acting via conserved levels and heightened phosphatidylinositol- 3-kinase activity of insulin receptor substrate(IRS)-2, insulin increased hepatic PKC- ι expression by a PKC- ι -(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. Conclusions/interpretations: PKC- ι is overexpressed/overactive in an insulin- driven cycle in hepatocytes of T2DM humans and accompanied by multiple lipid and carbohydrate abnormalities that are effectively overcome by liver-selective PKC- ι inhibitors. Our findings highlight the pathological importance of this aberrant signalling pathway and suggest inhibition of PKC- ι as potential therapy.