Acute interleukin-6 administration does not impair muscle glucose uptake or whole-body glucose disposal in healthy humans (original) (raw)
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Dose-Dependent Effects of Recombinant Human Interleukin-6 on Glucose Regulation
The Journal of Clinical Endocrinology & Metabolism, 1997
Inflammatory cytokines have metabolic actions that probably contribute to the general adaptation of the organism during infectious or inflammatory stress. To examine the effects of interleukin 6 (IL-6), the main circulating cytokine, on glucose metabolism in man, we performed dose-response studies of recombinant human IL-6 in normal volunteers. Increasing single doses of IL-6 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/Kg BW) were injected sc in 15 healthy male volunteers (3 in each dose) after a 12-h fast. All IL-6 doses were tolerated well and produced no significant adverse effects. We measured the circulating levels of glucose, insulin, C-peptide, and glucagon at baseline and half-hourly over 4 h after the IL-6 injection. Mean peak plasma levels of IL-6 were achieved between 120 and 240 min and were 8, 22, 65, 290, and 4050 pg/mL, respectively, for the 5 doses. After administration of the 2 smaller IL-6 doses, we observed no significant changes in plasma glucose levels, which, because of c...
Diabetes, Obesity and Metabolism, 2014
Aim To examine if physiological concentrations of both IL-6, in combination with IL-6R, are able to stimulate glucose uptake in human skeletal muscle and to identify the associated signalling pathways. Methods Skeletal muscle tissue (~60mg) obtained from healthy female volunteers via muscle biopsy was subjected to incubation in the absence or presence of insulin (60 μU.ml -1 ), rhIL-6 (4 ng.ml -1 ), or a combination of rhIL-6 (4 ng.ml -1 ) and rhIL-6R (100 ng.ml -1 ) for 30 min, with glucose transport measured for each incubation. Western blot analysis was conducted on key signalling proteins, protein kinase B, (PKB/Akt), adenosine monophosphate kinase (AMPK) and mammalian target of rapamycin (mTOR) to gain an early insight into any differing transport mechanisms. Results Human skeletal muscle exhibited increased glucose uptake with insulin (1.85 fold; P<0.05) and stimulated phosphorylation of PKB/Akt and AMPK (0.98 ± 0.23 and 1.49 ± 0.13, respectively, phosphorylated: total; P<0.05). IL-6/IL-6R increased phosphorylation of mTOR (4-fold, P<0.05) compared to insulin, IL-6 alone and basal control. IL-6 did not stimulate glucose uptake but combined with IL-6R, induced 1.5 fold increase in glucose uptake (P<0.05) and phosphorylation of AMPK (0.95 ± 0.19; phosphorylated: total, P<0.05). Conclusions IL-6 in combination with IL-6R and not IL-6 alone increased glucose uptake in human skeletal muscle. IL-6/IL-6R mediated glucose uptake occurred independently of PKB/Akt phosphorylation, showing that IL-6/IL-6R induced glucose uptake is dependent on a divergent pathway.
Effect of IL-6 on the insulin sensitivity in patients with type 2 diabetes
American Journal of Physiology-Endocrinology and Metabolism, 2014
Elevated interleukin-6 (IL-6) levels are associated with type 2 diabetes, but its role in glucose metabolism is controversial. We investigated the effect of IL-6 on insulin-stimulated glucose metabolism in type 2 diabetes patients and hypothesized that an acute, moderate IL-6 elevation would increase the insulin-mediated glucose uptake. Men with type 2 diabetes not treated with insulin [ n = 9, age 54.9 ± 9.7 (mean ± SD) yr, body mass index 34.8 ± 6.1 kg/m2, HbA1c7.0 ± 1.0%] received continuous intravenous infusion with either recombinant human IL-6 (rhIL-6) or placebo. After 1 h with placebo or rhIL-6, a 3-h hyperinsulinemic-isoglycemic clamp was initiated. Whole body glucose metabolism was measured using stable isotope-labeled tracers. Signal transducer and activator of transcription 3 (STAT3) phosphorylation and suppressor of cytokine signaling 3 (SOCS3) expression were measured in muscle biopsies. Whole body energy expenditure was measured using indirect calorimetry. In response...
Interleukin-6 in impaired fasting glucose
Prediabetes is associated with the features of metabolic syndrome and inflammation contributing directly to the pathogenesis of cardiovascular disease (CVD). This study was conducted to explore the utility of interleukin-6 (IL-6) in determining the risk of CVD in prediabetes. It involves estimation of IL-6 & insulin along with its correlation with insulin, fasting plasma glucose (FPG), Insulin resistance (IR) and physical measurements. Eighty subjects were grouped into 40 prediabetes and 40 normoglycemic on the basis of FPG values. The mean insulin, IL-6, Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) and anthropometric measurements were found to be significantly higher (P <0.05) in prediabetes group. IL-6 had a significant correlation with fasting insulin (r = −0.413) and HOMA-IR (r = −0.413), but no correlation with FPG (r = −0.227) in the prediabetes group. IL-6 also showed a positive correlation with body mass index BMI(r = −0.339), waist circumference WC (r = −484) and waist-to-hip ratio WHR (r = −0.430). This study concludes that prediabetes is associated with inflammation, increasing the risk of CVD in these individuals.
Altered Response of Skeletal Muscle to IL-6 in Type 2 Diabetic Patients
Diabetes, 2012
Interleukin-6 (IL-6) has a dual role in modulating insulin sensitivity, with evidence for this cytokine as both an enhancer and inhibitor of insulin action. We determined the effect of IL-6 exposure on glucose and lipid metabolism in cultured myotubes established from people with normal glucose tolerance or type 2 diabetes. Acute IL-6 exposure increased glycogen synthesis, glucose uptake, and signal transducer and activator of transcription 3 (STAT3) phosphorylation in cultured myotubes from normal glucose tolerant subjects. However, in type 2 diabetic patients, IL-6 was without effect on glucose metabolism and STAT3 signaling, concomitant with increased suppressor of cytokine signaling 3 (SOCS3) expression. IL-6 increased fatty acid oxidation in myotubes from type 2 diabetic and normal glucose tolerant subjects. Expression of IL-6, IL-6 receptor (IL-6R), or glycoprotein 130, as well as IL-6 secretion, was unaltered between cultured myotubes from normal glucose tolerant or type 2 di...
Interleukin-6 Stimulates Lipolysis and Fat Oxidation in Humans
The Journal of Clinical Endocrinology & Metabolism, 2003
Although IL-6 is a key modulator of immune function, it also plays a role in regulating substrate metabolism. To determine whether IL-6 affects lipid metabolism, 18 healthy men were infused for 3 h with saline (Con; n ؍ 6) or a high dose (High-rhIL6; n ؍ 6) or a low dose (Low-rhIL6; n ؍ 6) of recombinant human IL-6 (rhIL-6). The IL-6 concentration during Con, Low-rhIL6, and High-rhIL6 was at a steady state after 30 min of infusion at approximately 4, 140, and 320 pg/ml, respectively. Either dose of rhIL-6 was associated with a similar increase in fatty acid (FA) concentration and endogenous FA rate of appearance (R a ) from 90 min after the start of the infusion. The FA concentration and FA R a continued to increase until the cessation of rhIL-6 infusion, reaching levels approximately 50% greater than Con values. The elevated levels reached at the end of rhIL-6 infusion persisted at least 3 h postinfusion. Triacylglycerol concentrations were unchanged during rhIL-6 infusion, whereas whole body fat oxidation increased after the second hour of rhIL-6 infusion. Of note, during Low-rhIL6, the induced elevation in FA concentration and FA R a occurred in the absence of any change in adrenaline, insulin, or glucagon, and no adverse side effects were observed. In conclusion, the data identify IL-6 as a potent modulator of fat metabolism in humans, increasing fat oxidation and FA reesterification without causing hypertriacylglyceridemia. (J Clin Endocrinol Metab 88: [3005][3006][3007][3008][3009][3010] 2003)
Diabetologia, 2004
Aims/hypothesis. Our aim was to examine the possible direct relationship of interleukin-6 and TNFα with insulin sensitivity in humans. Methods. We carried out two series of euglycaemichyperinsulinaemic clamp experiments. In the first (CLAMP1), skeletal muscle mRNA expression and plasma concentrations of IL-6 and TNFα were examined in patients with Type 2 diabetes (n=6), subjects matched for age (n=6), and young healthy (n=11) control subjects during a 120-min supra-physiological hyperinsulinaemic (40 mU·m −2 ·min −1 ) euglycaemic clamp. In the second series of experiments (CLAMP2), patients with Type 2 diabetes (n=6) and subjects matched for age (n=7) were studied during a 240-min high-physiological hyperinsulinaemic (7 mU·m −2 ·min −1 ) euglycaemic clamp, during which arterial and venous (femoral and subclavian) blood samples were measured for IL-6 and TNFα flux. Results. In both experiments the glucose infusion rate in the patients was markedly lower than that in the other groups. In CLAMP1, basal skeletal muscle IL-6 and TNFα mRNA were the same in all groups. They were not affected by insulin and they were not related to the glucose infusion rate. In CLAMP2, neither cytokine was released from the arm or leg during insulin stimulation in either group. In both experiments plasma concentrations of these cytokines were similar in the patients and in the control subjects, although in CLAMP1 the young healthy control group had lower (p<0.05) plasma IL-6 concentrations. Using data from all subjects, a strong positive correlation (r=0.85; p<0.00001) was observed between basal plasma IL-6 and BMI. Conversely, a negative relationship (r=−0.345; p<0.05) was found between basal plasma TNFα and BMI, although this was not significant when corrected for BMI. When corrected for BMI, no relationship was observed between either basal plasma IL-6 or TNFα and GIR. Conclusions/interpretation. 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 TNFα are indicative of insulin resistance.
Correlation Analysis of Interleukin-6 on Blood Glucose in Prediabetes and Normal Glycemic Status
Medical Laboratory Technology Journal
Diabetes mellitus is a global health problem whose incidence rate continues to increase yearly. Most people with diabetes mellitus go through the prediabetes phase. Prediabetes is a condition where blood glucose levels are elevated but have not yet reached the criteria for diabetes mellitus. Low-grade chronic inflammation is one of the pathways known to interfere with insulin signalling that ultimately affects blood glucose levels. One of the most studied inflammatory pathways in the pathogenesis of diabetes mellitus is interleukin-6 (IL-6). This study aims to determine whether there were differences in IL-6 levels between groups of prediabetes subjects and normal subjects and to observe the correlation between IL-6 levels and blood glucose. This study is useful in providing additional scientific evidence on the development of diabetes mellitus, especially in blood glucose regulation through inflammatory pathways. The design of this study was analytic observational in 71 subjects wi...