Bmi-Related Progression Of Atypical Pkc-Dependent Aberrations In Insulin Signaling Through Irs-1, Akt, Foxo1 And Pgc-1 Alpha In Livers Of Obese And Type 2 Diabetic Humans

Information on insulin resistance in human liver is limited. In mouse diet-induced obesity (DIO), hepatic insulin resistance initially involves: lipid + insulin-induced activation of atypical protein kinase C (aPKC); elevated Akt activity/activation but selective impairment of compartmentalized Akt-dependent FoxO1 phosphorylation; and increases in gluconeogenic and lipogenic enzymes. In advanced stages, e.g., in hepatocytes of type 2 diabetes (T2D) humans, insulin activation of insulin receptor substrate-1(IRS-1) and Akt fails, further increasing FoxO1-dependent gluconeogenic/lipogenic enzyme expression. Increases in hepatic PGC-1 alpha also figure prominently, but uncertainly, in this scheme. Here, we examined signaling factors in liver samples harvested from human transplant donors with increasing BM, 20 -> 25 -> 30 -> 35 -> 40 -> 45.We found, relative to lean (BMI = 2025) humans, obese (BMI > 30) humans had all abnormalities seen in early mouse DIO, but, surprisingly, at all elevated BMI levels, had decreased insulin receptor-1 (IRS-1) levels, decreased Akt activity, and increased expression/abundance of aPKC-L and PGC-1. Moreover, with increasing BMI, there were: progressive increases in aPKC activity and PKC-L expression/abundance; progressive decreases in IRS-1 levels, Akt activity and FoxO1 phosphorylation; progressive increases in expression/abundance of PGC-1 alpha; and progressive increases in gluconeogenic and lipogenic enzymes. Remarkably, all abnormalities reached T2D levels at higher BM4 levels. Most importantly, both "early" and advanced abnormalities were largely reversed by 24-hour treatment of T2D hepatocytes with aPKC inhibitor. We conclude: hepatic insulin resistance in human obesity is: advanced; BM1-correlated; and sequentially involves increased aPKC-activating ceramide; increased aPKC levels and activity; decreases in IRS-1 levels, Akt activity, and FoxO1 phosphorylation; and increases in expression/abundance of PGC-1 alpha and gluconeogenic and lipogenic genes. Published by Elsevier Inc.