interleukin-8 and Hyperinsulinism

Mitochondrial dysfunction has been proposed to cause insulin resistance and that might stimulate cytokine production.. The objective of the study was to elucidate the association between mitochondrial myopathy, insulin sensitivity, and cytokine levels in muscle.. This was an experimental, controlled study in outpatients.. Eight overnight-fasted patients (P) with various inherited mitochondrial myopathies and eight healthy subjects (C) matched for sex, age, weight, height, and physical activity participated in the study.. The intervention included a 120-minute hyperinsulinemic, euglycemic clamp. Another morning, microdialysis of both vastus lateralis muscles for 4 hours, including one-legged, knee extension exercise for 30 minutes, was performed.. Glucose infusion rate during 90-120 minutes of insulin infusion was measured. Cytokine concentrations in dialysate were also measured.. Muscle strength, percentage fat mass, and creatine kinase in plasma did not differ between groups. The maximal oxygen uptake was 21 ± 3 (SE) (P) and 36 ± 3(C) mL/kg·min (2P < .05). Basal insulin, C-peptide, and glucagon were higher in P (55 ± 10, 980 ± 92, and 102 ± 13 pM) than in C (36 ± 12, 712 ± 98, and 44 ± 10 pM) (two-sided significance testing [2P ]< .05). The homeostasis model assessment insulin sensitivity index and glucose infusion rate (6.8 ± 1.0 vs 9.4 ± 1.3 mg/min·kg) were lower, and free fatty acids and glycerol at 120 minutes were higher in P vs C (2P < .05). Dialysate concentrations of TNF-α, IL-6, IL-8, IL-10, and monocyte chemoattractant protein-1 were higher in P vs C (2P < .05). Dialysate concentrations of these cytokines and of IL-1 receptor antagonist increased during exercise (2P < .05), identically in P and C. No differences existed in plasma cytokine concentrations.. In patients with a variety of mitochondrial myopathies, insulin sensitivity of muscle, adipose tissue, and pancreatic A cells is reduced, supporting that mitochondrial function influences insulin action. Furthermore, a local, low-grade inflammation of potential clinical importance exists in the muscle of these patients.

Topics: Adipose Tissue; Adult; Chemokine CCL2; Cytokines; Exercise; Female; Glucagon-Secreting Cells; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin Resistance; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged; Mitochondria; Mitochondrial Myopathies; Muscle, Skeletal; Outpatients; Tumor Necrosis Factor-alpha

Type 2 diabetes and obesity are associated with an enhanced release of a number of adipocytokines. Hyperinsulinemia, frequently present in type 2 diabetes and obesity, might be one of the drivers of the enhanced production of adipocytokines. The aim of this study was to investigate the interstitial levels of cytokines in subcutaneous adipose tissue (SCAT) in response to hyperinsulinemia and the effect of weight-reducing hypocaloric diet on this regulation in obese subjects. Thirteen obese premenopausal women participated in the study. Concentrations of seven cytokines were measured in plasma and in AT interstitial fluid collected by microdialysis during a euglycemic-hyperinsulinemic clamp and during control infusion of physiological saline. A subgroup of six women underwent a 4-wk very-low-calorie diet (VLCD). Microdialysis during the clamp was performed before and at the end of VLCD. Hyperinsulinemia induced an increase of monocyte chemoatractant protein (MCP-1) and IL-6 SCAT interstitial and plasma levels and elevated IL-8 levels in SCAT. The relative changes of IL-6 levels in the dialysate correlated with changes of IL-8 and MCP-1. The interstitial and plasma levels of IL-1β, IL-10, TNFα, and plasminogen activator inhibitor (PAI-1) remained unchanged in response to hyperinsulinemia. VLCD resulted in enhancement of the hyperinsulinemia-induced augmentation of MCP-1, IL-6, and IL-8 interstitial levels. In conclusion, hyperinsulinemia upregulates the interstitial levels of MCP-1, IL-6, and IL-8 in SCAT in obese women, whereas it does not affect IL-1β, IL-10, TNFα, and PAI-1 levels. Hypocaloric diet associated with weight reduction enhances the hyperinsulinemia-induced upregulation of MCP-1, IL-6, and IL-8 in SCAT.

Topics: Adult; Caloric Restriction; Chemokine CCL2; Chemokines; Cytokines; Female; Glucose Clamp Technique; Homeostasis; Humans; Hyperinsulinism; Insulin Resistance; Interleukin-6; Interleukin-8; Microdialysis; Middle Aged; Obesity; Subcutaneous Fat

Interleukin-6 has been implicated in the insulin resistance associated with obesity and impaired glucose tolerance. Previous studies in vitro have shown that IL-6 rapidly (1-2 h) impairs cellular insulin signalling and action through an increased expression of suppressor of cytokine signalling (SOCS)-3. In the present study, IL-6 or saline was infused in rats that were simultaneously in a state of hyperinsulinaemia. Muscle, liver and adipose tissue were excised after 2 h to examine potential effects on insulin signalling or gene expression.. The rats were infused with IL-6 or saline during a euglycaemic-hyperinsulinaemic clamp and the glucose infusion rate was measured after 90 to 120 min. Signal transducer and activator of transcription (STAT)3 phosphorylation and insulin-stimulated tyrosine phosphorylation of the insulin receptors and IRS were measured with immunoblotting and gene expression through real-time PCR.. No inhibitory effect of IL-6 on insulin-stimulated whole-body glucose uptake was seen in spite of high circulating levels of IL-6 (0.85+/-0.08 nmol/l). Tyrosine phosphorylation of the insulin receptors and IRS was also unchanged in the liver, skeletal muscles and adipose tissue. However, tyrosine phosphorylation of STAT3 was increased in all tissues, showing that IL-6 signalling was activated. IL-6 mRNA tended to increase, while GLUT4, peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) and adiponectin gene expression were unchanged.. Infusion of IL-6 for 120 min in rats during euglycaemic-hyperinsulinaemic conditions did not alter the effect of insulin on whole-body glucose homeostasis, plasma adiponectin levels or insulin signalling in target tissues. Thus, the acute effects of IL-6, associated with SOCS-3 induction, do not lead to whole-body insulin resistance. These data further underscore the importance of the chronic, and potentially tissue-specific effects of IL-6 on insulin signalling and action.

Topics: Animals; Blood Glucose; Female; Glucose Clamp Technique; Hyperinsulinism; Insulin; Insulin Resistance; Interleukin-8; Liver; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; Signal Transduction