Interleukin-6 Induces Cellular Insulin Resistance in Hepatocytes

Senn, Joseph J.; Klover, Peter; Nowak, Irena; Mooney, Robert A.

doi:10.2337/diabetes.51.12.3391

Cited by 759 publications

(624 citation statements)

References 56 publications

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“…Thus, lowgrade inflammation seems to be a key finding of diabetic nephropathy, and could even be the reason for the reduced insulin sensitivity in these patients. Such a view is supported by experimental data showing that IL-6 is capable of inducing insulin resistance in mouse hepatocytes and human hepatocarcinoma cell lines by affecting both proximal and distal events in hepatic insulin receptor signal transduction [24].…”

Section: Discussionmentioning

confidence: 85%

Diabetic nephropathy is associated with low-grade inflammation in Type 1 diabetic patients

et al. 2003

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Aims/hypothesis. Increased concentrations of C-reactive protein and interleukin-6, a finding suggestive of the presence of inflammation, have been observed in Type 2 diabetes. In such patients, C-reactive protein was predictive of diabetic nephropathy. Studies on low-grade inflammatory markers and nephropathy in Type 1 diabetic patients have shown conflicting results. Therefore we studied whether low-grade inflammation is associated with diabetic nephropathy in Type 1 diabetic patients. Methods. We divided 194 Type 1 diabetic patients into three groups from the Finnish Diabetic Nephropathy Study based upon their albumin excretion rate. Patients with normoalbuminuria (n=67) had no antihypertensive medication or signs of cardiovascular disease, while patients with microalbuminuria (n=64) or macroalbuminuria (n=63) were all treated with an angiotensin-converting enzyme inhibitor, a drug that could attenuate low-grade inflammation. As a measure of insulin sensitivity we used estimated glucose disposal rate. C-reactive protein was measured by radioimmunoassay and interleukin-6 by high sensitivity enzyme immunoassay.

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Section: Discussionmentioning

confidence: 85%

Diabetic nephropathy is associated with low-grade inflammation in Type 1 diabetic patients

et al. 2003

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“…While the role of IL-6 in whole-body insulin resistance is unclear, it is generally accepted that excessive circulating IL-6 causes hepatic insulin resistance [30]. This conclusion is based on several observations demonstrating that exogenous administration of IL-6 impairs insulin signal transduction in the liver in vitro [36,37] and in vivo [13]. In addition, IL-6-neutralising antibodies have been shown to reverse hepatic insulin resistance in mice [38,39], while transient overproduction of IL-6 in skeletal muscle by in vivo electroporation resulted in liver inflammation [40].…”

Section: Discussionmentioning

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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“…Taken together, the role of IL-6 in whole body energy homeostasis remains partly contradictory. However, several experimental studies have shown that IL-6 impairs insulin sensitivity and action in rodent and human hepatocytes as well as inducing hepatic insulin resistance in vivo in mice [48][49][50]. This insulin desensitising effect in liver cells is, in part, the result of IL-6 inducing marked inflammation in this tissue [29].…”

Section: Discussionmentioning

confidence: 99%

AMP-activated protein kinase inhibits IL-6-stimulated inflammatory response in human liver cells by suppressing phosphorylation of signal transducer and activator of transcription 3 (STAT3)

et al. 2010

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Aim/hypothesis The aim of the study was to examine the possible role of AMP-activated protein kinase (AMPK) in the regulation of the inflammatory response induced by cytokine action in human liver cells. Methods IL-6-stimulated expression of the genes for acutephase response markers serum amyloid A (SAA1, SAA2) and haptoglobin (HP) in the human hepatocarcinoma cell line HepG2 were quantified after modulation of AMPK activity by pharmacological agonists (5-amino-4-imidazolecarboxamideriboside [AICAR], metformin) or by using small interfering (si) RNA transfection. The intracellular signalling pathway mediating the effect of AMPK on IL-6-stimulated acute-phase marker expression was characterised by assessing the phosphorylation levels of the candidate protein signal transducer and activator of transcription 3 (STAT3) in response to AMPK agonists. Results AICAR and metformin markedly blunt the IL-6-stimulated expression of SAA cluster genes as well as of haptoglobin in a dose-dependent manner. Moreover, the repression of AMPK activity by siRNA significantly reversed the inhibition of SAA expression by both AICAR and metformin, indicating that the effect of the agonists is dependent on AMPK. For the first time we show that AMPK appears to regulate IL-6 signalling by directly inhibiting the activation of the main downstream target of IL-6, STAT3. Conclusions/interpretation We provide evidence for a key function of AMPK in suppression of the acute-phase response caused by the action of IL-6 in liver, suggesting that AMPK may act as an intracellular link between chronic low-grade inflammation and metabolic regulation in peripheral metabolic tissues.

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Interleukin-6 Induces Cellular Insulin Resistance in Hepatocytes

Cited by 759 publications

References 56 publications

Diabetic nephropathy is associated with low-grade inflammation in Type 1 diabetic patients

Diabetic nephropathy is associated with low-grade inflammation in Type 1 diabetic patients

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

AMP-activated protein kinase inhibits IL-6-stimulated inflammatory response in human liver cells by suppressing phosphorylation of signal transducer and activator of transcription 3 (STAT3)

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