Mechanisms for Insulin Resistance: Common Threads and Missing Links

Abstract

Insulin resistance is a complex metabolic disorder that defies a single etiological pathway. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response (UPR) pathway and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. However, these pathways are also closely linked to changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition. Ultimately, accumulation of specific lipid metabolites (diacylglycerols and/or ceramides) in liver and skeletal muscle, may be a common pathway leading to impaired insulin signaling and insulin resistance.

Ameliorative effect of Ruellia tuberosa L. on hyperglycemia in type 2 diabetes mellitus and glucose uptake in mouse C2C12 myoblasts

“…Del Aguila, Claffey, and Kirwan (1999) utilized C2C12 cells induced by TNF‐α at a concentration of 10 ng/ml for 1 hr and found that under these conditions, the activity of IRS‐1/2 is inhibited, resulting in a decrease in PI3‐kinase activity and The present study demonstrates inhibition of P42 MARK and P44 MARK phosphorylation, thereby enabling insulin to stimulate the decrease in glucose uptake of C2C12 cells. When TNF‐α binds to its receptor, it activates the JNK pathway and directly inhibits the activity of IRS‐1/2, resulting in the failure of the insulin signaling pathway, leading to cellular IR emergence (Boden et al., 2005; Samuel & Shulman, 2012; Tuncman et al., 2006). Thus, in the present study, a concentration of 10 ng/ml of TNF‐α was also used as a cellular model for the induction of IR in C2C12 cells.…”

“…To maintain homeostasis of blood glucose in the body, pancreatic β cells compensatorily secrete more insulin to elevate the blood insulin level, subsequently contributing to hyperinsulinemia (ADA, 2015; Jiang, Chang, Tai, Chen, & Chuang, 2012; Samuel & Shulman, 2012). …”

“…Various factors are involved in the pathogenesis of IR, such as ectopic lipid metabolite accumulation, unfolded protein response activation, and innate immune responses (Samuel & Shulman, 2012). These pathogenic mechanisms may be related to abnormal fat metabolism and synthesis or energy consumption caused by the accumulation of ectopic lipid metabolites (Chang, Shen, & Wu, 2013; Chang et al., 2015; Longato, Tong, Wands, & de la Monte, 2012; McNeilly, Williamson, Sutherland, Balfour, & Stewart, 2011).…”

“…It may eventually generate some specific lipid metabolites that converge to the liver and skeletal muscle, resulting in the destruction of the insulin signaling pathway and the occurrence of IR (Chang & Shen, 2013; Chang et al., 2013, 2015). Previous studies reported that tumor necrosis factor‐α (TNF‐α) may activate the inhibitor of nuclear factor κ‐B kinase and c‐Jun N‐terminal protein kinase (JNK) pathways, resulting in IR in skeletal muscle cells (Boden et al., 2005; Samuel & Shulman, 2012; Tuncman et al., 2006). …”

Vascular endothelial growth factor-B: Impact on physiology and pathology

“…Importantly, it is the intramyocellular diacylglycerols, 37 not the circulating lipids, that interrupt the insulin signaling and are responsible for insulin resistance progression. Besides, ectopic deposition of lipids in metabolically active organs can induce pathological activation of inflammation 38 , 39 and endoplasmic reticulum stress, 38 , 40 the ability of which to regulate insulin action may be reliant on their ability to alter the levels of key signaling intermediates. 38 It is highly likely that dysregulations of these pathways collectively contribute to insulin resistance.…”