Insulin resistance, metabolic stress, and atherosclerosis

Abstract

Atherosclerosis, a pathological process that underlies the development of cardiovascular disease, is the primary cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). T2DM is characterized by hyperglycemia and insulin resistance (IR), in which target tissues fail to respond to insulin. Systemic IR is associated with impaired insulin signaling in the metabolic tissues and vasculature. Insulin receptor is highly expressed in the liver, muscle, pancreas, and adipose tissue. It is also expressed in vascular cells. It has been suggested that insulin signaling in vascular cells regulates cell proliferation and vascular function. In this review, we discuss the association between IR, metabolic stress, and atherosclerosis with focus on 1) tissue and cell distribution of insulin receptor and its differential signaling transduction and 2) potential mechanism of insulin signaling impairment and its role in the development of atherosclerosis and vascular function in metabolic disorders including hyperglycemia, hypertension, dyslipidemia, and hyperhomocysteinemia. We propose that insulin signaling impairment is the foremost biochemical mechanism underlying increased cardiovascular morbidity and mortality in atherosclerosis, T2DM, and metabolic syndrome.

Figure 1

Insulin signaling. Insulin binds to its receptor causes a conformational change, autophosphorylation of the receptor, and activation of two pathways; The PI3K/Akt pathway leads to IRS tyrosine phosphorylation, which further phosphorylate PI3K subunit p85 and heterodimerization of p85 and p110. Akt activation upon the heterodimerization leads to PIP3 generation, which causes tyrosine phosphorylation/activation of PDK1; leading to serine phosphorylation/activation of Akt (also termed PKB). Activated Akt/PKB causes serine phosphorylation of eNOS/activation, rab-GTPase-activating protein-AS160, and HSL serine phosphorylation, inhibition of glycogen synthase kinase-3, threonine phosphorylation of S6K, and induction in Bcl-x gene expression; leading to NO generation, GLUT4 membrane translocation/glucose uptake, anti-lipolysis, glycogen synthesis, protein synthesis, and reduced-apoptosis. Exercise or insulin sensitizer adiponectin activates AMPK, which causes serine phosphorylation of IRS (at amino acid position 789- a positive regulation), eNOS (a positive regulation), and rab-GTPase-activating protein-AS160 and threonine phosphorylation of TSC1/2 (a negative regulation); leading to PI3K/Akt activation, NO production, glucose uptake, and protein synthesis inhibition. The MAPK cascade leads to activation of Ras signaling, cell proliferation, and inhibits apoptosis. IRS: insulin receptor substrate, PIP2: phosphatidylinositol 4,5-bisphosphate, PIP3: phosphatidylinositol 3,4,5-trisphosphate, PDK1: phosphoinositide-dependent kinase-1, PI3K: phosphatidylinositol 3-kinase, PKB: protein kinase B, eNOS: endothelial nitric oxide synthase, AS160: Akt substrate of 160 kDa, HSL: hormone sensitive lipase, S6K: ribosomal protein S6 kinase, NO: nitric oxide, GLUT4: glucose transporter4, AMP: adenosine monophosphate, ATP: adenosine triphosphate, AMPK: 5′-adenosine monophosphate-activated protein kinase, TSC1/2: tuberous sclerosis protein 1 and 2-tumor suppressor, Shc: sh2 domain-containing alpha-2 collagen-related protein, Grb2: growth factor receptor-bound protein 2, Sos: son of sevenless, MAPK: mitogen-activated protein kinase, MEK: mitogen-activated protein kinase kinase, Erk1/2: extracellular signal-regulated kinase1/2.

Figure 2

PI3K/Akt pathway impairment is a key feature of IR and vascular dysfunction. Parallel and balanced insulin signaling between PI3K/Akt/eNOS and Ras/MAPK maintains normal vascular tone in healthy conditions. A variety of stimuli, including hyperglycemia, elevated FFA levels, cytokines, and others, increase production of ROS, RNS, and oxidative stress. These leads to activation of IKKbeta and other stress sensitive Ser/Thr kinases, which cause serine phosphorylation of IRS (at amino acid position 307-a negative regulation) and PI3K/Akt inhibition (IR effect). While PI3K/Akt/eNOS signaling is impaired, the Ras/MAPK pathway is less affected or even enhanced due to hyperinsulinemia, leading to reduce NO production and enhance ET-1 secretion, resulting in impaired vascular function. AMPK counteract the stress induced IR by serine phosphorylation of eNOS (a positive regulation) and IRS (at amino acid position 789-a positive regulation), which improves vascular function and IR. IR: insulin resistance, IRS: insulin receptor substrate, PI3K: phosphatidylinositol 3-kinase, eNOS: endothelial nitric oxide synthase, NO: nitric oxide, MAPK: mitogen-activated protein kinase, Erk1/2: extracellular signal-regulated kinase1/2, ET-1: endothelin-1, FFA: free fatty acid, ROS: reactive oxygen species, RNS: reactive nitrogen species, TNF-alpha: tumor necrosis factor-alpha, IKKbeta: inhibitor of nuclear factor kappa B kinase beta subunit, Ser/Thr: Serine/Threonine, VSMCs: vascular smooth muscle cells, AMPK: 5′ adenosine monophosphate-activated protein kinase.

Figure 3

Mechanism of metabolic syndrome: A vicious circle. ECs: endothelial cells, VSMCs: vascular smooth muscle cells, MΦ: macrophages.