Tissue-Specific Difference in the Molecular Mechanisms for the Development of Acute Insulin Resistance after Injury

Abstract

Acute insulin resistance occurs after injury, hemorrhage, infection, and critical illness. However, little is known about the development of this acute insulin-resistant state. In the current study, we found that insulin resistance develops rapidly in skeletal muscle, with the earliest insulin signaling defects at 60 min. However, defects in insulin signaling were measurable even earlier in liver, by as soon as 15 min after hemorrhage. To begin to understand the mechanisms for the development of acute insulin resistance, serine phosphorylation of insulin receptor substrate (IRS)-1 and c-Jun N-terminal kinase phosphorylation/activation was investigated. These markers (and possible contributors) of insulin resistance were increased in the liver after hemorrhage but not measurable in skeletal muscle. Because glucocorticoids are important counterregulatory hormones responsible for glucose homeostasis, a glucocorticoid synthesis inhibitor, metyrapone, and a glucocorticoid receptor antagonist, RU486, were administered to adult rats prior to hemorrhage. In the liver, the defects of insulin signaling after hemorrhage, including reduced tyrosine phosphorylation of the insulin receptor and IRS-1, association between IRS-1 and phosphatidylinositol 3-kinase and serine phosphorylation of Akt in response to insulin were not altered by pretreatment of rats with metyrapone or RU486. In contrast, hemorrhage-induced defects in insulin signaling were dramatically reversed in skeletal muscle, indicating a prevention of insulin resistance in muscle. These results suggest that distinct mechanisms for hemorrhage-induced acute insulin resistance are present in these two tissues and that glucocorticoids are involved in the rapid development of insulin resistance in skeletal muscle, but not in the liver, after hemorrhage.

Adenovirus infection results in alterations of insulin signaling and glucose homeostasis

“…The surgical trauma procedures were performed as described previously (16,21,22,46). Rats were fasted for 18 -20 h and then anesthetized by inhalation of 1.5% isoflurane, and a 5-cm midline laparotomy was performed.…”

“…Liver, skeletal muscle, and fat tissues were homogenized in lysis buffer as described previously (16,21,22,46). Protein concentrations were measured by BCA assay (Pierce, Rockford, IL).…”

“…Previous work from our laboratory focused on the development of acute hepatic insulin resistance following surgical trauma and hemorrhage (16,21,22,46). We wished to study the mechanisms underlying this acute onset of insulin resistance after injury using Ad as a gene transfer tool to express proteins in vivo.…”

Regulation of hepatic insulin receptor activity following injury

“…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.…”

“…Serine (S944) phosphorylation of the IR likely contributes to insulin resistance in the liver of obese rats (18), and multiple serine kinases have been implicated in IR serine phosphorylation (3,18). JNK, a serine kinase, is widely known to be involved in both the acute and chronic development of insulin resistance through inducing phosphorylation of insulin receptor substrate 1 (IRS1) on serine residues (6,10,13,16,22,24,25,27,28). Hepatic activation of JNK activity occurs rapidly following trauma and hemorrhage, and inhibition of JNK1 results in improved IR activation and downstream insulin signaling (13,22,25).…”