Insulin resistance, metabolic stress, and atherosclerosis

Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Frontiers in bioscience (Scholar edition) 01/2012; 4(3):916-31.
Source: PubMed


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.

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    • "Out of the six IRS isoforms described so far, isoforms 1 (IRS1) and 2 (IRS2) are particularly important for the metabolic effects of insulin in adipose tissue and the liver, respectively. Then, a complex network of intracellular downstream pathways is triggered, culminating, among other effects, in glucose uptake, gluconeogenesis suppression and/or glycogen, protein, fatty acids and triacylglycerols synthesis[4,12,13,20,21]. Fructose consumption is associated with metabolic changes similar to those observed in MS22232425. "

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    • "Even in normal physiological circumstances of healthy tissues, the potential interactome may inform our understanding of tissue-specific signaling events. A variety of tissues can respond to insulin stimulation, including adipose, muscle, pancreas, liver, brain etc. [75,76]. SH2 domain-containing proteins vary widely in their expression in various cells and tissues (Figure 5C). "
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