Homocysteine thiolactone inhibits insulin signaling, and glutathione has a protective effect

Abstract

Hyperhomocysteinemia and insulin resistance are independent factors for cardiovascular disease. Most of the angiotoxic effects of homocysteine are related to the formation of homocysteine thiolactone and the consequent increase in oxidative stress. The oxidative stress has also been shown to impair insulin action, therefore leading to insulin resistance. In order to study a putative direct effect of homocysteine on insulin signaling, we have characterized the molecular counter-regulation of the early events in the signal transduction of the insulin receptor, and the metabolic end-point of glycogen synthesis. We employed HTC rat hepatoma cells transfected with the human insulin receptor. A 10 min exposure to homocysteine thiolactone (50 µM) resulted in a significant inhibition of insulin-stimulated tyrosine phosphorylation of the insulin receptor -subunit and its substrates IRS-1 and p60-70, as well as their association with the p85 regulatory subunit of phosphatidylinositol 3-kinase.These effects led to impairment of the insulinstimulated phosphatidylinositol 3-kinase activity, which plays a central role in regulating insulin action. Thus, insulin-stimulated glycogen synthesis was also inhibited by homocysteine thiolactone. To investigate whether oxidative stress was mediating the counter-regulatory effect of homocysteine thiolactone on insulin signaling, we preincubated the cells (5 min) with 250 µM glutathione prior to the incubation with homocysteine (10 min) and subsequent insulin challenge. Glutathione completely abolished the effects of homocysteine thiolactone on insulin-receptor signaling and restored the insulin-stimulated glycogen synthesis. In conclusion, these data suggest that homocysteine thiolactone impairs insulin signaling by a mechanism involving oxidative stress, leading to a defect in insulin action.

Expression of adrenomedullin in adipose tissue of lean and obese women

“…It has been shown that AM deficiency induces insulin resistance in mice (35) and that acute hyperinsulinemia increases circulating AM levels in diabetic patients (36) or in uncomplicated obese subjects (37). In obese and/or diabetic patients, AM may, in turn, interact with the regulation of insulinemia (37)(38)(39)(40).…”

Inhibition of Hepatic Glycogen Synthesis by Hyperhomocysteinemia Mediated by TRB3

“…Although in vivo and in vitro studies 8,9,11,12 suggest that homocysteine causes insulin resistance, the mechanisms of homocysteine-induced insulin resistance are incompletely understood. In the present study, we found that the fasting basal levels of serum insulin were elevated twofold in HHcy mice, suggesting compensatory hypersecretion due to peripheral insulin resistance.…”

“…41 In vitro studies 11,12 have demonstrated that homocysteine thiolactone disrupts insulin signaling by inhibiting insulin-stimulated phosphatidylinositol 3-kinase activity and phosphorylation of GSK3␤ and glycogen synthesis in HTC hepatoma cells. We observed that the phosphorylation of Akt in the liver was significantly lower in HHcy mice than in control mice.…”

“…In vitro studies indicate that the oxidative stress produced by homocysteine thiolactone interrupts the insulin signaling pathway by inhibiting the phosphorylation of insulin receptor tyrosine kinase, phosphatidylinositol 3-kinase, and glycogen synthase kinase 3␤ (GSK3␤) in HTC-IR hepatoma cells. 11,12 The accumulation of misfolded proteins within the endoplasmic reticulum triggers the activation of an unfolded protein response (UPR). 13 The UPR leads to transcriptional up-regulation of several target genes, such as 78-kDa glucose-regulated protein and C/EBP homology protein/growth arrest and DNA damage-inducible protein 153 (CHOP).…”

Oxidative Stress in Multiple Organ Damage in Hypertension, Diabetes and CKD, Mechanisms and New Therapeutic Possibilities

“…In turn, it is hypothesized that oxidative stress can induce diabetes by series of studies; oxidative stress impairs insulin internalization (Bertelsen et al, 2001), blocks insulin receptor substrate phosphorylation, impairs phosphoinositide-3 kinase activity (Najib & Sanchez-Margalet, 2001), induces protein glycation and as a consequence of advanced glycation end-products-receptor binding that leads to cytotoxicity in pancreatic beta cells and reduces the translocation of glucose transporter type-4 (Rudich et al, 1997;Rudich et al, 1998). An in vivo study also showed that the administration of oxidative stress aggravated diabetes in diabetes-prone obese-Zucker rats (Laight et al, 2000).…”