BMI-related progression of atypical PKC-dependent aberrations in insulin signaling through IRS-1, Akt, FoxO1 and PGC-1α in livers of obese and type 2 diabetic humans

Abstract

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-1α also figure prominently, but uncertainly, in this scheme. Here, we examined signaling factors in liver samples harvested from human transplant donors with increasing BMI, 20→25→30→35→40→45. We found, relative to lean (BMI=20–25) 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-ι and PGC-1α. Moreover, with increasing BMI, there were: progressive increases in aPKC activity and PKC-ι expression/abundance; progressive decreases in IRS-1 levels, Akt activity and FoxO1 phosphorylation; progressive increases in expression/abundance of PGC-1α; and progressive increases in gluconeogenic and lipogenic enzymes. Remarkably, all abnormalities reached T2D levels at higher BMI 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; BMI-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-1α and gluconeogenic and lipogenic genes.

Hepatic IRS1 and ß-catenin expression is associated with histological progression and overt diabetes emergence in NAFLD patients

“…Sajan et al reported that hepatic IRS1 levels diminished as BMI increased [50]. They concluded that hepatic insulin resistance progressed with BMI due to decreases in hepatic IRS1 expression.…”

Ceramide Content in Liver Increases Along with Insulin Resistance in Obese Patients

“…To our knowledge, only two other studies related to human insulin resistance and obesity were targeting hepatic ceramides. The study by Sajan et al [41] was performed on cryopreserved liver samples from liver transplant donors with varying degree of obesity and diabetic status. Both short-chain and long-chain ceramide species accumulated in livers of obese and T2D subjects with C14:0-Cer and C16:0-Cer positively correlating with BMI values.…”

Computational Analysis of Insulin-Glucagon Signalling Network: Implications of Bistability in Metabolic Homeostasis and Disease states

“…Hence our analysis provides insights on possible mechanisms by which differential insulin resistance could be responsible for diabetes, obesity and cancer, simultaneously. Furthermore, our model predicts signalling abnormalities like progressive decrease in IRS and AKT activity along with increase in aPKC and mTOR activity with increase in body mass index (BMI) in human subjects (lean, obese & T2DM) and mouse, with diet induced obesity 59 . These observations can easily be explained by our model where increase in FA and AA levels (in obese and T2DM) lead to respective increase in PKC, mTOR-S6K1p and subsequent inhibition of IRS and downstream kinases like AKTp.…”