Redox regulation of the insulin signalling pathway

Abstract

The peptide hormone insulin is a key regulator of energy metabolism, proliferation and survival. Binding of insulin to its receptor activates the PI3K/AKT signalling pathway, which mediates fundamental cellular responses. Oxidants, in particular H 2 O 2 , have been recognised as insulin-mimetics. Treatment of cells with insulin leads to increased intracellular H 2 O 2 levels affecting the activity of downstream signalling components, thereby amplifying insulin-mediated signal transduction. Specific molecular targets of insulin-stimulated H 2 O 2 include phosphatases and kinases, whose activity can be altered via redox modifications of critical cysteine residues. Over the past decades, several of these redox-sensitive cysteines have been identified and their impact on insulin signalling evaluated. The aim of this review is to summarise the current knowledge on the redox regulation of the insulin signalling pathway.

The role of selenium in type-2 diabetes mellitus and its metabolic comorbidities

“…A large number of potentially interactive pathological mechanisms may affect the insulin target tissues as well as the pancreatic islets and the intestinal tract, thus contributing to the development of metabolic dysfunction. These include chronic low-grade inflammation, redox imbalance, mitochondrial dysfunction, ER stress, alterations in plasma levels of factors involved in inter-organ communication, leakage of the intestinal barrier, and alterations in the intestinal microbiota [ 4 , 8 , [37] , [38] , [39] , [40] , [41] , [42] ].…”

“…In addition, the insulin-regulated fuel metabolism is closely intertwined with redox homeostasis. Reactive oxygen species (ROS), in particular H 2 O 2 , are required for proper insulin biosynthesis, secretion, and signaling [ 4 , 37 , 40 ]. ROS at low levels do not injure cells.…”

“…Nutrient oversupply, hyperglycemia, dyslipidemia and chronic inflammation have all been reported to be associated with oxidative stress. Disturbance of redox homeostasis may promote mitochondrial dysfunction and insulin resistance as well as ER stress, impaired insulin biosynthesis and β-cell de-differentiation [ 4 , 37 , 40 ]. While diabetes has been found to be associated with decreased levels of intracellular antioxidants such as glutathione or vitamins C and E, it should be noted, however, that an “antioxidant therapy” by simply supplementing antioxidants was generally not effective in diabetic patients [ 44 ].…”

Skeletal Muscle Microvascular Dysfunction in Obesity-Related Insulin Resistance: Pathophysiological Mechanisms and Therapeutic Perspectives

“…It has been suggested that endothelial dysfunction and vascular insulin resistance may result from the impairment of cellular adaptive mechanisms against mitochondrial dysfunction and oxidative stress such as the redox-sensitive transcription factor nuclear factor E2-related factor 2 (Nrf2) and the antioxidant response element (ARE), which modulate cellular antioxidant activity [127,128]. Insulin resistance and persistent hyperglycaemia further exacerbate redox dysregulation through a positive feedback loop [129].…”

Drugs Interfering with Insulin Resistance and Their Influence on the Associated Hypermetabolic State in Severe Burns: A Narrative Review

“…SH2 (Src homology 2) domain proteins, such as the regulatory subunits of class 1A PI3K, GRB2/SOS (growth factor receptor-bound protein 2/son of sevenless), and SHP2 (SH2 domain containing protein tyrosine phosphatase-2), are activated by Tyr phosphorylation of IRS [16]. Subsequently, PIP3 (phosphatidylinositol 3,4,5-trisphosphate) is produced in the plasma membrane through the phosphorylation of PIP2 (phosphatidylinositol 4,5-bisphosphate) by PI3K and, in turn, recruits AKT, which is then activated through the phosphorylation of the T308 (threonine 308) site of protein kinase B and other analogues in aPKCs λ/ι and ζ (calcium-and diacylglycerol-independent atypical protein kinase C isoforms λ/ι and ζ) [17,18].…”