Hyperglycaemia due to insulin resistance caused by interferon-γ

Shiba, Teruo; Higashi, Natsumi; Nishimura, Youji

doi:10.1002/(sici)1096-9136(199805)15:5<435::aid-dia566>3.0.co;2-n

Cited by 35 publications

(12 citation statements)

References 6 publications

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“…Pro and anti-inflammatory cytokines play a key role in identifying patients at elevated risk for several diseases (7). Previous studies indicate that certain pro and/or anti-inflammatory cytokines are capable of interfering with insulin sensitive glucose uptake and induce insulin resistance (8).…”

Section: Introductionmentioning

confidence: 99%

Association of IL-10 and IL-6 Gene Polymorphisms with Type 2 Diabetes Mellitus among Egyptian Patients

et al. 2013

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Recent findings indicate that certain cytokines are capable of interfering with insulin sensitive glucose uptake and induce insulin resistance. To test for the association of IL-10-1082 and IL-6-174 Key words: IL-10, IL-6, gene polymorphism, type 2 diabetes, Egypt Mısır'lı Hastalarda Tip 2 Diyabet ile IL-10 ve IL-6 Gen Poliformizmi Arasındaki İlişki ÖZET Son yıllarda bazı sitokinlerin insülin duyarlı glikoz alınımı ile ilişkiye girebilme ile birlikte insülin direnci meydana

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Section: Introductionmentioning

confidence: 99%

Association of IL-10 and IL-6 Gene Polymorphisms with Type 2 Diabetes Mellitus among Egyptian Patients

et al. 2013

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“…This is in part due to the strong correlation between elevations in the local and circulating proinflammatory cytokines (tumor necrosis factor [TNF]-␣, interleukin [IL]-1, interferon-␥, and IL-6) and insulin resistance (1,(3)(4)(5)(6)(7). It is well known that these cytokines are elevated in cases of cancer, cachexia, and severe infection, and insulin resistance frequently accompanies these clinical conditions (8).…”

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confidence: 99%

Interleukin-6 Induces Cellular Insulin Resistance in Hepatocytes

et al. 2002

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Interleukin (IL)-6 is one of several proinflammatory cytokines that have been associated with insulin resistance and type 2 diabetes. A two-to threefold elevation of circulating IL-6 has been observed in these conditions. Nonetheless, little evidence supports a direct role for IL-6 in mediating insulin resistance. Here, we present data that IL-6 can inhibit insulin receptor (IR) signal transduction and insulin action in both primary mouse hepatocytes and the human hepatocarcinoma cell line, HepG2. This inhibition depends on duration of IL-6 exposure, with a maximum effect at 1-1.5 h of pretreatment with IL-6 in both HepG2 cells and primary hepatocytes. The IL-6 effect is characterized by a decreased tyrosine phosphorylation of IR substrate (IRS)-1 and decreased association of the p85 subunit of phosphatidylinositol 3-kinase with IRS-1 in response to physiologic insulin levels. In addition, insulin-dependent activation of Akt, important in mediating insulin's downstream metabolic actions, is markedly inhibited by IL-6 treatment. Finally, a 1.5-h preincubation of primary hepatocytes with IL-6 inhibits insulin-induced glycogen synthesis by 75%. These data suggest that IL-6 plays a direct role in insulin resistance at the cellular level in both primary hepatocytes and HepG2 cell lines and may contribute to insulin resistance and type 2 diabetes.

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“…Chronic production of proinflammatory cytokines is considered a major link between obesity and insulin resistance (1). Elevated local and circulating levels of proinflammatory cytokines, such as tumor necrosis factor-␣ and interleukin (IL) 3 -6, are known to be associated with obesity in both human and rodent models (2)(3)(4)(5). Although adipose-derived tumor necrosis factor-␣ may act locally in autocrine and paracrine manners, adipose-derived IL-6 is thought to enter circulation and play a systemic role in modulating insulin actions (6).…”

mentioning

confidence: 99%

Regulation of Interleukin-6-induced Hepatic Insulin Resistance by Mammalian Target of Rapamycin through the STAT3-SOCS3 Pathway

Kim

Liu

et al. 2008

Journal of Biological Chemistry

131

126

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The proinflammatory cytokine interleukin (IL)-6 has been proposed to be one of the mediators that link obesity-derived chronic inflammation with insulin resistance. Signaling through the mammalian target of rapamycin (mTOR) has been found to impact insulin sensitivity under various pathological conditions, through serine phosphorylation and inhibition of insulin receptor substrate by the downstream effector of mTOR, ribosomal S6 kinase 1 (S6K1). However, an involvement of mTOR in IL-6-induced insulin resistance has not yet been reported. Here we show that rapamycin, the inhibitor of mTOR signaling, rescues insulin signaling and glycogen synthesis from IL-6 inhibition in HepG2 hepatocarcinoma cells as well as in mouse primary hepatocytes. IL-6 activates S6K1 in these cells, but unexpectedly, S6K1 is not involved in IL-6 inhibition of insulin signaling, since the effect of IL-6 persists in cells with drastically reduced S6K1 levels induced by RNA interference, suggesting that the function of mTOR signaling is through a mechanism different from the prevailing model of S6K1 phosphorylation of insulin receptor substrate-1. Interestingly, we find that the phosphorylation of STAT3 on Ser 727 and STAT3 transcriptional activity are regulated by mTOR upon IL-6 stimulation and that STAT3 is required for IL-6 inhibition of insulin signaling. Furthermore, IL-6-induced SOCS3 expression is inhibited by rapamycin, and ectopic expression of SOCS3 blocks the ability of rapamycin to enhance insulin sensitivity in the presence of IL-6. Taken together, we propose that mTOR plays a key role in IL-6-induced hepatic insulin resistance by regulating STAT3 activation and subsequent SOCS3 expression.Insulin resistance, a major risk factor and the principle defect in type II diabetes, is commonly observed with obesity. Chronic production of proinflammatory cytokines is considered a major link between obesity and insulin resistance (1). Elevated local and circulating levels of proinflammatory cytokines, such as tumor necrosis factor-␣ and interleukin (IL) 3 -6, are known to be associated with obesity in both human and rodent models (2-5). Although adipose-derived tumor necrosis factor-␣ may act locally in autocrine and paracrine manners, adipose-derived IL-6 is thought to enter circulation and play a systemic role in modulating insulin actions (6). Depletion of IL-6 improves insulin action in a mouse model of obesity (7), whereas in humans, elevated plasma IL-6 levels positively correlate with obesity and insulin resistance and predict the development of type 2 diabetes (2, 8, 9). Furthermore, IL-6 administration to healthy individuals induces blood glucose increases (10). In vitro, IL-6 has been shown to induce insulin resistance in hepatic cells (11). Although the role of IL-6 within peripheral tissues (adipose and skeletal muscle) is still being debated, it is generally accepted that at least in the liver, IL-6 causes insulin resistance (12).A mechanism of IL-6-induced insulin resistance in the liver has been proposed, which involves the...

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Hyperglycaemia due to insulin resistance caused by interferon-γ

Cited by 35 publications

References 6 publications

Association of IL-10 and IL-6 Gene Polymorphisms with Type 2 Diabetes Mellitus among Egyptian Patients

Association of IL-10 and IL-6 Gene Polymorphisms with Type 2 Diabetes Mellitus among Egyptian Patients

Interleukin-6 Induces Cellular Insulin Resistance in Hepatocytes

Regulation of Interleukin-6-induced Hepatic Insulin Resistance by Mammalian Target of Rapamycin through the STAT3-SOCS3 Pathway

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