Atypical PKC: a target for treating insulin-resistant disorders of obesity, the metabolic syndrome and type 2 diabetes mellitus.

ABSTRACT

INTRODUCTION: The prevalence of obesity, the metabolic syndrome and type 2 diabetes mellitus have reached pandemic levels. Present therapies do not directly target the key factor responsible for the insulin resistance that underlies the development of these syndromes. AREAS COVERED This review focuses on hepatic atypical PKC (aPKC) as a key target for treating these disorders. It reviews data obtained from multiple experimental mouse models of obesity and type 2 diabetes, and hepatocytes of type 2 diabetic humans. EXPERT OPINION The review shows that hepatic aPKC is excessively activated by diet-derived lipids and by insulin itself in hyperinsulinemic states. It also shows how excessively activated hepatic aPKC increases expression of gluconeogenic, lipogenic and proinflammatory factors that underlie the development of glucose intolerance, insulin resistance, obesity, hepatosteatosis and hyperlipidemia. Most importantly, the review shows how the selective inhibition of hepatic aPKC by a variety of means, including expression of inhibitory forms of aPKC, genetic deletion of aPKC and use of several newly developed small-molecular-weight chemical agents result in correction of hepatic abnormalities, such as excessive expression of gluconeogenic, lipogenic and proinflammatory factors, and correction or improvement in clinical abnormalities (glucose intolerance, obesity, hepatosteatosis and hyperlipidemia).