Interleukin-6 and tumor necrosis factor-? are not increased in patients with Type 2 diabetes: evidence that plasma interleukin-6 is related to fat mass and not insulin responsiveness

Carey, Andrew L.; Bruce, Clinton R.; Sacchetti, Massimo; Anderson, Mitchell; Olsen, David B.; Saltin, Bengt; Hawley, John A.; Febbraio, Mark A.

doi:10.1007/s00125-004-1403-x

Cited by 153 publications

(133 citation statements)

References 50 publications

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“…103 TNF-a is a strong inducer of lipolysis 104 and data from rodents and humans support a role in the development of insulin resistance. [105][106][107] The latter, however, has been challenged by others 108 and although TNF-a levels are increased in obesity, 109,110 there is little direct release from abdominal subcutaneous adipose tissue in vivo. 111 Interestingly, in a similar set of studies it was found that abdominal subcutaneous adipose tissue releases the soluble TNF receptor type 1 and that its levels correlate with BMI.…”

Section: Inflammatory Cytokinesmentioning

confidence: 99%

Gluteofemoral body fat as a determinant of metabolic health

2010

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Body fat distribution is an important metabolic and cardiovascular risk factor, because the proportion of abdominal to gluteofemoral body fat correlates with obesity-associated diseases and mortality. Here, we review the evidence and possible mechanisms that support a specific protective role of gluteofemoral body fat. Population studies show that an increased gluteofemoral fat mass is independently associated with a protective lipid and glucose profile, as well as a decrease in cardiovascular and metabolic risk. Studies of adipose tissue physiology in vitro and in vivo confirm distinct properties of the gluteofemoral fat depot with regards to lipolysis and fatty acid uptake: in day-to-day metabolism it appears to be more passive than the abdominal depot and it exerts its protective properties by long-term fatty acid storage. Further, a beneficial adipokine profile is associated with gluteofemoral fat. Leptin and adiponectin levels are positively associated with gluteofemoral fat while the level of inflammatory cytokines is negatively associated. Finally, loss of gluteofemoral fat, as observed in Cushing's syndrome and lipodystrophy is associated with an increased metabolic and cardiovascular risk. This underlines gluteofemoral fat's role as a determinant of health by the long-term entrapment of excess fatty acids, thus protecting from the adverse effects associated with ectopic fat deposition.

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Section: Inflammatory Cytokinesmentioning

confidence: 99%

Gluteofemoral body fat as a determinant of metabolic health

2010

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“…These pro-inflammatory cytokines can, in turn, act via transmembrane receptors to phosphorylate serine/threonine kinases, which are known to disrupt insulin signal transduction [1]. Given this pro-inflammatory response and the observation that systemic IL-6 concentrations are elevated in obesity and patients with type 2 diabetes [2], it is generally accepted that IL-6 contributes to obesityinduced insulin resistance [3]. However, the discovery that IL-6 can be produced and released from skeletal muscle during exercise, led many investigators, as reviewed by Pedersen and Febbraio [4], to challenge this concept because insulin action is enhanced in the immediate postexercise period.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance

et al. 2010

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Aims/hypothesis The role of IL-6 in the development of obesity and hepatic insulin resistance is unclear and still the subject of controversy. We aimed to determine whether global deletion of Il6 in mice (Il6 −/− ) results in standard chow-induced and high-fat diet (HFD)-induced obesity, hepatosteatosis, inflammation and insulin resistance. Methods Male, 8-week-old Il6 −/− and littermate control mice were fed a standard chow or HFD for 12 weeks and phenotyped accordingly. Results Il6 −/− mice displayed obesity, hepatosteatosis, liver inflammation and insulin resistance when compared with control mice on a standard chow diet. When fed a HFD, the Il6 −/− and control mice had marked, equivalent gains in body weight, fat mass and ectopic lipid deposition in the liver relative to chow-fed animals. Despite this normalisation, the greater liver inflammation, damage and insulin resistance observed in chow-fed Il6 −/− mice relative to control persisted when both were fed the HFD. Microarray analysis from livers of mice fed a HFD revealed that genes associated with oxidative phosphorylation, the electron transport chain and tricarboxylic acid cycle were uniformly decreased in Il6 −/− relative to control mice. This coincided with reduced maximal activity of the mitochondrial enzyme β-hydroxyacyl-CoA-dehydrogenase and decreased levels of mitochondrial respiratory chain proteins. Conclusions/interpretation Our data suggest that IL-6 deficiency exacerbates HFD-induced hepatic insulin resistance and inflammation, a process that appears to be related to defects in mitochondrial metabolism.

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“…Circulating and adipose tissue IL-6 levels are increased in patients with obesity, insulin resistance and type 2 diabetes [3][4][5][6][7][8][9], the increased level correlating with degree of insulin resistance measured as insulin-stimulated glucose uptake [7][8][9]. Although difficult to firmly prove, it has been suggested that the increased plasma concentrations of IL-6 in patients with type 2 diabetes are an indicator of the increased fat mass rather than insulin resistance as such [10]. However, it is well established that the adipose tissue is an important source of IL-6 production in man [5].…”

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confidence: 99%

Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice

et al. 2008

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Aims/hypothesis IL-6 is released by the adipose tissue and increased circulating levels in obesity are associated with hyperinsulinaemia and insulin resistance. Short-term experiments suggest that increased IL-6 release by the skeletal muscle following exercise may improve insulin sensitivity. Methods In order to examine the effect of chronically elevated IL-6 levels, we overexpressed Il6 in skeletal muscle in mice using an electro-transfer procedure.Results Circulating IL-6 levels were increased and the animals rapidly lost both weight and body fat, but food intake was unchanged, which is consistent with the finding that IL-6 increased energy expenditure. Insulin levels were inappropriately elevated and combined with hypoglycaemia in spite of reduced 2-deoxy-D-glucose uptake by skeletal muscle. Insulin-stimulated glucose uptake by skeletal muscles ex vivo was reduced, probably due to the decreased amounts of glucose transporter (GLUT)-4. Beta cell insulin content was increased, while apparent beta cell mass was unchanged. Circulating serum amyloid A cluster levels were increased tenfold due to a pronounced proinflammatory state in the liver with infiltration of inflammatory cells. However, no liver steatosis was found, which may be accounted for by concomitant AMP kinase activation. Conclusions/interpretation Chronically elevated IL-6 levels lead to inappropriate hyperinsulinaemia, reduced body weight, impaired insulin-stimulated glucose uptake by the skeletal muscles and marked inflammation in the liver. Thus, the pleiotrophic effects of chronically elevated IL-6 levels preclude any obvious usefulness in treating obesity or its associated metabolic complications in man, despite the fact that weight reduction may be expected.

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Interleukin-6 and tumor necrosis factor-? are not increased in patients with Type 2 diabetes: evidence that plasma interleukin-6 is related to fat mass and not insulin responsiveness

Abstract: These data show that the increased circulating IL-6 concentrations seen in patients with Type 2 diabetes are strongly related to fat mass and not insulin responsiveness, and suggest that neither IL-6 nor TNFalpha are indicative of insulin resistance.

Cited by 153 publications

References 50 publications

Gluteofemoral body fat as a determinant of metabolic health

Gluteofemoral body fat as a determinant of metabolic health

Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance

Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice

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