Short-term infusion of interleukin-6 does not induce insulin resistance in vivo or impair insulin signalling in rats

Sopasakis, Victoria Rotter; Larsson, Bo; Johansson, A.; Holmäng, Agneta; Smith, Ulf

doi:10.1007/s00125-004-1544-y

Cited by 40 publications

(33 citation statements)

References 56 publications

(76 reference statements)

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“…In contrast, an acute increase in IL-6 levels has no significant effect on serum insulin concentration in either rodents or humans in vivo (33). In fact, similar to our findings in the MKOs, short-term infusion of IL-6 does not induce insulin resistance in rats in vivo despite SOCS3 induction (36). Moreover, IL-6 knockout animals have normal insulin levels, although they develop obesity at the age of 6-7 months (33).…”

Section: Discussionsupporting

confidence: 72%

Abnormal glucose homeostasis in skeletal muscle–specific PGC-1α knockout mice reveals skeletal muscle–pancreatic β cell crosstalk

Handschin¹,

Choi²,

Chin³

et al. 2007

J. Clin. Invest.

315

327

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The transcriptional coactivator PPARγ coactivator 1α (PGC-1α) is a strong activator of mitochondrial biogenesis and oxidative metabolism. While expression of PGC-1α and many of its mitochondrial target genes are decreased in the skeletal muscle of patients with type 2 diabetes, no causal relationship between decreased PGC-1α expression and abnormal glucose metabolism has been established. To address this question, we generated skeletal muscle-specific PGC-1α knockout mice (MKOs), which developed significantly impaired glucose tolerance but showed normal peripheral insulin sensitivity. Surprisingly, MKOs had expanded pancreatic β cell mass, but markedly reduced plasma insulin levels, in both fed and fasted conditions. Muscle tissue from MKOs showed increased expression of several proinflammatory genes, and these mice also had elevated levels of the circulating IL-6. We further demonstrated that IL-6 treatment of isolated mouse islets suppressed glucose-stimulated insulin secretion. These data clearly illustrate a causal role for muscle PGC-1α in maintenance of glucose homeostasis and highlight an unexpected cytokine-mediated crosstalk between skeletal muscle and pancreatic islets.

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Section: Discussionsupporting

confidence: 72%

Abnormal glucose homeostasis in skeletal muscle–specific PGC-1α knockout mice reveals skeletal muscle–pancreatic β cell crosstalk

Handschin¹,

Choi²,

Chin³

et al. 2007

J. Clin. Invest.

315

327

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“…Initially, we hypothesized that continuous IL-6 stimulation might induce liver injury and fibrosis, and neutralizing the Blockade of IL-6 Receptor in MCD Diet-Fed db/db Mice K Yamaguchi et al IL-6 receptor by treatment with MR16-1 would attenuate liver injury and prevent the development of NASH in MCD diet-fed db/db mice, as in wild-type mice, because previous reports showed that long-term IL-6 exposure induced SOCS3 expression, caused insulin resistance and exacerbated liver injury. [27][28][29][30] Expectedly, we found that an MCD diet induced severe NASH in db/db mice. Unexpectedly, however, this diet induced IL-6 resistance.…”

Section: Discussionmentioning

confidence: 65%

Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-Fed db/db mice

Yamaguchi

Itoh

Yokomizo

et al. 2011

Laboratory Investigation

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Our previous study revealed that blockade of interleukin-6 (IL-6)-STAT3 signaling ameliorated liver injury, although hepatic STAT3 À/À or GP130 À/À mice have been reported to develop severe liver injury, in a murine methionine choline deficient (MCD) diet-induced model of non-alcoholic steatohepatitis (NASH). In this study, to determine whether profound blockade of IL-6-STAT3 signaling may still ameliorate liver injury, we studied db/db mice, which have impaired leptin-mediated STAT3 activation, using the MCD diet-induced NASH model. Male lean and db/db mice (6 weeks old) were fed either control chow or an MCD diet for 8 or 12 weeks. Half of the mice were treated with 15 mg/kg rat anti-mouse IL-6 receptor neutralizing antibody (MR16-1) intraperitoneally twice weekly, the remainder were injected with 15 mg/kg rat IgG as a control. Hepatic steatosis, injury, fibrosis, markers of lipid peroxidation/oxidant stress and antiapoptotic gene expression were evaluated. Plasma IL-6 levels were elevated in all groups of db/db mice. Although hepatic IL-6/ GP130 signaling was activated in chow-fed db/db mice, this was suppressed in MCD diet-fed db/db mice, accompanied by downregulation of hepatic IL-6 receptor and GP130 mRNA expression. MR16-1 treatment of MCD dietfed db/db mice further repressed STAT3 activities and expression of STAT3-related antiapoptotic genes, such as Bcl-2 and Ref-1, but increased plasma-free fatty acid and hepatic markers of lipid peroxidation/oxidant stress, leading to increased liver injury, hepatocyte apoptosis and liver fibrosis. Although 'moderate' blockade of enhanced IL-6-STAT3 signaling may be beneficial in NASH, as we reported previously, these findings demonstrate that a profound defect in STAT3 activation is detrimental in terms of liver injury, hepatocyte apoptosis and liver fibrosis, indicating the hepato-protective role of IL-6 signaling in this severe NASH model.

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“…mRNA analyses and immunoblotting The experimental procedures have been described previously [37]. For detailed information, see ESM.…”

Section: Immunohistochemistry On Liver Sections and Flow Cytometry Anmentioning

confidence: 99%

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

et al. 2008

Self Cite

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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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Short-term infusion of interleukin-6 does not induce insulin resistance in vivo or impair insulin signalling in rats

Cited by 40 publications

References 56 publications

Abnormal glucose homeostasis in skeletal muscle–specific PGC-1α knockout mice reveals skeletal muscle–pancreatic β cell crosstalk

Abnormal glucose homeostasis in skeletal muscle–specific PGC-1α knockout mice reveals skeletal muscle–pancreatic β cell crosstalk

Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-Fed db/db mice

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

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