Regulation of hepatic insulin receptor activity following injury

Abstract

Jiang S, Gavrikova TA, Messina JL. Regulation of hepatic insulin receptor activity following injury. Am J Physiol Gastrointest Liver Physiol 306: G886 -G892, 2014. First published April 3, 2014 doi:10.1152/ajpgi.00128.2013.-Impaired insulin receptor (IR) activity has been found in various models of insulin resistance, including models of injury or critical illness and Type 2 diabetes. However, mechanisms that modulate IR function remain unclear. With an animal model of critical-illness diabetes, we found insulin-induced IR tyrosine phosphorylation in the liver was impaired as early as 15 min following trauma and hemorrhage. Possible mechanisms for this defect were examined, including IR protein levels and IR posttranslational modifications. The total amounts of hepatic IR␣ and IR␤ subunits and the membrane localization of the IR were not altered by trauma and hemorrhage, and, likewise, no change in IR tyrosine nitration was found in the liver. However, there was a decrease in the level of protein O-linked ␤-N-acetlyglucosamine (O-GlcNac) modification on Ser/Thr in the liver following trauma and hemorrhage. Inhibition of JNK increased IR O-GlcNac modification, implicating an involvement of JNK. These findings suggest that a balance between O-GlcNac modification and JNK-induced phosphorylation may exist, with decreased Ser/Thr O-GlcNac modification following trauma and hemorrhage, allowing JNK to phosphorylate the IR on neighboring Ser/Thr residues, which subsequently inhibits IR activity. The present studies suggest potential mechanisms of hemorrhage-induced defects in IR activity and a potential role for acutely decreased O-GlcNac and increased serine phosphorylation of the IR.O-linked ␤-N-acetlyglucosamine; c-Jun NH2-terminal kinase; insulin resistance; liver; injury THE INSULIN RECEPTOR (IR) consists of two extracellular ␣ subunits and two transmembrane ␤ subunits, disulfide linked into an ␣ 2 ␤ 2 heterotetrameric complex. Binding of insulin to the ␣ subunit results in a conformational change and subsequent activation of the receptor's protein tyrosine kinase activity, which, in turn, activates downstream insulin signaling (14, 23). Defects in IR activity have been found in patients with Type 2 diabetes (23) and in various animal models of insulin resistance, including after sepsis (17) and viral infections (11). With animal models of surgical trauma and hemorrhage, we previously observed impaired IR activity following trauma and hemorrhage, which is characterized by defects in insulininduced IR phosphorylation on multiple tyrosine residues (12,13,15,16,21,22,25,26). Although the evidence suggests that acute and chronic regulation of IR contributes to impaired insulin sensitivity and glucose homeostasis, the molecular mechanisms underlying the impaired IR activation after injuries remain largely unclear.Possible mechanisms accounting for impaired insulin signaling at the level of IR include cell surface IR content or modification of IR enzymatic activity. Reduced IR cell surface content and insulin binding ca...

Irisin Preserves Cardiac Performance and Insulin Sensitivity in Response to Hemorrhage

“…It has been shown that hemorrhages result in metabolic disorders and insulin resistance, which contribute to the sequala of symptoms that result following a hemorrhage. The suppression of insulin resistance has demonstrated a protective effect against hemorrhage [ 14 , 15 ]. Our study revealed that mice, when exposed to hemorrhage, experienced glucose intolerance along with hyperinsulinemia, but the administration of irisin improved and attenuated the glucose intolerance induced by the hemorrhage and magnitude of hyperinsulinemia, indicating that irisin can ameliorate insulin sensitivity following a hemorrhage.…”

“…Our study revealed that mice, when exposed to hemorrhage, experienced glucose intolerance along with hyperinsulinemia, but the administration of irisin improved and attenuated the glucose intolerance induced by the hemorrhage and magnitude of hyperinsulinemia, indicating that irisin can ameliorate insulin sensitivity following a hemorrhage. Our previous studies, and others, have demonstrated that irisin-attenuated metabolic disorders, improved insulin sensitivity, and activated insulin signaling pathways contribute to the beneficial effects of irisin [ 15 , 16 , 17 ]. Although the precise molecular mechanism by which irisin mediates insulin sensitivity in hemorrhages is currently unknown, the improved insulin sensitivity by irisin plays a key role in protecting against hemorrhage.…”