The Concept of CMR

Inflammation and insulin resistance

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Inflammation is increasingly acknowledged as an important component of both CVD (14) and type 2 diabetes (15). Many studies have linked inflammation to insulin resistance (16), which could even predict type 2 diabetes (17, 18).

There is evidence to suggest that TNF-α and IL-6 play a role in obesity-linked insulin resistance. These findings are consistent with previous studies that showed increased levels of circulating TNF-α and IL-6 among subjects with insulin resistance (19-23). Although it is unclear how adipose TNF-α and IL-6 expression may cause insulin resistance, they have both been shown to interfere with insulin signalling in adipose tissue (24, 25) and the liver (4, 26). Rotter et al. (24) reported that, unlike TNF-α IL-6 did not increase serine phosphorylation of insulin resistance sustrate-1 (IRS-1). Instead, similar to TNF-α it suppressed gene transcription of IRS-1 and GLUT-4 (glucose transporters) as well as peroxisome proliferator-activated receptor gamma (PPAR-γin adipose tissue. The authors also demonstrated that IL-6 is mainly a chronic modulator of insulin action and that its effects may be tissue-specific (27). TNF-α(28) and IL-6 (29) are also known to promote lipolysis and secretion of free fatty acids (FFA) from adipose tissue into the circulation, which contributes to insulin resistance, increases hepatic glucose production, and reduces hepatic insulin extraction. A third potential mechanism by which TNF-α influences insulin resistance has also recently been identified. TNF-α signalling strongly reduces adiponectin secretion by adipocytes (30), and TNF-α seems to be a crucial mediator of insulin sensitivity. This may explain how the paracrine effects of TNF-α within fat could cause systemic insulin resistance. Another proposed mechanism is the induction by proinflammatory cytokines of suppressor of cytokines signalling (SOCS) proteins, which are known to alter insulin signalling and could therefore play a role in mediating cytokine-dependent insulin resistance in the liver and other insulin-responsive tissues (31).

Furthermore, insulin is known to inhibit the release of cytokines, such as IL-6, that stimulate acute-phase protein gene expression (32, 33). If insulin action is impaired, insulin would therefore no longer be able to block IL-6 release, causing a prolonged acute-phase reaction (22).

These findings are consistent with the hypothesis that proinflammatory cytokines secreted by adipose tissue may link obesity to insulin resistance (3, 21) (Figure 2).

Reference

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