Genetic variation within IL18 is associated with insulin levels, insulin resistance and postprandial measures

Smart, Melissa; Dedoussis, George; Yiannakouris, Nikos; Grisoni, ML; Dror, Gie Ken; Yannakoulia, Mary; Papoutsakis, Constantina; Louizou, Eirini; Mantzoros, Christos S.; Melistas, Labros; Kontogianni, Meropi D.; Humphries, Steve E.; Talmud, Philippa J.

doi:10.1016/j.numecd.2009.12.004

Cited by 17 publications

(8 citation statements)

References 32 publications

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“…Some reports have shown that increased circulating IL-18 or genetic variation of IL-18 is linked with insulin resistance in patients with type 2 diabetes mellitus, obesity, or polycystic ovary syndrome [14,15,24,25]. By contrast, our study identified insulin resistance during acute endotoxemia only in the absence of IL-18.…”

Section: Discussioncontrasting

confidence: 79%

Endogenous Interleukin 18 Suppresses Hyperglycemia and Hyperinsulinemia during the Acute Phase of Endotoxemia in Mice

Yamashita

Ishikawa

Takahara

et al. 2015

Surgical Infections

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Background: Hyperglycemia associated with insulin resistance is common among critically ill patients. Interleukin (IL)-18 has been linked with hyperglycemia and insulin resistance in chronic disease, but the relation between IL-18 and insulin resistance during critical illness was unexplored. This study investigated whether IL-18 modulates hyperglycemia and insulin resistance during acute inflammation. Methods: We injected lipopolysaccharide (LPS) 40 mg/kg into wild-type (WT) and IL-18 knockout (KO) mice to induce endotoxemia and examined insulin resistance and insulin-dependent signaling pathways during the acute phase. Results: During the first hour after LPS treatment, IL-18 KO mice showed higher blood glucose and insulin and less insulin receptor substrate-1 and less phosphorylated Akt in the liver compared with WT mice. Interleukin-18 KO mice exhibited better survival after LPS treatment. Conclusions: The findings suggest that endogenous IL-18 may attenuate hyperglycemia and modulate insulin signaling in liver. Accordingly, IL-18 may modulate glucose tolerance during acute inflammation.

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Section: Discussioncontrasting

confidence: 79%

Endogenous Interleukin 18 Suppresses Hyperglycemia and Hyperinsulinemia during the Acute Phase of Endotoxemia in Mice

Yamashita

Ishikawa

Takahara

et al. 2015

Surgical Infections

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“…An IL-1 ␤ -mediated increase in intestinal TG secretion may contribute to the tendency toward higher abdominal obesity previously observed in these subjects ( 36 ). Similar to IL-1 ␤ , genetic variation in IL-18 has been associated with postprandial TG levels ( 37 ), suggesting that the absence of caspase-1 may reduce TG-rich lipoprotein production indirectly via these cytokines. Future studies may verify whether our current observations are mediated via IL-1 ␤ or IL-18.…”

Section: Discussionmentioning

confidence: 69%

Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion

Diepen

Stienstra

Vroegrijk

et al. 2013

Journal of Lipid Research

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Obesity is accompanied by low-grade chronic systemic infl ammation characterized by increased circulating levels of proinfl ammatory cytokines, including interleukin (IL)-1 ␤ , tumor necrosis factor (TNF)-␣ , and IL-6 ( 1 ). Activation of infl ammatory pathways induces metabolic disturbances, leading to insulin resistance, dyslipidemia, and cardiovascular diseases. Caspase-1 is a cysteine protease that is known for its crucial role in the activation of the proinfl ammatory cytokines IL-18 and IL-1 ␤ . Additionally, caspase-1 has been shown to cleave other substrates, including proteins involved in energy metabolism ( 2-4 ). Caspase-1 activation is controlled by the infl ammasome, a multiprotein Abstract Caspase-1 is known to activate the proinfl ammatory cytokines IL-1 ␤ and IL-18. Additionally, it can cleave other substrates, including proteins involved in metabolism. Recently, we showed that caspase-1 defi ciency in mice strongly reduces high-fat diet-induced weight gain, at least partly caused by an increased energy production. Increased feces secretion by caspase-1-defi cient mice suggests that lipid malabsorption possibly further reduces adipose tissue mass. In this study we investigated whether caspase-1 plays a role in triglyceride-(TG)-rich lipoprotein metabolism using caspase-1-defi cient and wild-type mice. Caspase-1 defi ciency reduced the postprandial TG response to an oral lipid load, whereas TG-derived fatty acid (FA) uptake by peripheral tissues was not affected, demonstrated by unaltered kinetics of [ Lipid composition of fecesMice were individually housed for 4 days to determine food intake and collect feces quantitatively. Feces were weighed, freeze-dried, and ground, and fecal fatty acids (FA) were derivatized by methyl esterifi cation. Therefore, 2 ml methanol/hexane (4:1 v/v) containing 80 µg pentadecanoic acid (C15:0) as an internal standard (Fluka) was added to 15 mg of feces. Then, 200 µL acetyl chloride (Merck) was added, and samples were incubated at 95°C. After cooling to 4°C, 5 ml 6% K 2 CO 3 (Sigma) was added, and samples were centrifuged (10 min; 4,000 rpm, 4°C). The upper hexane layer was isolated and used for GC analysis of FA methyl esters (FAME). FAME were separated on a 50 m × 0.25 mm capillary GC column (CP Sil 88; Agilent technologies) in a 3800 GC gas chromatograph (Varian) equipped with a fl ame ionization detector. The injector and fl ame ionization detector were kept at 270°C. The column temperature was programmed from 170°C to 210°C. FAME were introduced by split injection (split ratio 20:1). Quantifi cation was based on the area ratio of the individual FA to the internal standard.To extract total cholesterol from feces, dried feces (10 mg) were incubated in 1 ml alkaline methanol (CH 3 OH: 1 M NaOH = 3:1 [v/v]) for 2 h at 80°C in screw-capped tubes using 5 ␣ -cholestane as internal standard. Tubes were cooled to room temperature, and the cholesterol was extracted twice with 2 ml petroleum ether. The combined petroleum ether layers were evaporated to dryness, and the ...

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“…Moreover, IL-18 levels were restored in individuals that lost weight after bariatric surgery [112]. Furthermore, several polymorphisms in the IL-18 gene were associated with risk factors for the metabolic syndrome, including increased blood pressure [110], insulin resistance [113, 114] impaired glucose regulation [111], the development of obesity [115] and associated with a higher prevalence of type 2 diabetes [111]. Interestingly, IL-18 was found to be secreted from adipose tissue at a higher rate in obese individuals as compared to lean controls [116, 117].…”

Section: Il-18mentioning

confidence: 99%

IL-1 family members in the pathogenesis and treatment of metabolic disease: Focus on adipose tissue inflammation and insulin resistance

et al. 2015

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Obesity is characterized by a chronic, low-grade inflammation that contributes to the development of insulin resistance and type 2 diabetes. Cytokines and chemokines produced by immunocompetent cells influence local as well as systemic inflammation and are therefore critical contributors to the pathogenesis of type 2 diabetes. Hence, cytokines that modulate inflammatory responses are emerging as potential targets for intervention and treatment of the metabolic consequences of obesity. The interleukin-1 (IL-1) family of cytokines and receptors are key mediators of innate inflammatory responses and exhibit both pro- and anti-inflammatory functions. During the last decades, mechanistic insights into how the IL-1 family affects the initiation and progression of obesity-induced insulin resistance have increased significantly. Here, we review the current knowledge and understanding, with emphasis on the therapeutic potential of individual members of the IL-1 family of cytokines for improving insulin sensitivity in patients with diabetes.

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Genetic variation within IL18 is associated with insulin levels, insulin resistance and postprandial measures

Cited by 17 publications

References 32 publications

Endogenous Interleukin 18 Suppresses Hyperglycemia and Hyperinsulinemia during the Acute Phase of Endotoxemia in Mice

Endogenous Interleukin 18 Suppresses Hyperglycemia and Hyperinsulinemia during the Acute Phase of Endotoxemia in Mice

Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion

IL-1 family members in the pathogenesis and treatment of metabolic disease: Focus on adipose tissue inflammation and insulin resistance

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