interleukin-8 and Insulin-Resistance

It is well-known for a long-time, that intensive exercise is favourable for many metabolic parameters. Up-till now the exact mechanism has not been clarified. Recently it has turned out, that the muscular system is an extended endocrine organ, which, during contraction, secretes many hundred peptides, so called adipomyokines into the blood stream. Many of them improve glucose-utilization of the muscular system, and insulin-sensitivity, via endocrine, paracrine, or autocrine pathways. Worldwide intensive research takes place to clear up the exact pathomechanism of these processes. It came to light: 1. The newly discovered adipomyokine, irisin induces "browning" of beige precursor fat-cells, which are present in white adipose tissue. The developed beige adipose tissue by this way disposes with the advantegous properties of the brown adipose tissue. Taking together these facts, irisin might be a therapeutic choice in treating certain diseases, caused by inactive life-style. 2. Therapeutic application of brown adipose tissue in obesity, metabolic syndrome, and type 2 diabetes seems to be successful. This mechanism is based on removal of unnecessary calories via thermogenesis. 3. The role of myostatin, which is also produced by muscle contraction, is contradictory. It is not clear, why does the muscle system produce damaging product for the metabolism. On the other hand, inhibition of myostatin might be a therapeutic option. It is still questionable, whether the other hundreds of myokines could possess practicable roles on glucose, lipid, insulin secretion/effects. At present one can establish, that regular exercise is essential for the everyday practise, in order to optimise quality of life.. Régóta ismeretes, hogy az intenzív izommunka számos metabolikus paramétert kedvezően befolyásol. E folyamat mechanizmusa eddig nem volt tisztázott. Újabban kiderült, hogy a vázizomzat kiterjedt endokrin szerv, amely kontrakciója során több száz adipomiokint szekretál a véráramba, amelyek egy része endokrin, parakrin vagy autokrin úton javítja a vázizomzat glükózfelhasználását, fokozza inzulinérzékenységét. Világszerte intenzív kutatás igyekszik e folyamatok pontos mechanizmusát felderíteni. Három fontos területen történt előrehaladás: 1. Az újonnan felfedezett adipomiokin, az irisin a fehér zsírszövetben jelen lévő bézs prekurzor zsírsejtekben „barnásítást” indít meg, és az így létrejött bézs zsírszövet a továbbiakban a barna zsírszövet előnyös anyagcserehatásaival rendelkezik. Az irisin perspektivikusan terápiás opció lehet az inaktív életmód okozta betegségek kezelésében. 2. Kiderült, hogy a barna zsírszövet terápiás alkalmazása obesitasban, metabolikus szindrómában és 2-es típusú diabetesben eredményes, ami a felesleges kalóriák hőtermelés útján való eliminálásán alapszik. 3. Az ugyancsak kontrakció hatására termelődő myostatin szerepe ellentmondásos, nem világos, hogy az izomzat miért expresszál magára az izomzatra és az anyagcserére is káros anyagot, ugyanakkor a myostatin gátlása terápiásan felhasználható lehet. Kérdéses, hogy a többi sok száz miokinnek milyen szerepe lehet a fontos metabolikus paraméterek (glükóz, inzulin, lipidek) szekréciójában és hatásában, azonban a mindennapi gyakorlat számára már most leszögezhető, hogy a mozgás elengedhetetlen az életminőség optimalizálása szempontjából. Orv. Hetil., 2014, 155(37), 1469–1477.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Body Mass Index; Diabetes Mellitus, Type 2; Dietary Fats; Energy Metabolism; Fibronectins; Follistatin; Glucose; Humans; Inflammation; Insulin Resistance; Interleukin-15; Interleukin-6; Interleukin-8; Metabolic Syndrome; Muscle Contraction; Muscle, Skeletal; Myocardium; Myostatin; Obesity; Physical Exertion; Sedentary Behavior

Metabolic tissues, including skeletal muscle, adipose tissue and the digestive system, dynamically secrete various factors depending on the metabolic state, communicate with each other and orchestrate functions to maintain body homeostasis. Skeletal muscle secretes cytokines such as interleukin-6 (IL-6), IL-15, fibroblast growth factor-21 (FGF21) and IL-8. These compounds, myokines, play important roles in biological homeostasis such as energy metabolism, angiogenesis and myogenesis. New technological advances have allowed secretomics - analysis of the secretome - to be performed. The application of highly sensitive mass spectrometry makes qualitative and quantitative analysis of the secretome of skeletal muscle possible. Secretory proteins derived from skeletal muscle cells under various conditions were analyzed, and many important factors were suggested. In-depth studies of the secretome from metabolic cells in various conditions are strongly recommended. This study will provide information on methods of novel communication between metabolic tissues.

Topics: Adipose Tissue; Angiogenesis Inducing Agents; Animals; Cell Communication; Computational Biology; Energy Metabolism; Humans; Insulin Resistance; Interleukin-15; Interleukin-6; Interleukin-8; Mass Spectrometry; Muscle Development; Muscle Fibers, Skeletal

Diabetes is a complex disease that affects many organs directly or indirectly. Type 2 diabetes mellitus is characterized by insulin resistance with a relative deficiency in insulin secretion. It has become apparent that inter-organ communication is of great importance in the pathophysiology of diabetes. Far from being an inert tissue in terms of inter-organ communication, it is now recognized that skeletal muscle can secrete so-called myokines that can impact on the function of distant organs/tissues both favourably and unfavourably. We have proposed that communication between insulin-resistant skeletal muscle and β-cells occurs in diabetes. This is a novel route of communication that we further suggest is modified by the prevailing degree of insulin resistance of skeletal muscle. This review focuses on the various myokines [interleukin-6 (IL-6), tumor necrosis factor-α, CXCL10, follistatin and IL-8] which have been identified either after different types of exercise or in the secretome from control and insulin-resistant human skeletal myotubes. We will also summarize studies on the impact of several myokines on pancreatic β-cell proliferation, survival and function.

Topics: Animals; Cell Proliferation; Chemokine CXCL10; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follistatin; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Interleukin-6; Interleukin-8; Male; Muscle Fibers, Skeletal; Rats; Tumor Necrosis Factor-alpha

White adipose tissue and skeletal muscle are the largest organs in the body and both are composed of distinct cell types. The signature cell of adipose tissue is the adipocyte while myocytes are the defining cell of skeletal muscle. White adipocytes are major secretory cells and this is increasingly apparent also for myocytes. Both cells secrete a range of bioactive proteins, generally termed adipokines in the case of adipocytes and myokines for muscle cells. There has, however, been some confusion over nomenclature and we suggest that the name myokine is restricted to a protein that is secreted from myocytes, while the term adipokine should be used to describe all proteins secreted from any type of adipocyte (white, brown or brite). These definitions specifically exclude proteins secreted from other cells within adipose tissue and muscle, including macrophages. There is some commonality between the myokines and adipokines in that both groups include inflammation-related proteins - for example, IL-6, Il-8 and MCP-1. Adipokines and myokines appear to be involved in local autocrine/paracrine interactions within adipose tissue and muscle, respectively. They are also involved in an endocrine cross-talk with other tissues, including between adipose tissue and skeletal muscle, and this may be bi-directional. For example, IL-6, secreted from myocytes may stimulate lipolysis in adipose tissue, while adipocyte-derived IL-6 may induce insulin resistance in muscle.

Topics: Adipocytes; Adipokines; Adipose Tissue; Adiposity; Animals; Cell Communication; Chemokine CCL2; Humans; Insulin; Insulin Resistance; Interleukin-6; Interleukin-8; Mice; Muscle Cells; Muscle, Skeletal; Obesity; Rats

Diabetes mellitus is a systemic disease with several major complications affecting both the quality and length of life. One of these complications is periodontal disease (periodontitis). Periodontitis is much more than a localized oral infection. Recent data indicate that periodontitis may cause changes in systemic physiology. The interrelationships between periodontitis and diabetes provide an example of systemic disease predisposing to oral infection, and once that infection is established, the oral infection exacerbates systemic disease. In this case, it may also be possible for the oral infection to predispose to systemic disease. In order to understand the cellular/molecular mechanisms responsible for such a cyclical association, one must identify common physiological changes associated with diabetes and periodontitis that produce a synergy when the conditions coexist. A potential mechanistic link involves the broad axis of inflammation, specifically immune cell phenotype, serum lipid levels, and tissue homeostasis. Diabetes-induced changes in immune cell function produce an inflammatory immune cell phenotype (upregulation of proinflammatory cytokines from monocytes/polymorphonuclear leukocytes and downregulation of growth factors from macrophages). This predisposes to chronic inflammation, progressive tissue breakdown, and diminished tissue repair capacity. Periodontal tissues frequently manifest these changes because they are constantly wounded by substances emanating from bacterial biofilms. Diabetic patients are prone to elevated low density lipoprotein cholesterol and triglycerides (LDL/TRG) even when blood glucose levels are well controlled. This is significant, as recent studies demonstrate that hyperlipidemia may be one of the factors associated with diabetes-induced immune cell alterations. Recent human studies have established a relationship between high serum lipid levels and periodontitis. Some evidence now suggests that periodontitis itself may lead to elevated LDL/TRG. Periodontitis-induced bacteremia/endotoxemia has been shown to cause elevations of serum proinflammatory cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), which have been demonstrated to produce alterations in lipid metabolism leading to hyperlipidemia. Within this context, periodontitis may contribute to elevated proinflammatory cytokines/serum lipids and potentially to systemic disease arising from chronic hyperlipidemia and/o

Topics: Bacteremia; Bacterial Infections; Biofilms; Blood Glucose; Cholesterol, LDL; Diabetes Complications; Diabetes Mellitus; Disease Susceptibility; Down-Regulation; Endotoxemia; Growth Substances; Homeostasis; Humans; Hyperlipidemias; Inflammation; Inflammation Mediators; Insulin Resistance; Interleukin-8; Islets of Langerhans; Periodontitis; Phenotype; Risk Factors; Triglycerides; Tumor Necrosis Factor-alpha; Up-Regulation; Wound Healing

Oxidative stress and inflammation are involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Bayberries contain high levels of polyphenols that possess antioxidative and anti-inflammatory properties in vitro. The purpose of this study was to investigate whether the consumption of bayberry juice beneficially alters the levels of oxidative, inflammatory, and apoptotic biomarkers in young individuals with features of NAFLD.. In this randomized, placebo-controlled, double-blind, crossover study, 44 participants (ages 18-25 y) were given 250 mL of either bayberry juice or placebo twice daily for 4 wk. Several anthropometric characteristics were measured, and fasting blood samples were drawn before and after each intervention period. The levels of plasma glucose, insulin, lipids, and some NAFLD-related biomarkers were determined.. No significant effects on the anthropometric parameters and the homeostasis model assessment for insulin resistance were observed. Compared with placebo, the consumption of bayberry juice significantly decreased the plasma levels of protein carbonyl groups (P = 0.038), tumor necrosis factor-α (P < 0.001), and interleukin-8 (P = 0.022). The apoptosis markers analysis revealed significant differences between the treatment and the placebo in the levels of tissue polypeptide-specific antigen (P < 0.001) and cytokeratin-18 fragment M30 (P < 0.001).. The consumption of bayberry juice for a period of 4 wk can protect against NAFLD in young adults by improving the plasma antioxidant status and inhibiting the inflammatory and apoptotic responses that are involved in this disease.

Topics: Adolescent; Adult; Anthropometry; Antioxidants; Apoptosis; Beverages; Biomarkers; Blood Glucose; Cross-Over Studies; Double-Blind Method; Fatty Liver; Female; Fruit; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-8; Male; Myrica; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Plant Extracts; Polyphenols; Tumor Necrosis Factor-alpha; Young Adult

Fibre intake among North Americans is currently less than half the recommended amount. Consumers are interested in food products that could promote weight loss and improve health. Consequently, evaluation of unique fibre sources with potential gut-mediated benefits for metabolic health warrants investigation. Our objective is to assess the effects of yellow pea fibre supplementation on weight loss and gut microbiota in an overweight and obese adult population.. In a double blind, placebo controlled, parallel group study, overweight and obese (BMI = 25-38) adults will be randomized to either a 15 g/d yellow pea fibre supplemented group or isocaloric placebo group for 12 weeks (n = 30/group). The primary outcome measure is a change in body fat from baseline to 12 weeks. Secondary outcomes include glucose tolerance, appetite regulation, serum lipids and inflammatory markers. Anthropometric data (height, weight, BMI, and waist circumference) and food intake (by 3-day weighed food records) will be measured at baseline and every 4 weeks thereafter. Subjective ratings of appetite will be recorded by participants at home on a weekly basis using validated visual analogue scales. At week 0 and at the end of the study (week 12), an ad libitum lunch buffet protocol for objective food intake measures and dual-energy X-ray absorptiometry (DXA) scan for body composition will be completed. Participants will be instructed not to change their exercise habits during the 12 week study. Glucose and insulin will be measured during an oral glucose tolerance test at weeks 0 and 12. Levels of lipids and CRP will be measured and inflammatory markers (adiponectin, leptin, TNF-α, IL-6 and IL-8) in the serum will be quantified using Milliplex kits. Mechanisms related to changes in gut microbiota, serum and fecal water metabolomics will be assessed.. Globally the development of functional foods and functional food ingredients are critically needed to curb the rise in metabolic disease. This project will assess the potential of yellow pea fibre to improve weight control via gut-mediated changes in metabolic health in overweight and obese adults.. ClinicalTrials.gov (NCT01719900) Registered October 23, 2012.

Topics: Absorptiometry, Photon; Adiponectin; Adolescent; Adult; Aged; Appetite; Body Composition; Body Mass Index; C-Reactive Protein; Cholesterol, HDL; Cholesterol, LDL; Dietary Supplements; Double-Blind Method; Female; Glucose Tolerance Test; Humans; Insulin Resistance; Interleukin-6; Interleukin-8; Intestines; Leptin; Male; Microbiota; Middle Aged; Obesity; Overweight; Pisum sativum; Treatment Outcome; Triglycerides; Tumor Necrosis Factor-alpha; Weight Loss; Young Adult

Hypertension is known to be one of the main risk factors for cardiovascular disease.. To evaluate the safety and efficacy of a fixed olmesartan/amlodipine (Olme/Amlo) combination in improving blood pressure control, lipid profile, insulin sensitivity and some inflammatory and insulin resistance markers. Two hundred and seventy-six hypertensive patients were randomly assigned to olmesartan 20 mg, amlodipine 10 mg or a single pill containing an Olme/Amlo combination 20/5 mg for 12 months. We evaluated after 6 and 12 months: body weight, body mass index (BMI), systolic and diastolic blood pressure (SBP and DBP, respectively), fasting plasma glucose (FPG), fasting plasma insulin (FPI), lipid profile, vaspin, visfatin, interleukins 8 and 10 (IL-8 and IL-10, respectively). Patients also underwent an euglycemic, hyperinsulinemic clamp.. Olme/Amlo combination was more effective in decreasing SBP, and DPB compared to single monotherapies after 12 months. Olme/Amlo combination, but not amlodipine, decreased FPG after 12 months. FPI and HOMA index were decreased, and M value increased by Olme/Amlo combination compared to olmesartan monotherapy, and to amlodipine monotherapy. Olme/Amlo significantly decreased IL-8 and IL-10 better than each monotherapy.. Olme/Amlo single pill combination can be a safe and effective option to reduce blood pressure, improve insulin sensitivity and decrease inflammatory markers.

Topics: Adipokines; Amlodipine; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypertension; Imidazoles; Inflammation; Insulin; Insulin Resistance; Interleukin-10; Interleukin-8; Lipids; Male; Middle Aged; Tetrazoles

Chronic low-grade systemic inflammation presented in Type 2 diabetes mellitus plays a major role in disease progression as well as development of micro- and macro-vascular complications of diabetes. Therefore, reducing inflammation can be beneficial in prevention of diabetes complications.. To investigate the association between insulin resistance and inflammatory markers, and assessing the effects of oral Calcitriol on inflammatory cytokines in type 2 diabetic patients.. In this double-blind randomized placebo-controlled trial, 70 participants with type-2 diabetes were randomly divided to two groups. One group received two capsules of Calcitriol (0.25 μg 1,25-dihydroxy cholecalciferol per each capsule) per day. The second group received placebo tablets. At the beginning of the study, we assessed insulin resistance and its relation to inflammatory profile. Serum high sensitive C-reactive protein (hs CRP), interleukin-6 and interleukin-18 were also measured at the beginning and the end of the 12-week supplementation trial.. Mean calcium, phosphorus and vitamin D concentrations in the study participants were 8.98 ± 0.79 mg/dL, 3.86 ± 0.50 mg/dL and 40.91 ± 30.9 ng/mL, respectively. IL-18 and hsCRP had significant positive associations with insulin resistance markers and negative associations with insulin sensitivity markers. At the end of the 12-week supplementation trial, no significant difference was seen in serum levels of hsCRP, IL-6 and IL-18 between the two groups, while these values were adjusted for baseline values.. Inflammation was associated with insulin resistance in diabetic patients. No anti-inflammatory effect of Calcitriol in terms of decreasing hsCRP, IL-6 and IL-18 detected.

Topics: Adult; Aged; C-Reactive Protein; Calcitriol; Calcium; Calcium Channel Agonists; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Interleukin-6; Interleukin-8; Male; Middle Aged; Treatment Outcome; Vitamin D

We performed this study to examine the metabolic differences arising from higher liver fat accumulation in obese Hispanic adolescents, with a particular focus on circulating levels of adipocytokines and insulin resistance.. Forty-one obese Hispanic adolescents (15.3 ± 1.0 years, body mass index percentile: 97.0 ± 3.9) were assessed for: visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and hepatic fat fraction (HFF) by magnetic resonance imaging; fasting measures of serum glucose, insulin and adipocytokines; homeostasis model assessment of insulin resistance (HOMA-IR); and insulin sensitivity (SI) and the acute insulin response to glucose (AIR) by intravenous glucose tolerance test. Subjects with normal levels of HFF (below 5%; n = 25) were compared to those with HFF > 5% (n = 16).. The two groups differing in HFF were similar for total body fat, VAT and SAT. The group with HFF > 5% had significantly (P < 0.05) higher interleukin-8 (IL-8) (6.1 ± 1.6 vs. 3.2 ± 0.4 pg mL(-1) ), NGF (30.2 ± 9.9 vs. 13.9 ± 1.6 pg mL(-1) ), HOMA-IR (8.8 ± 1.1 vs. 5.5 ± 0.5), AIR (1869 ± 206 vs. 1092 ± 165) and a tendency for lower SI (1.2 ± 0.4 vs. 2.1 ± 0.3; P = 0.06), with no significant differences in any of other factors measured.. These data suggest that elevated liver fat is most closely associated with elevated serum IL-8 and NGF levels as well as increased AIR and HOMA-IR. These elevated factors may play significant roles in the metabolic abnormalities associated with elevated liver fat in obese Hispanics.

Topics: Adipokines; Adolescent; Blood Glucose; Body Composition; California; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fatty Liver; Female; Glucose Tolerance Test; Hispanic or Latino; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-8; Male; Nerve Growth Factor; Non-alcoholic Fatty Liver Disease; Obesity; Patient Education as Topic

Chromium and cysteine supplementation have been shown to improve glucose metabolism in animal studies. This study examined the hypothesis that chromium dinicocysteinate (CDNC), a complex of chromium and l-cysteine, is beneficial in lowering oxidative stress, vascular inflammation, and glycemia in type 2 diabetic subjects.. Type 2 diabetic subjects enrolled in this study were given placebo for 1 month for stabilization and then randomized into one of three groups: placebo (P), chromium picolinate (CP), or CDNC, after which they received daily oral supplementation for 3 months. Of the 100 patients enrolled in the study, 74 patients completed it. There were 25 patients in the P supplemented group, 25 in the CP supplemented and 24 in the CDNC supplemented group who completed the study. Blood markers of glycemia, vascular inflammation, HOMA insulin resistance, and oxidative stress were determined at randomization and after 3 months of supplementation with P, CP, or CDNC. There was a significant decrease at 3 months in insulin resistance (p = 0.02) and in the levels of protein oxidation (p = 0.02) and TNF-α (p = 0.01) in the CDNC supplemented cohort compared to baseline. However, there was no statistically significant change in these markers in the CP supplemented group compared to baseline. Insulin levels significantly decreased (p = 0.01) for subjects receiving CDNC but not CP. There was no significant impact of supplementation on HbA(1c) or glucose levels in either of the groups.. CDNC supplementation lowers insulin resistance by reducing blood levels of TNF-α, insulin, and oxidative stress in type 2 diabetic subjects. Therefore, CDNC supplementation has potential as an adjunct therapy for individuals with type 2 diabetes.

Topics: Adult; Cysteine; Diabetes Mellitus, Type 2; Dietary Supplements; Double-Blind Method; Female; Humans; Insulin; Insulin Resistance; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Male; Middle Aged; Organometallic Compounds; Oxidative Stress; Tumor Necrosis Factor-alpha

Prognostic biomarkers are needed to identify children at increased cardiometabolic risk. The objective was to study whether markers of metabolism and inflammation, for example, circulating plasma adiponectin, leptin, interleukin-8, and hepatocyte growth factor, are associated with cardiometabolic risk factors in childhood and adolescence. This was a cross-sectional and prospective study, and the setting was the Danish part of the European Youth Heart Studies I and II. Participants were randomly selected girls and boys 8 to 10 years of age with complete baseline data (n = 256) and complete follow-up data 6 years later (n = 169). Cardiometabolic risk profile was calculated using a continuous composite score derived from summing of 6 factors standardized to the sample means (Z scores): body mass index, homeostasis model assessment of insulin resistance, total serum cholesterol to serum high-density lipoprotein cholesterol ratio, serum triglycerides, systolic blood pressure, and the reciprocal value of fitness (maximum watts per kilogram). Overweight was defined using international classification of body mass index cutoff points for children. Plasma adiponectin, leptin, interleukin-8, and hepatocyte growth factor were assessed using immunochemical assays. Linear relationships were found between metabolic risk score and both plasma adiponectin (inverse, P = .02) and plasma leptin (P < .0001) at baseline after adjustment for several confounders. In overweight but not normal-weight children, plasma adiponectin at baseline was inversely associated with metabolic risk score 6 years later (P = .04). In childhood, both hypoadiponectinemia and hyperleptinemia accompany a negative metabolic risk profile. In addition, circulating plasma adiponectin may be a useful biomarker to identify overweight children at greater future risk of the cardiometabolic adverse effects of overweight.

Topics: Adiponectin; Adolescent; Blood Pressure; Body Mass Index; Child; Cytokines; Denmark; Disease Progression; Female; Hepatocyte Growth Factor; Humans; Insulin Resistance; Interleukin-8; Leptin; Lipids; Male; Metabolic Diseases; Overweight; Regression Analysis; Risk Assessment

Type 2 diabetes (T2D) is known to be associated with chronic inflammation, but the inflammatory regulators/markers are not exactly defined and the link between them remains undetermined. The objective of this study is to identify these markers by testing traditional (IL6 & IL8) and non-traditional (TREM1 & uPAR) inflammatory markers.. Data and blood samples were obtained from 114 T2D and 74 non-diabetic Kuwaiti subjects attending health facilities in Kuwait. Chemical analyzers were used to measure glycemic and lipid profiles, while ELISA was used to measure plasma levels of insulin and several inflammatory markers.. Showed that the IL-6 and TREM1 were significantly higher in T2D compared to non-diabetic controls, and the uPAR level was borderline higher in T2D but significantly correlated with IL-6 levels. Unexpectedly, IL8 was significantly below normal in T2D and IL6/IL8 ratio was significantly higher in T2D patients. Unlike other tested markers, uPAR was in addition strongly correlated with insulin levels and HOMA-IR index.. Raised levels of IL6, TREMI, IL6/IL8 ratio, and the strong positive correlation of plasma levels of uPAR with IL-6, insulin, and HOMA-IR index, are reliable spectators of chronic inflammation in T2D patients. The reduced level of IL-8 in T2D was a peculiar observation that needs further explanation. Finally, the consequences and impact of the sustained rise of these inflammatory regulators in diabetic tissues need to be meticulously explored.

Topics: Biomarkers; Diabetes Mellitus, Type 2; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Interleukin-8; Interleukins; Receptors, Urokinase Plasminogen Activator; Triggering Receptor Expressed on Myeloid Cells-1

Adiponectin (ADIPO) and interleukin-8 (IL-8) are proteins that play a significant, albeit opposing, role in metabolic syndrome (MetS). The reported data on the effect of physical activity on the levels of these hormones in the population of people with MetS are conflicting. The aim of the study was to evaluate the changes in hormone concentrations, insulin-resistance indices and body composition after two types of training. The study included 62 men with MetS (age 36.6 ± 6.9 years, body fat [BF] = 37.53 ± 4.5%), randomly assigned to: an experimental group EG1 (n = 21) with aerobic exercise intervention, an experimental group EG2 (n = 21) with combined aerobic and resistance exercise intervention, both for 12 weeks, and a control group CG (n = 20) without interventions. Anthropometric measurements and body composition (fat-free mass [FFM], gynoid body fat [GYNOID]), as well as a biochemical blood analysis (adiponectin [ADIPO], interleukin-8 [IL-8], homeostatic model assessment-adiponectin (HOMA-AD) and homeostatic model assessment-triglycerides (HOMA-TG) were performed at baseline, and at 6 and 12 weeks of intervention and 4 weeks after the intervention (follow-up). Intergroup (between groups) and intragroup (within each group) changes were statistically evaluated. In the experimental groups EG1 and EG2, no significant changes were observed in the ADIPO concentration, but a decrease of GYNOID and insulin-resistance indices was confirmed. The aerobic training led to favorable changes in IL-8 concentration. The use of combined resistance and aerobic training led to improved body composition, decreased waist circumference and better insulin-resistance indices in men with MetS.

Topics: Adiponectin; Adult; Arrhythmias, Cardiac; Body Mass Index; Carbohydrate Metabolism; Humans; Insulin; Insulin Resistance; Interleukin-8; Male; Metabolic Syndrome; Obesity

Adipose tissue secretions are depot-specific and vary based on anatomical location. Considerable attention has been focused on visceral (VAT) and subcutaneous (SAT) adipose tissue with regard to metabolic disease, yet our knowledge of the secretome from these depots is incomplete. We conducted a comprehensive analysis of VAT and SAT secretomes in the context of metabolic function. Conditioned media generated using SAT and VAT explants from individuals with obesity were analyzed using proteomics, mass spectrometry, and multiplex assays. Conditioned media were administered in vitro to rat hepatocytes and myotubes to assess the functional impact of adipose tissue signaling on insulin responsiveness. VAT secreted more cytokines (IL-12p70, IL-13, TNF-α, IL-6, and IL-8), adipokines (matrix metalloproteinase-1, PAI-1), and prostanoids (TBX2, PGE2) compared with SAT. Secretome proteomics revealed differences in immune/inflammatory response and extracellular matrix components. In vitro, VAT-conditioned media decreased hepatocyte and myotube insulin sensitivity, hepatocyte glucose handling, and increased basal activation of inflammatory signaling in myotubes compared with SAT. Depot-specific differences in adipose tissue secretome composition alter paracrine and endocrine signaling. The unique secretome of VAT has distinct and negative impact on hepatocyte and muscle insulin action.

Topics: Adipokines; Animals; Culture Media, Conditioned; Dinoprostone; Glucose; Humans; Insulin Resistance; Interleukin-13; Interleukin-6; Interleukin-8; Intra-Abdominal Fat; Isophane Insulin, Human; Matrix Metalloproteinase 1; Obesity; Plasminogen Activator Inhibitor 1; Rats; Secretome; Subcutaneous Fat; Tumor Necrosis Factor-alpha

Low vitamin D concentrations are associated with metabolic derangements, notably insulin resistance and pancreatic beta-cell dysfunction in Caucasian populations. Studies on its association with the clinical, metabolic, and immunologic characteristics in black African adult populations with new-onset diabetes are limited. This study aimed to describe the clinical, metabolic, and immunologic characteristics of a black Ugandan adult population with recently diagnosed diabetes and hypovitaminosis D.. Serum vitamin D concentrations were measured in 327 participants with recently diagnosed diabetes. Vitamin D deficiency, vitamin D insufficiency, and normal vitamin D status were defined as serum 25 hydroxyvitamin D levels of < 20 ng/ml, 21-29 ng/ml, and ≥ 30 ng/ml, respectively.. The median (IQR) age, glycated haemoglobin, and serum vitamin D concentration of the participants were 48 years (39-58), 11% (8-13) or 96 mmol/mol (67-115), and 24 ng/ml (18-30), respectively. Vitamin D deficiency, vitamin D insufficiency, and normal vitamin D status were noted in 105 participants (32.1%), 140 participants (42.8%), and 82 participants (25.1%), respectively. Compared with those having normal serum vitamin D levels, participants with vitamin D deficiency and insufficiency had higher circulating concentrations of interleukin (IL) 6 (29 [16-45] pg/ml, 23 [14-40] pg/ml vs 18 [14-32] pg/ml, p = 0.01), and IL-8 (24 [86-655] pg/ml, 207 [81-853] pg/ml vs 98 [67-224], p = 0.03). No statistically significant differences were noted in the markers of body adiposity, insulin resistance, and pancreatic beta-cell function between both groups.. Vitamin D deficiency and insufficiency were highly prevalent in our study population and were associated with increased circulating concentrations of pro-inflammatory cytokines. The absence of an association between pancreatic beta-cell function, insulin resistance, and low vitamin D status may indicate that the latter does not play a significant role in the pathogenesis of type 2 diabetes in our adult Ugandan population.

Topics: Adult; Cytokines; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Insulin Resistance; Interleukin-8; Middle Aged; Uganda; Vitamin D; Vitamin D Deficiency; Vitamins

Obesity is resulted from energy surplus and is characterized by abnormal adipose tissue accumulation and/or distribution. Adipokines secreted by different regional adipose tissue can induce changes in key proteins of the insulin signaling pathway in hepatocytes and result in impaired hepatic glucose metabolism. This study aimed to investigate whether exenatide affects key proteins of IRS2/PI3K/Akt2 signaling pathway in hepatocytes altered by the different regional fat depots. Six non-obese patients without endocrine diseases were selected as the research subjects. Their subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT)were co-cultured with HepG2 cells in the transwell chamber. In the presence or absence of exenatide, adipokines content in the supernatant of each experimental group was detected by ELISA. In addition, HepG2 cells in each co-culture group with and without insulin were collected, and the expression of key proteins IRS2, p-IRS2(S731), PI3K-p85, Akt2, and p-Akt2(S473) was detected by western blotting (WB). The results showed that the adipokines IL-8, MCP-1, VEGF, and sTNFR2 in the supernatant of HepG2 cells induced by different regional adipose tissue were significantly higher than those in the HepG2 group, and VAT released more adipokines than SAT. Furthermore, these adipokines were significantly inhibited by exenatide. Importantly, the different regional fat depot affects the IRS2/PI3K/Akt2 insulin signaling pathway of hepatocytes. Exenatide can up-regulate the expression of hepatocyte proteins IRS2, PI3K-p85, p-Akt2(S731) inhibited by adipose tissue, and down-regulate the expression of hepatocyte proteins p-IRS2(S731) promoted by adipose tissue. The effect of VAT on the expression of these key proteins in hepatocytes is more significant than that of SAT. But there was no statistical difference in the expression of Akt2 protein among each experimental group, suggesting that exenatide has no influence on the expression of Akt2 protein in hepatocytes. In conclusion, exenatide may improve hepatic insulin resistance (IR) by inhibiting adipokines and regulating the expression of key proteins in the IRS2/PI3K/Akt2 pathway.

Topics: Adipokines; Adipose Tissue; Exenatide; Glucose; Hepatocytes; Humans; Insulin; Insulin Resistance; Interleukin-8; Obesity; Phosphatidylinositol 3-Kinases; Vascular Endothelial Growth Factor A

Sleep apnoea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) and is a risk factor for insulin resistance/Type 2 diabetes. The induction of insulin resistance in skeletal muscle is a key phenomenon to develop diabetes. However, the mechanisms linking IH stress and insulin resistance remain elusive. We exposed human RD and mouse C2C12 muscle cells to normoxia or IH and measured their mRNA levels by real-time RT-PCR. We found that IH significantly increased the mRNA and protein levels of muscle-derived insulin resistance-factors (myokines) such as IL-8, osteonectin (ON), and myonectin (MN) in muscle cells. We further analysed the IH-induced expression mechanisms of IL-8, ON, and MN genes in muscle cells. Deletion analyses of the human myokine promoter(s) revealed that the regions -152 to -151 in IL-8, -105 to -99 in ON, and - 3741 to -3738 in MN promoters were responsible for the activation by IH in RD cells. The promoters contain consensus transcription factor binding sequences for OCT1 in IL-8 and MN promoters, and for NRF2 in ON promoter, respectively. The introduction of siRNA for OCT1 abolished the IH-induced expression(s) of IL-8 and MN and siRNA for NRF2 abolished the IH-induced expression of ON.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypoxia; Insulin Resistance; Interleukin-8; Mice; Muscle Fibers, Skeletal; NF-E2-Related Factor 2; Osteonectin; RNA, Messenger; RNA, Small Interfering; Up-Regulation

Aging is characterized by adipose tissue senescence, inflammation, and fibrosis, with trunk fat accumulation. Aging HIV-infected patients have a higher risk of trunk fat accumulation than uninfected individuals-suggesting that viral infection has a role in adipose tissue aging. We previously demonstrated that HIV/SIV infection and the Tat and Nef viral proteins were responsible for adipose tissue fibrosis and impaired adipogenesis. We hypothesized that SIV/HIV infection and viral proteins could induce adipose tissue senescence and thus lead to adipocyte dysfunctions.. Features of tissue senescence were evaluated in subcutaneous and visceral adipose tissues of SIV-infected macaques and in human adipose stem cells (ASCs) exposed to Tat or Nef for up to 30 days.. p16 expression and p53 activation were higher in adipose tissue of SIV-infected macaques than in control macaques, indicating adipose tissue senescence. Tat and Nef induced higher senescence in ASCs, characterized by higher levels of senescence-associated beta-galactosidase activity, p16 expression, and p53 activation vs. control cells. Treatment with Tat and Nef also induced oxidative stress and mitochondrial dysfunction. Prevention of oxidative stress (using N-acetyl-cysteine) reduced senescence in ASCs. Adipocytes having differentiated from Nef-treated ASCs displayed alterations in adipogenesis with lower levels of triglyceride accumulation and adipocyte marker expression and secretion, and insulin resistance.. HIV/SIV promotes adipose tissue senescence, which in turn may alter adipocyte function and contribute to insulin resistance.

Topics: Acetylcysteine; Adipocytes; Adipogenesis; Adipose Tissue; Animals; Cellular Senescence; Humans; Insulin Resistance; Interleukin-6; Interleukin-8; Macaca fascicularis; Mitochondria; nef Gene Products, Human Immunodeficiency Virus; Oxidative Stress; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Stem Cells; tat Gene Products, Human Immunodeficiency Virus

Clinical partial remission (CPR) in most patients with type 1 diabetes (T1D) is observed shortly after clinical diagnosis. Increasing body weight and impaired insulin sensitivity may play a role in the pathogenesis of CPR. Several cytokines can also participate in the development of insulin resistance.. To evaluate the relationship between birth weight, body mass index, and the concentrations of IL-8 and Fetuin-A, and the presence of clinical partial remission in children at the T1D onset.. The study group consisted of 134 children with a newly diagnosed T1D in whom the presence of CPR was evaluated in a further 2-year course of diabetes. The control group included 47 children without glucose tolerance disorders. The concentrations of IL-8 and Fetuin-A were determined by the ELISA method.. CPR occurred in 75.34% of T1D patients. At T1D onset, higher values of BMI SDS in the remitters as compared to the patients without remission were observed. At the T1D onset, the concentrations of Fetuin-A (p=0.031) and IL-8 (p=0.042) were significantly higher in patients compared to those without CPR.. Evaluation of Fetuin-A and IL-8 levels in patients with a newly diagnosed T1D can differentiate between patients with or without CPR.

Topics: Adolescent; alpha-2-HS-Glycoprotein; Biomarkers; Body Mass Index; Child; Child, Preschool; Cytokines; Diabetes Mellitus, Type 1; Disease Management; Enzyme-Linked Immunosorbent Assay; Female; Humans; Insulin Resistance; Interleukin-8; Male; Odds Ratio; ROC Curve

Despite long term antiretroviral therapy (ART), insulin resistance (IR) is common among people living with HIV/AIDS (PLWHA) exposing this population to a greater risk of cardiometabolic complications when compared to their uninfected counterparts. We previously identified an expansion in monocyte subpopulations in blood that were linked to the degree of IR in persons with HIV on stable ART. In this study, we directly assessed monocyte inflammatory functional properties from PLWHA on ART (

Topics: Antirheumatic Agents; Blood Glucose; Cardiometabolic Risk Factors; Cytokines; Fasting; Female; HIV Infections; Humans; Insulin Resistance; Interleukin-1beta; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Lipoproteins, LDL; Male; Middle Aged; Monocytes; Tumor Necrosis Factor-alpha

Adipocyte-macrophage crosstalk plays a critical role to regulate adipose tissue microenvironment and cause chronic inflammation in the pathogenesis of obesity. Interleukin-29 (IL-29), a member of type 3 interferon family, plays a role in host defenses against microbes, however, little is known about its role in metabolic disorders. We explored the function of IL-29 in the pathogenesis of obesity-induced inflammation and insulin resistance. We found that serum IL-29 level was significantly higher in obese patients. IL-29 upregulated IL-1β, IL-8, and monocyte chemoattractant protein-1 (MCP-1) expression and decreased glucose uptake and insulin sensitivity in human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes through reducing glucose transporter 4 (GLUT4) and AKT signals. In addition, IL-29 promoted monocyte/macrophage migration. Inhibition of IL-29 could reduce inflammatory cytokine production in macrophage-adipocyte coculture system, which mimic an obese microenvironment. In vivo, IL-29 reduced insulin sensitivity and increased the number of peritoneal macrophages in high-fat diet (HFD)-induced obese mice. IL-29 increased M1/M2 macrophage ratio and enhanced MCP-1 expression in adipose tissues of HFD mice. Therefore, we have identified a critical role of IL-29 in obesity-induced inflammation and insulin resistance, and we conclude that IL-29 may be a novel candidate target for treating obesity and insulin resistance in patients with metabolic disorders.

Topics: Adipocytes; Adipose Tissue; Animals; Arrhythmias, Cardiac; Cell Differentiation; Cell Movement; Chemokine CCL2; Diet, High-Fat; Genetic Diseases, X-Linked; Gigantism; Glucose Transporter Type 4; Heart Defects, Congenital; Inflammation; Insulin Resistance; Intellectual Disability; Interferons; Interleukin-1beta; Interleukin-6; Interleukin-8; Interleukins; Lipopolysaccharides; Macrophages; Mice, Inbred C57BL; Mice, Obese; Obesity; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Interleukin; Up-Regulation

We have shown in 2 independent studies that cows who received recombinant bovine interleukin-8 (rbIL-8) administered intrauterinely shortly after parturition have a significant and long-lasting increase in milk yield. In the present study, we hypothesized that the increased milk production associated with rbIL-8 treatment is a consequence of increased postpartum dry matter intake (DMI) and orchestrated homeorhetic changes that prioritize milk production. Cows were enrolled into 1 of 3 treatment groups: those assigned to the control group (CTR; n = 70) received an intrauterine (IU) administration of 500 mL of Dulbecco's phosphate-buffered saline (DPBS) solution and 1 mL of DPBS solution intravenously (IV; jugular vein), those assigned to the rbIL-8 IV group (rbIL8-IV, n = 70) received an IV injection of 167 μg of rbIL-8 and 500 mL of DPBS solution IU, and cows assigned to the rbIL-8 IU group (rbIL8-IU, n = 70) received an IU administration with 1,195 μg of rbIL-8 diluted in 499.5 mL of DPBS solution and 1 mL of DPBS solution IV. Animals were housed in a tiestall from calving to 30 d in milk (DIM) to measure DMI. Blood samples were collected daily from calving to 7 DIM and weekly until 28 DIM. Insulin resistance was evaluated using an intravenous glucose tolerance test and intravenous insulin challenge test (IVICT) in a subgroup of cows (n = 20/treatment) at 10 and 11 DIM, respectively. Additionally, liver biopsy samples were taken at 14 DIM from the same subgroup of cows to measure triglyceride levels and cell proliferation and apoptosis. Cows treated with rbIL8-IU produced more milk (CTR = 36.9 ± 1.5; rbIL8-IU = 38.5 ± 1.5; rbIL8-IV = 36.6 ± 1.5 kg/d), energy-corrected milk (CTR = 42.9 ± 0.9; rbIL8-IU = 46.1 ± 0.8; rbIL8-IV = 43.7 ± 0.9 kg/d), and fat-corrected milk (CTR = 44.3 ± 0.9; rbIL8-IU = 47.8 ± 0.9; rbIL8-IV = 45.2 ± 0.9 kg/d) yields when compared with CTR cows, and no differences were observed between rbIL8-IV and CTR cows. The administration of rbIL8-IU significantly increased DMI compared with CTR (CTR = 18.8 ± 0.3; rbIL8-IU = 19.9 ± 0.3; rbIL8-IV = 19.3 ± 0.3 kg/d). Recombinant bIL-8 treatment did not affect glucose, insulin, or fatty acids (i.e., IVICT only) concentrations or their area under the curve in response to an intravenous glucose tolerance test and IVICT when compared with CTR. Moreover, rbIL-8 treatment administered IU or IV increased liver triglyceride levels. Additionally, cows treated with rbIL8-IU tended to have lower odds of d

Topics: 3-Hydroxybutyric Acid; Animals; Apoptosis; Cattle; Cell Proliferation; Diet; Eating; Fatty Acids; Female; Glucose; Growth Hormone; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Interleukin-8; Ketosis; Lactation; Liver; Milk; Parturition; Postpartum Period; Pregnancy; Recombinant Proteins

Interleukin-8 (IL-8, also named CXCL8) binds to its receptors (CXCR1 and CXCR2) with subsequent recruitment of neutrophils and enhancement of their infiltration into inflamed sites, which exaggerates inflammation in many diseases. Recent studies have proposed that metabolic disorders can be attenuated by counteracting certain inflammatory signal pathways. In this study, we examined whether intervention with G31P, an antagonist of CXCL8, could attenuate tissue inflammation and development of metabolic disorders in

Topics: Animals; Cytokines; Diabetes Mellitus, Type 2; Disease Models, Animal; Fatty Acids, Nonesterified; Gluconeogenesis; Insulin; Insulin Resistance; Interleukin-6; Interleukin-8; Lipid Metabolism; Liver; Macrophages; Mice; Peptide Fragments; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Tumor Necrosis Factor-alpha

Insulin resistance and inflammation are strongly linked to non-alcoholic fatty liver disease (NAFLD) as a feature of the metabolic syndrome. Furthermore, the role of dysregulation of miR-34a, miR-451, and miR-33a in pathogenesis and progression of NAFLD has been identified. trans-Chalcone is a simple chalcone with anti-diabetic and anti-inflammatory activities. However, to the best of our knowledge, miRNA-dependent mechanisms of these protective effects under pathologic conditions are not understood. Thus, this study, for the first time, aimed to evaluate the effects of trans-Chalcone on miR-34a, miR-451, and miR-33a signaling pathways in the liver of high-fat (HF) emulsion-fed rats. To this aim, twenty-one rats were randomly and equally divided into three groups: control, which was gavaged with 10% tween 80; HF, which was gavaged with HF emulsion and 10% tween 80; and HF + trans-Chalcone (HF + TC), which was gavaged with HF emulsion and trans-Chalcone. Then, circulating levels of glucose and insulin were measured and used for the calculation of HOMA-IR. Hepatic expression levels of miR-34a, miR-451, miR-33a, SIRT1, and ABCA1 and also protein levels of ABCA1 and IL-8 were assayed. In this study, trans-chalcone increased hepatic cholesterol efflux and prevented insulin resistance and liver inflammation in HF emulsion-fed rats. These protective effects were modulated through the down-regulation of miR-34a and its associated elevation of SIRT1, the up-regulation of miR-451 which was associated with a reduction in IL-8, and the inhibition of miR-33a which was related to the elevation of ABCA1 in the liver of HF emulsion-fed rats. Therefore, trans-Chalcone exerts its beneficial effects by targeting hepatic miR-34a-, miR-451-, and miR-33a-related pathways.

Topics: Animals; ATP Binding Cassette Transporter 1; Chalcones; Cholesterol; Diet, High-Fat; Humans; Insulin; Insulin Resistance; Interleukin-8; Male; MicroRNAs; Non-alcoholic Fatty Liver Disease; Rats; Rats, Wistar; Sirtuin 1; Triglycerides

Overweight and obese children have an increased risk to develop cardiovascular diseases (CVDs) in which thyroid-stimulating hormone (TSH) has been suggested as an intermediary factor. However, results of cross-sectional studies are inconclusive, and intervention studies investigating changes in TSH concentrations in association with changes in cardiovascular risk parameters in overweight and obese children are scarce.. To gain insight in associations of circulating TSH concentrations and cardiovascular risk parameters in overweight and obese children.. Nonrandomized lifestyle intervention.. Centre for Overweight Adolescent and Children's Healthcare.. Three hundred thirty euthyroid overweight and obese children.. Long-term lifestyle intervention.. TSH concentrations, pituitary TSH release in response to thyrotropin-releasing hormone (TRH), and cardiovascular risk parameters.. At baseline, serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triacylglycerol (TAG), and monocyte chemotactic protein 1 concentrations were significantly associated with serum TSH concentrations. TSH release by the pituitary in response to exogenous TRH was not associated with cardiovascular risk parameters. During lifestyle intervention, several cardiovascular risk parameters significantly improved. In children whose body mass index z score improved, changes in TSH concentrations were significantly associated with changes in TC, LDL-C, and TAG concentrations.. In euthyroid overweight and obese children, circulating TSH concentrations are positively associated with markers representing increased CVD risk. Changes in TSH concentrations are also associated with changes in lipid concentrations in children with successful weight loss, which is consistent with TSH being an intermediary factor in modulating lipid and lipoprotein metabolism.

Topics: Adolescent; Blood Glucose; Blood Pressure; Body Mass Index; Cardiovascular Diseases; Chemokine CCL2; Child; Child, Preschool; Cholesterol; Cholesterol, LDL; Female; Humans; Insulin; Insulin Resistance; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Life Style; Male; Overweight; Pediatric Obesity; Risk; Thyrotropin; Triglycerides; Vascular Cell Adhesion Molecule-1; Weight Reduction Programs

In cells and tissues resistin affects IL-1β, IL-6, IL-8, IL-12 and TNF-α expression, thus suggesting the existence of a multi-cytokine "resistin pathway". We investigated whether such pathway does exist in humans and, if so, if it is associated with cardiovascular risk factors and with major adverse cardiovascular events (MACE). Serum cytokines were measured in 280 healthy subjects from the Gargano Study 2 (GS2) whose BMI, waist circumference, HOMA

Topics: Adult; Aged; Blood Pressure; Body Mass Index; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Gene Expression Regulation; Humans; Insulin Resistance; Interleukin-12; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Middle Aged; Prospective Studies; Resistin; Risk Factors; Signal Transduction; Triglycerides; Tumor Necrosis Factor-alpha; Waist Circumference

Myokines have been shown to affect muscle physiology and exert systemic effects. We endeavored to investigate a panel of myokine mRNA expression after a single exercise bout (studies 1 and 2) to measure myokine mRNA in primary human myotubes in an in vitro exercise model (study 2).. Vastus lateralis muscle biopsies were obtained from 20 healthy males (age, 24.0 ± 4.5 yr; BMI, 23.6 ± 1.8 kg·m)(-2) before and after a single exercise bout (650 kcal at 50% V˙O2max). Primary myotubes from active and sedentary male donors were treated with a pharmacological cocktail (palmitate, forskolin, and ionomycin (PFI)) to mimic exercise-stimulated contractions in vitro.. Interleukin 6 and 8 (IL-6 and IL-8), leukocyte-inducing factor, and connective tissue growth factor (CTGF) mRNA levels increased approximately 10-fold after a single exercise bout (all P < 0.001), whereas myostatin levels decreased (P < 0.05). Key correlations between myokine expression and parameters of muscle and whole-body physiology were found: myostatin versus skeletal muscle citrate synthase activity (r = -0.69, P < 0.001), V˙O2max (r = -0.64, P = 0.002) and the percentage of Type I fibers (r = -0.55, P = 0.01); IL-6 versus the RER (r = 0.45, P = 0.04), homeostatic model assessment of insulin resistance (r = 0.44, P = 0.05), and serum lactate (r = 0.50, P = 0.02). Myokine expressions in myotubes from sedentary donors for CTGF and myostatin decreased, whereas IL-6 and IL-8 increased after PFI treatment. In myotubes from active donors, myokine expression increased for IL-6, CTGF, and myostatin but decreased for IL-8 after PFI treatment.. These data offer insight into the differences in regulation of myokine expression and their possible physiologic relationships.

Topics: Adult; Biopsy; Cells, Cultured; Colforsin; Connective Tissue Growth Factor; Exercise; Humans; Insulin Resistance; Interleukin-6; Interleukin-8; Ionomycin; Lactic Acid; Male; Muscle Fibers, Skeletal; Myostatin; Palmitates; Quadriceps Muscle; Young Adult

Topics: Acne Vulgaris; Adolescent; Adult; Female; Humans; Insulin Resistance; Interleukin-6; Interleukin-8; Male; Phosphorylation; Protein Processing, Post-Translational; Ribosomal Protein S6 Kinases, 70-kDa; Skin; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha; Young Adult

The aim of this study was to explore the mechanism by which amentoflavone (AME) improves insulin resistance in a human hepatocellular liver carcinoma cell line (HepG2).. A model of insulin resistant cells was established in HepG2 by treatment with high glucose and insulin. The glucose oxidase method was used to detect the glucose consumption in each group. To determine the mechanism by which AME improves insulin resistance in HepG2 cells, enzyme-linked immunosorbent assay (ELISA) and western blotting were used to detect the expression of phosphatidyl inositol 3-kinase (PI3K), Akt, and pAkt; the activity of the enzymes involved in glucose metabolism; and the levels of inflammatory cytokines.. Insulin resistance was successfully induced in HepG2 cells. After treatment with AME, the glucose consumption increased significantly in HepG2 cells compared with the model group (MG). The expression of PI3K, Akt, and pAkt and the activity of 6-phosphofructokinas (PFK-1), glucokinase (GCK), and pyruvate kinase (PK) increased, while the activity of glycogen synthase kinase-3 (GSK-3), phosphoenolpyruvate carboxylase kinase (PEPCK), and glucose-6-phosphatase (G-6-Pase) as well as the levels of interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), and C reactive protein (CRP) decreased.. The mechanism by which treatment with AME improves insulin resistance in HepG2 cells may involve the PI3K-Akt signaling pathway, the processes of glucose oxygenolysis, glycogen synthesis, gluconeogenesis and inflammatory cytokine expression.

Topics: Biflavonoids; Carcinoma, Hepatocellular; Gene Expression Regulation, Neoplastic; Glucose; Glycogen Synthase Kinase 3; Hep G2 Cells; Humans; Insulin; Insulin Resistance; Interleukin-6; Interleukin-8; Liver Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Tumor Necrosis Factor-alpha

Menopausal transition is usually associated with changes in body composition and a decrease in physical activity energy expenditure. Adipose tissue, especially visceral fat, is an important source of inflammatory markers, which contributes to the development of a proinflammatory state. Conversely, high levels of physical activity and exercise have an anti-inflammatory effect. This study aimed to investigate the impact of menopausal transition and physical activity on inflammatory makers.. One hundred two healthy premenopausal women participated in a 5-year longitudinal study. The present secondary analyses were performed on 58 participants with a full set of data (age: 49.6 ± 1.7 y; body mass index: 23.3 ± 2.4 kg/m). Measures included body composition, waist circumference, fasting glucose and insulin levels, insulin sensitivity, plasma lipid levels, cardiorespiratory fitness, physical activity energy expenditure, and inflammatory markers.. Repeated measure analyses revealed, after the 5-year follow-up, significant increases in ferritin, interleukin-8 (IL-8), and soluble tumor necrosis factor-α receptor 1 and 2 (sTNFR1 and sTNFR2) (P < 0.001), and a significant decrease in serum high-sensitive C-reactive protein (P < 0.05). Positive correlations were observed between change (year 5 to baseline) in waist circumference and changes in high-sensitive C-reactive protein, orosomucoid (ORM), haptoglobin, and apolipoprotein B (ApoB) levels (0.26 ≤ r ≤ 0.34; P < 0.05), and between change in peripheral fat and changes in ORM, ApoB, sTNFR2 (0.28 ≤ r ≤ 0.39; P < 0.05). On the contrary, negative correlations were found between change in physical activity energy expenditure and changes in ORM as well as ApoB (r = -0.35 and r = -0.36, respectively; P < 0.05). No significant correlations were found between change in cardiorespiratory fitness, glucose, insulin, insulin sensitivity and changes in inflammatory markers. Multiple regression analyses showed that changes in physical activity energy expenditure and waist circumference together explained 23% of the individual variance of change in ORM (P < 0.05). Also, change in physical activity energy expenditure explained 15% (P < 0.05) of the variance of change in ApoB. Fat mass change explained 15% (P < 0.05) of the variance of change in IL-8, and finally change in peripheral fat explained 15% of variance of change in sTNFR2 (P < 0.05).. The present study indicates that the menopausal transition is accompanied by an increase in inflammatory markers, namely ferritin, IL-8, sTNFR1, and sTNFR2. The increase in IL-8 and sTNFR2 with menopause could be explained, in part, by changes in fat mass and peripheral fat, respectively.

Topics: Blood Glucose; Body Composition; Energy Metabolism; Exercise; Fasting; Female; Ferritins; Follow-Up Studies; Healthy Volunteers; Humans; Inflammation Mediators; Insulin; Insulin Resistance; Interleukin-8; Lipids; Longitudinal Studies; Menopause; Middle Aged; Physical Fitness; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Waist Circumference

Obesity triggers complex inflammatory networks within the innate immune system. During pregnancy, the placenta amplifies the low-grade inflammation through activation of Toll-like receptor 4 (TLR4) signalling pathways. The purpose of this study was to investigate the impact of obesity on placental TLR4 expression and inflammatory signals. The secondary aim was to analyse the placental cell type responsible for TLR4 activation.. Thirty-nine women recruited at term-scheduled Caesarean section were grouped according to their pre-gravid BMI (<25 kg/m(2) and >30 kg/m(2)). Placenta, venous maternal and cord blood were obtained at delivery for analysis. Data were analysed with linear regression and Spearman's rank correlation coefficient analysis.. TLR4, IL6 and IL8 expression was increased three- to ninefold (p < 0.001) in the placenta of obese vs lean women. There was a positive correlation between placental TLR4 and maternal systemic and placental IL6 and IL8 concentrations. Placental TLR4 expression was correlated with maternal pre-gravid BMI, insulin resistance index, plasma insulin and C-reactive protein (r = 0.57, 0.31, 0.35, 0.53, respectively; p < 0.001) but not with plasma glucose, maternal age, gestational age and gestational weight gain (r < 0.2; p > 0.1). TLR4 was located in both trophoblast and macrovascular endothelial cells lining fetal vasculature. Lipopolysaccharide-induced TLR4 activation was more robust in trophoblasts than in endothelial vascular cells (100-fold vs tenfold; p < 0.001).. Trophoblastic TLR4 is strongly implicated in the propagation of placental inflammation. Placental inflammation is related to maternal metabolic conditions such as pre-gravid BMI, whilst gestational weight gain or gestational age are not. These results implicate the pre-gravid condition as a significant contributor to metabolic inflammation in late pregnancy.

Topics: C-Reactive Protein; Female; Gestational Age; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Interleukin-8; Obesity; Placenta; Pregnancy; Signal Transduction; Toll-Like Receptor 4

Maternal peripheral insulin resistance and increased inflammation are two features of pregnancies complicated by pre-existing maternal obesity and gestational diabetes mellitus (GDM). There is now increasing evidence that activation of Toll-like receptor (TLR) signalling pathways by viral products may play a role in the pathophysiology of diabetes. Thus, the aim of this study was to assess the effect of the TLR3 ligand and viral dsRNA analogue polyinosinic polycytidilic acid (poly(I:C)) on inflammation and the insulin signalling pathway in skeletal muscle from pregnant women.. Human skeletal muscle tissue explants were performed to determine the effect of poly(I:C) on the expression and secretion of markers of inflammation, and the insulin signalling pathway and glucose uptake.. Poly(I:C) significantly increased the expression of a number of inflammatory markers in skeletal muscle from pregnant women. Specifically, there was an increase in the expression and/or secretion of the pro-inflammatory cytokines TNF-α, and IL-6 and the pro-inflammatory chemokines IL-8 and MCP-1. These effect of poly(I:C) appear to mediated via a number of signalling molecules including the pro-inflammatory transcription factor NF-κB, and the serine threonine kinases GSK3 and AMPKα. Additionally, poly(I:C) decreased insulin stimulated GLUT-4 expression and glucose uptake in skeletal muscle from pregnant women.. The in vitro data presented in this study suggests that viral infection may contribute to the pathophysiology of pregnancies complicated by pre-existing maternal obesity and/or GDM. It should be noted that the in vitro studies cannot be directly used to infer the same outcomes in the intact subject.

Topics: Adult; AMP-Activated Protein Kinases; Blotting, Western; Chemokine CCL2; Diabetes, Gestational; Female; Glucose Transporter Type 4; Glycogen Synthase Kinase 3; Humans; In Vitro Techniques; Inflammation; Insulin Resistance; Interleukin-6; Interleukin-8; Muscle, Skeletal; Poly I-C; Pregnancy; Real-Time Polymerase Chain Reaction; RNA; Signal Transduction; Statistics, Nonparametric; Tumor Necrosis Factor-alpha

Circulating cytokines are frequently cited as contributors to insulin resistance in children with obesity. This study examined whether circulating adipocytokines, independent of adiposity, predicted pubertal changes in insulin sensitivity (SI), insulin secretion (AIR), and β-cell function in high-risk adolescents.. 158 Hispanic adolescents with overweight or obesity were followed for a median of 4 years. Adipocytokines were measured using Luminex technology. SI, AIR, and the disposition index were derived from an intravenous glucose tolerance test and minimal modeling. Total fat mass was measured by DXA and visceral adipose tissue (VAT) by MRI.. Surprisingly, mean IL-8, IL-1β, IL-6, and TNF-α decreased between 5% and 6.5% per year from baseline (P < 0.001). Despite the general temporal trends, gaining 1-SD of VAT was associated with a 2% and 5% increase in MCP-1 and IL-8 (P < 0.05). In addition, a 1-SD higher MCP-1 or IL-6 concentration at baseline was associated with a 16% and 21% greater decline in SI during puberty vs. prepuberty (P < 0.05).. Several adipocytokines decreased during adolescence and were weakly associated with VAT and lower SI during puberty. Circulating adipocytokines have relatively limited associations with pubertal changes in diabetes risk; however, the consistent findings with MCP-1 warrant further investigation.

Topics: Adipokines; Adolescent; Female; Glucose Tolerance Test; Hispanic or Latino; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Interleukin-6; Interleukin-8; Intra-Abdominal Fat; Male; Pediatric Obesity; Risk Factors; Sexual Maturation; Tumor Necrosis Factor-alpha

To examine for the first time the associations between pro-inflammatory cytokines and obesity-related metabolic biomarkers in, exclusively prepubertal, otherwise healthy obese and non-obese Black and White children, 7-9 years of age.. Body mass index (BMI), homeostasis model assessment-estimated insulin resistance, visceral adipose tissue and subcutaneous adipose tissue (SAT (magnetic resonance imaging)); total body fat (dual-energy X-ray absorptiometry), ectopic, intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) fat (proton magnetic resonance spectroscopy) and serum levels of interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein-1 were measured in 40 obese and non-obese children. Relationships between inflammatory cytokines and obesity were assessed by analysis of variance and Spearman's rank correlation.. Significant inverse correlations were found between BMI z-score, SAT, total BF, and IHL and levels of TNF-α (Spearman's ρ=-0.36, -0.39, -0.43 and -0.39, respectively; P<0.05). Levels of IL-8 were significantly and inversely correlated with IMCL (-0.39; P=0.03) and remained significant after adjusting for race. IMCL was inversely associated with TNF-α only after adjusting for race (-0.37; P=0.04).. Relationships between pro-inflammatory and metabolic markers commonly observed in adults are reversed in healthy, Black and White children before puberty. Prospective studies are warranted to determine how these inverse relationships modify chronic disease risk later in life.

Topics: Absorptiometry, Photon; Biomarkers; Black or African American; Blood Glucose; Body Composition; Cardiovascular Diseases; Child; Diabetes Mellitus, Type 2; Female; Humans; Inflammation; Insulin Resistance; Interleukin-1; Interleukin-6; Interleukin-8; Intra-Abdominal Fat; Lipid Metabolism; Lipids; Male; Pediatric Obesity; Puberty; Subcutaneous Fat; Tumor Necrosis Factor-alpha; White People

CHI3L1 (chitinase-3-like protein 1) is a glycoprotein consisting of 383 amino acids with a molecular mass of 40 kDa, and its serum level is elevated in inflammatory diseases. Although CHI3L1 is described as a biomarker of inflammation, the function of this protein is not completely understood. In the present study, we examined the regulation of CHI3L1 in primary human skeletal muscle cells. Moreover, we analysed potential autocrine effects of CHI3L1. We show that myotubes express CHI3L1 in a differentiation-dependent manner. Furthermore, pro-inflammatory cytokines up-regulate CHI3L1 expression (6-fold) and release (3-fold). Importantly, CHI3L1 treatment blocked TNFα (tumour necrosis factor α)-induced inflammation by inhibiting NF-κB (nuclear factor κB) activation in skeletal muscle cells. We show that this effect is mediated via PAR2 (protease-activated receptor 2). In addition, CHI3L1 treatment diminished the TNFα-induced expression and secretion of IL (interleukin)-8, MCP1 (monocyte chemoattractant protein 1) and IL-6. In addition, impaired insulin action at the level of Akt and GSK3α/β (glycogen synthase kinase 3α/β) phosphoryl-ation and insulin-stimulated glucose uptake was normalized by CHI3L1. In conclusion, the novel myokine CHI3L1, which is induced by pro-inflammatory cytokines, can counteract TNFα-mediated inflammation and insulin resistance in human skeletal muscle cells, potentially involving an auto- and/or para-crine mechanism.

Topics: Adipokines; Adolescent; Adult; Cell Differentiation; Cells, Cultured; Chemokine CCL2; Chitinase-3-Like Protein 1; Cytokines; Female; Humans; Insulin Resistance; Interleukin-6; Interleukin-8; Lectins; Male; Muscle Fibers, Skeletal; Muscle, Skeletal; NF-kappa B; Receptor, PAR-2; Recombinant Proteins; Signal Transduction; Tumor Necrosis Factor-alpha; Up-Regulation; Young Adult

Chronic low-grade inflammation in adipose tissue often accompanies obesity, leading to insulin resistance and increasing the risk for metabolic diseases. MAP3K8 (TPL2/COT) is an important signal transductor and activator of pro-inflammatory pathways that has been linked to obesity-induced adipose tissue inflammation. We used human adipose tissue biopsies to study the relationship of MAP3K8 expression with markers of obesity and expression of pro-inflammatory cytokines (IL-1β, IL-6 and IL-8). Moreover, we evaluated obesity-induced adipose tissue inflammation and insulin resistance in mice lacking MAP3K8 and WT mice on a high-fat diet (HFD) for 16 weeks. Individuals with a BMI >30 displayed a higher mRNA expression of MAP3K8 in adipose tissue compared to individuals with a normal BMI. Additionally, high mRNA expression levels of IL-1β, IL-6 and IL-8, but not TNF -α, in human adipose tissue were associated with higher expression of MAP3K8. Moreover, high plasma SAA and CRP did not associate with increased MAP3K8 expression in adipose tissue. Similarly, no association was found for MAP3K8 expression with plasma insulin or glucose levels. Mice lacking MAP3K8 had similar bodyweight gain as WT mice, yet displayed lower mRNA expression levels of IL-1β, IL-6 and CXCL1 in adipose tissue in response to the HFD as compared to WT animals. However, MAP3K8 deficient mice were not protected against HFD-induced adipose tissue macrophage infiltration or the development of insulin resistance. Together, the data in both human and mouse show that MAP3K8 is involved in local adipose tissue inflammation, specifically for IL-1β and its responsive cytokines IL-6 and IL-8, but does not seem to have systemic effects on insulin resistance.

Topics: Adipose Tissue; Animals; Blood Proteins; Blotting, Western; Body Mass Index; Cells, Cultured; Diet, High-Fat; Glucose Tolerance Test; Humans; Immunoenzyme Techniques; Inflammation; Insulin; Insulin Resistance; Interleukin-1beta; Interleukin-6; Interleukin-8; MAP Kinase Kinase Kinases; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Proto-Oncogene Proteins; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha

We aimed to investigate the impact of maternal vitamin D deficiency during pregnancy on insulin resistance in male offspring and examine its mechanism.. Pregnant Sprague-Dawley rats were maintained on a vitamin-D-free diet with ultraviolet-free light during pregnancy (early-VDD group). Insulin resistance in the male offspring was assessed by HOMA-IR, OGTT and euglycaemic clamp. NEFA, oxidative stress and inflammation levels were estimated as risk factors for insulin resistance. DNA methylation was examined by bisulfate sequencing PCR analysis. Luciferase reporter assay was performed to validate the effect of DNA methylation.. The offspring in the early-VDD group had significantly higher fasting insulin and HOMA-IR levels, markedly reduced glucose tolerance and significantly lower tissue sensitivity to exogenous insulin at 16 weeks (all p < 0.05) compared with control offspring. Significantly higher serum and liver IL-1β, IL-6, IL-8 and TNF-α concentrations were observed in the offspring of the early-VDD group at 0, 3, 8 and 16 weeks. Expression of hepatic Iκbα (also known as Nfkbia) mRNA and nuclear factor κB inhibitor α (IκBα) protein was persistently lower in the early-VDD offspring at all time points, and their hepatic Iκbα methylation levels at the cytosine phosphate guanine site +331 were significantly higher at 0 and 16 weeks (all p < 0.01). Methylation at Iκbα first exon +331 markedly decreased the luciferase activity (p < 0.05).. Maternal vitamin D deficiency during pregnancy results in insulin resistance in the offspring, which is associated with persistently increased inflammation. Persistently decreased Iκbα expression, potentially caused by changes in Iκbα methylation, plays an important role in persistent inflammation.

Topics: Animals; Female; I-kappa B Proteins; Insulin; Insulin Resistance; Interleukin-6; Interleukin-8; Methylation; NF-KappaB Inhibitor alpha; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Vitamin D Deficiency

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

To investigate the protective effects and possible mechanism of Mycelium of Hirsutella hepiali Chen et Shen (MHCS) on metabolic syndromes, free fatty acid and MHCS-treated hepatocytes were used for detecting autophagy-related LC3, p62 and lipid accumulation. Moreover, high fat diet fed mice were used to establish metabolic syndromes model. 50-weeks age mice were randomly divided into: control group, model group and MHCS group. At 80-weeks age, 15 mice were randomly chosen from each group separately for examining oral glucose tolerance, serum insulin, insulin-like growth factor 1 (IGF-1), hepatic LC3, p62, p-NF-kappaB p65, NF-kappaB p65, IL-6 and CXCL-8. Moreover, insulin resistance index (IRI) was calculated. Hepatic pathological changes, including vacuoles, lipids accumulation and fibrosis were observed. Remaining mice were fed with diet separately to 110 weeks-age for statistics of mortality. MHCS promoted autophagy of free fatty acid treated hepatocytes. Mice fed with high fat plus MHCS diet exhibited improved oral glucose tolerance, insulin resistance, hepatic pathology, inflammation, mortality and activated autophagy. The protective effects of MHCS against metabolic syndroms might be through the activation of hepatic autophagy.

Topics: Animals; Autophagy; Diet, High-Fat; Glucose Tolerance Test; Hepatocytes; Hypocreales; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Interleukin-6; Interleukin-8; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Mycelium; Random Allocation; Transcription Factor RelA; Transcription Factor TFIIH; Transcription Factors

Recent studies have described bone as an endocrine organ regulating glucose metabolism, with insulin signaling regulating osteocalcin secretion and osteocalcin regulating β cell function. We have previously demonstrated increased bone expression of TXNIP in patients with endogenous Cushing's syndrome (CS), and we hypothesized that TXNIP could contribute to the dysregulated glucose metabolism in CS. We studied 33 CS patients and 29 matched controls, with bone biopsies from nine patients, before and after surgical treatment. In vitro, the effect of silencing TXNIP (siTXNIP) in osteoblasts, including its effect on human islet cells, was examined. Our major findings were: (i) The high mRNA levels of TXNIP in bone from CS patients were significantly associated with high levels of glucose and insulin, increased insulin resistance, and decreased insulin sensitivity in these patients. (ii) Silencing TXNIP in osteoblasts enhanced their OC response to insulin and glucose and down-regulated interleukin (IL)-8 levels in these cells. (iii) Conditional media from siTXNIP-treated osteoblasts promoted insulin content and anti-inflammatory responses in human islet cells. We recently demonstrated that the thioredoxin/TXNIP axis may mediate some detrimental effects of glucocorticoid excess on bone tissue in CS. Here we show that alterations in this axis also may affect glucose metabolism in these patients.

Topics: Analysis of Variance; Blotting, Western; Bone and Bones; Carrier Proteins; Cushing Syndrome; DNA Primers; Energy Metabolism; Gene Silencing; Glucose; Homeostasis; Humans; Insulin; Insulin Resistance; Interleukin-8; Islets of Langerhans; Microarray Analysis; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction

Adipose tissue expansion during obesity is associated with a state of low-grade inflammation and an increase in macrophage infiltration, which predisposes to insulin resistance and vascular malfunction. Growing evidence suggests that vitamin D3 has immunoregulatory effects and adipose tissue could be a target for vitamin D3 action. Preadipocytes, one of the major cell types in adipose tissue, are actively involved in inflammatory processes.. This study investigated whether the active form of vitamin D3 (1,25(OH)2D3) affects the production of proinflammatory chemokines/cytokines and the monocyte recruitment by human preadipocytes.. The secretion levels of monocyte chemoattractant proteint-1 (MCP-1), IL-8 and IL-6 were significantly higher in preadipocytes than in differentiated adipocytes, suggesting that preadipocytes could be a major source of proinflammatory mediators. Cytokine profile analysis revealed that 1,25(OH)2D3 (10 nM) markedly reduced the release of MCP-1, IL-6 and IL-8 by preadipocytes. The involvement of NFκB signalling was shown by the upregulation of IκBα protein abundance by 1,25(OH)2D3 in preadipocytes. In addition, 1,25(OH)2D3 was able to decrease the migration of THP-1 monocytes. Treatment with proinflammatory stimuli, including macrophage-conditioned (MC) medium, TNFα and IL-1β, led to a marked increase in protein release of MCP-1 and IL-6 by preadipocytes. Pretreatment with 1,25(OH)2D3 (10 nM and 100 nM) significantly decreased the stimulatory effects of MC medium, TNFα and IL-1β on MCP-1 expression and protein release, although the effect on stimulated release of IL-6 was less potent.. These results demonstrate that 1,25(OH)2D3 decreases the production of MCP-1 and other proinflammatory mediators by preadipocytes and reduces monocyte migration. Thus, vitamin D3 may protect against adipose tissue inflammation by disrupting the deleterious cycle of macrophage recruitment.

Topics: Adipocytes; Adipose Tissue, White; Adult; Blotting, Western; Cell Differentiation; Chemokine CCL2; Cytokines; Female; Humans; Inflammation; Inflammation Mediators; Insulin Resistance; Interleukin-6; Interleukin-8; Monocytes; NF-kappa B; Obesity; Signal Transduction; Tumor Necrosis Factor-alpha; Vitamin D

In obesity, adipose tissue becomes a significant source of chemokines and inflammatory cytokines that are associated with chronic systemic low-grade inflammation and may lead to insulin resistance. Studies in children have mainly focused on inflammatory cytokines and there are limited data for chemokines in adolescents and young adults. We studied the relation of chemokines to cardiovascular (CV)-risk factors, insulin resistance and adipocytokines in 18-21-year-old individuals.. Cross-sectional data collected in a cohort originally enrolled at mean age 13, with data for the present study obtained from 252 examined at age 18.7±0.1 years.. Multiple linear regression models were used to analyze the associations among chemokines (monocyte chemotactic protein-1, macrophage inflammatory protein-1β (MIP-1β), visfatin and interleukin-8 (IL-8)) and between chemokines and body mass index (BMI), glucose, lipids, blood pressure (BP), insulin resistance (euglycemic hyperinsulinemic clamp) and adipocytokines (IL-6, TNF-α and adiponectin).. Chemokine levels were significantly intercorrelated. Significant associations (P<0.05) with adjustment for age, race and sex included: MIP-1β with waist circumference and IL-6, IL-8 with systolic BP and visfatin with IL-6. No other significant relations were found between the chemokines and the other variables. Further adjustment for BMI did not alter these conclusions.. Considered in the context of prior studies in children and adults, these results suggest that in large part, the association between chemokines and CV risk or inflammatory factors does not appear to develop until adult life.

Topics: Adipokines; Adolescent; Biomarkers; Blood Glucose; Blood Pressure; Body Mass Index; Cardiovascular Diseases; Chemokine CCL4; Chemokines; Cross-Sectional Studies; Female; Glucose Clamp Technique; Humans; Inflammation; Insulin Resistance; Interleukin-6; Interleukin-8; Lipids; Male; Nicotinamide Phosphoribosyltransferase; Obesity; Risk Factors; Tumor Necrosis Factor-alpha; United States; Young Adult

Oxidized low-density lipoprotein (oxLDL) in complex with β2-glycoprotein I (β2GPI) has been associated with autoimmune diseases, diabetes mellitus, chronic renal disease and coronary atherosclerosis. The aim of our study was to determine whether plasma levels of oxLDL/β2GPI complexes are associated with insulin resistance, inflammation and markers of endothelial damage in obese middle-aged men and, if so, whether oxLDL/β2GPI correlates better with insulin resistance parameters than oxLDL, advanced oxidation protein products (AOPP) or thioredoxin.. A total of 72 healthy men were recruited (41 obese and 31 nonobese individuals). Waist circumference >94 cm was used as the criterion for abdominal obesity.. The obese men demonstrated higher oxLDL/β2GPI levels (p < 0.001), homeostasis model assessment of insulin resistance (p < 0.01) and intima-media thickness of the common carotid artery (p < 0.01). oxLDL/β2GPI correlated with more insulin resistance parameters compared to AOPP, thioredoxin or oxLDL. Furthermore, oxLDL/β2GPI was associated with plasminogen activator inhibitor-I (PAI-I; r = 0.365, p < 0.001) and negatively with interleukin-8 (r = -0.297, p < 0.05).. In summary, oxLDL/β2GPI reflects the criterion for abdominal obesity and markers of insulin resistance in our study. The independent positive correlation with PAI-I indicates that oxLDL/β2GPI may serve as an early marker of low-grade inflammation and atherosclerosis initiation.

Topics: Adult; Advanced Oxidation Protein Products; Atherosclerosis; beta 2-Glycoprotein I; Biomarkers; Carotid Intima-Media Thickness; Case-Control Studies; Humans; Insulin Resistance; Interleukin-8; Lipoproteins, LDL; Male; Middle Aged; Multivariate Analysis; Obesity, Abdominal; Oxidative Stress; Plasminogen Activator Inhibitor 1; Regression Analysis; Thioredoxins; Waist Circumference

Endothelial progenitor cells (EPCs) are decreased in number and function in type 2 diabetes. Mechanisms by which this dysfunction occurs are largely unknown. We tested the hypothesis that a chronic inflammatory environment leads to insulin signaling defects in EPCs and thereby reduces their survival. Modifying EPCs by a knockdown of nuclear factor-κB (NF-κB) can reverse the insulin signaling defects, improve EPC survival, and decrease neointimal hyperplasia in Zucker fatty rats postangioplasty.. EPCs from Zucker fatty insulin-resistant rats were cultured and exposed to tumor necrosis factor-α (TNF-α). Insulin signaling defects and apoptosis were measured in the presence and absence of an NF-κB inhibitor, BAY11. Then, EPCs were modified by a knockdown of NF-κB (RelA) and exposed to TNF-α. For in vivo experiments, Zucker fatty rats were given modified EPCs post-carotid angioplasty. Tracking of EPCs was done at various time points, and neointimal hyperplasia was measured 3 weeks later.. Insulin signaling as measured by the phosphorylated-to-total AKT ratio was reduced by 56% in EPCs exposed to TNF-α. Apoptosis was increased by 71%. These defects were reversed by pretreatment with an NF-κB inhibitor, BAY11. Modified EPCs exposed to TNF-α showed a lesser reduction (RelA 20%) in insulin-stimulated AKT phosphorylation versus a 55% reduction in unmodified EPCs. Apoptosis was 41% decreased for RelA knockdown EPCs. Noeintimal hyperplasia postangioplasty was significantly less in rats receiving modified EPCs than in controls (intima-to-media ratio 0.58 vs. 1.62).. In conclusion, we have shown that insulin signaling and EPC survival is impaired in Zucker fatty insulin resistant rats. For the first time, we have shown that this defect can be significantly ameliorated by a knockdown of NF-κB and that these EPCs given to Zucker fatty rats decrease neointimal hyperplasia post-carotid angioplasty.

Topics: Animals; Apoptosis; Cells, Cultured; Diabetes Mellitus, Type 2; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Inflammation; Insulin Resistance; Interleukin-8; NF-kappa B; Nitriles; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Rats, Zucker; Reverse Transcriptase Polymerase Chain Reaction; Stem Cells; Sulfones; Tumor Necrosis Factor-alpha

Biomarkers of metabolism and inflammation may predict children with increased diabetes risk.. To study plasma adiponectin, leptin, IL-8, and hepatocyte growth factor (HGF) in childhood and their independent associations with insulin insensitivity, cross-sectional and in 6-yr prospective.. Danish 8- to 10-yr-olds and 14- to 16-yr-olds from the European Youth Heart Studies I and II.. Cross-sectional (n = 386) and prospective (n = 246) linear regressions of baseline concentrations of plasma biomarkers and insulin insensitivity at baseline and 6 yr later. Adjustments were made at four progressive steps for sex, sexual maturity, body mass index (BMI), other biomarkers, physical activity, and school location as well as baseline insulin insensitivity in prospective analyses. Insulin insensitivity was measured using homeostasis model assessment standardized to the sample mean [homoestasis model assessment (HOMA) Z-scores]. Plasma biomarkers were quantified using solid-phase protein immunoassays. Overweight was defined as the highest BMI tertile.. Among overweight but not lean children at baseline, one SD difference in baseline plasma adiponectin was associated with -0.41 SD difference in HOMA Z-scores 6 yr later (p = 0.006). At baseline, one SD difference in plasma leptin was associated with 0.36 SD difference in HOMA Z-scores (p =< 0.0001) among 8- to 10-yr-olds, but a prospective association was not found.. We found a direct relationship between childhood hypo-adiponectinaemia and insulin insensitivity in adolescence. This association was stronger for overweight than for normal weight children. Hyper-leptinaemia was associated with concurrent insulin insensitivity at baseline but not 6 yr later.

Topics: Adiponectin; Adolescent; Blood Glucose; Body Mass Index; Child; Cross-Sectional Studies; Down-Regulation; Female; Hepatocyte Growth Factor; Humans; Ideal Body Weight; Insulin Resistance; Interleukin-8; Leptin; Male; Overweight; Time Factors

Type 2 diabetes mellitus (T2D) is predicted by central obesity and circulating adipokines regulating inflammation. We hypothesized that visceral adipose tissue (VAT) in T2D expresses greater levels of proinflammatory molecules. Paired samples of subcutaneous (SAT) and VAT were excised at elective surgery (n = 16, 6 with T2D, n = 8 age- and gender- matched controls). Metabolic parameters were measured in the fasted state: body composition by dual-energy X-ray absorptiometry and insulin action by hyperinsulinemic-euglycemic clamp. Adipose tissue mRNA gene expression was measured by quantitative reverse transcriptase-PCR. Subjects with T2D had higher VAT expression of molecules regulating inflammation (tumor necrosis factor-alpha (TNFalpha), macrophage inflammatory protein (MIP), interleukin-8 (IL-8)). Fasting glucose related to VAT expression of TNFalpha, MIP, serum amyloid A (SAA), IL-1alpha, IL-1beta, IL-8, and IL-8 receptor. Abdominal fat mass was related to VAT expression of MIP, SAA, cAMP response element-binding protein (CREBP), IL-1beta, and IL-8. Insulin action related inversely to VAT complement C3 expression only. There were depot-specific differences in expression of serum T2D predictors: VAT expressed higher levels of complement C3; SAT expressed higher levels of retinol-binding protein-4 (RBP4), adiponectin, and leptin. In summary, VAT in T2D expresses higher levels of adipokines involved in inflammation. VAT expression of these molecules is related to fasting glucose and insulin action. Increased production of these proinflammatory molecules by VAT may explain the links observed between visceral obesity, insulin resistance, and diabetes risk.

Topics: Adipokines; Adult; Aged; Body Mass Index; Chemokine CCL3; Diabetes Mellitus, Type 2; Female; Gene Expression; Humans; Inflammation; Insulin Resistance; Interleukin-8; Intra-Abdominal Fat; Male; Middle Aged; Obesity; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Statistics, Nonparametric; Subcutaneous Fat; Tumor Necrosis Factor-alpha; Waist Circumference

Hepatic insulin resistance and inflammatory cytokine production contribute to the manifestation of the metabolic syndrome. As amino acids have been implicated in modulating insulin signaling and inflammation, we have investigated the effects of glutamine, leucine and proline on markers of inflammation and insulin sensitivity in HepG2 liver cells. Cells were incubated with IL-1β (5 ng/mL) to stimulate IL-8 production. After 24 h, glutamine inhibited IL-8 production significantly (p<0.05) at 2, 5 and 10 mM (to 82, 73 and 72% of control), whereas leucine reduced IL-8 production significantly only at 10 mM (66%) and proline at 5 and 10 mM (71 and 52%). Glutamine, leucine and proline all reduced NF-κB activity after 3 h of IL-1β stimulation at 2, 5 and 10 mM (p<0.001). Insulin-induced (1 nM) Akt phosphorylation was reduced in cells treated with tumour necrosis factor-α (10 ng/mL) for 24 h, but was partly restored by simultaneous incubation with glutamine, leucine and proline (25 mM). Phosphorylation of glycogen synthase kinase-3β was unaffected by insulin stimulation and amino acid treatment. Our results indicate that glutamine, leucine and proline attenuate IL-8 production, probably through inhibition of NF-κB, and that they increase Akt phosphorylation in HepG2 cells.

Topics: Glutamine; Hep G2 Cells; Humans; Insulin; Insulin Resistance; Interleukin-1beta; Interleukin-8; Leucine; Models, Biological; NF-kappa B; Phosphorylation; Proline; Proto-Oncogene Proteins c-akt; Signal Transduction; Tumor Necrosis Factor-alpha

To evaluate the insulin sensitivity (IS) and levels of peptides with impact on IS in polymyalgia rheumatica (PMR) before and after prednisolone treatment.. Fifteen PMR patients and 15 controls were included. Subjects were studied before and after treatment with prednisolone for 14 days (20 mg/day). Composite IS indices were calculated from glucose and insulin concentrations during an oral glucose tolerance test (OGTT). Plasma concentrations of tumour necrosis factor alpha (TNF), interleukin (IL)-6, IL-8, monocyte chemoattractant protein 1 (MCP-1), resistin, leptin, and adiponectin were measured.. Prednisolone abolished symptoms and increased physical activity within 1–2 days; erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were normalized at day 14. Before treatment, IS was lower in patients vs. controls (p < 0.001). Following treatment, IS was restored in patients (p < 0.01) but not changed in controls (p > 0.05). IL-6, TNF, and IL-8 were higher in patients vs. controls before treatment (p < 0.05–0.001), and decreased after treatment in patients (p < 0.001) but did not change in controls. Before treatment, adiponectin was lower in patients vs. controls (p < 0.05). During treatment, adiponectin increased in both groups (p < 0.05). Leptin did not differ between untreated patients and controls but increased in both groups (p < 0.05). MCP-1 and resistin did not differ (p > 0.05).. IS is decreased in PMR, probably reflecting abnormal cytokine and adipokine levels. Treatment with prednisolone improves IS along with normalization of cytokine and adipokine levels and physical activity.

Topics: Adiponectin; Aged; Aged, 80 and over; Blood Glucose; Case-Control Studies; Chemokine CCL2; Chemokines; Cytokines; Female; Glucocorticoids; Humans; Insulin; Insulin Resistance; Interleukin-6; Interleukin-8; Leptin; Male; Middle Aged; Motor Activity; Polymyalgia Rheumatica; Prednisolone; Resistin; Tumor Necrosis Factor-alpha

Lactoferrin is an innate immune system protein with multiple beneficial health activities.. To gain insight in the interaction between innate immune system and metabolic disturbances (obesity and insulin resistance), we investigated the relationship between circulating lactoferrin and chronic inflammation-associated insulin resistance according glucose tolerance status in Caucasian population.. Circulating nonstressed lactoferrin (ELISA), metabolic variables, and inflammatory markers were measured in 229 men, 94 with normal (NGT) and 135 with altered glucose tolerance (AGT). Lactoferrin secretion by neutrophil was investigated in whole-blood culture (four young NGT subjects, four older NGT subjects, and four patients with type 2 diabetes) under microbial lipopolysaccharide (LPS) with IL-6 and rosiglitazone treatment. We also tested the lactoferrin action in THP-1 cells under LPS stimulus.. Circulating lactoferrin was significantly decreased in patients with AGT (431.5 +/- 187.5 vs. 493.5 +/- 238.9 ng/ml, P = 0.02). In addition, circulating lactoferrin was negatively associated with hyperglycemia and obesity measures and positively with insulin sensitivity. Lactoferrin was negatively related to inflammatory markers, especially in AGT subjects. In ex vivo experiments, we found a significant decrease in LPS-induced lactoferrin release from neutrophils in subjects with type 2 diabetes. IL-6 coincubation decreased LPS-induced lactoferrin release in NGT subjects (P < 0.001). Finally, rosiglitazone treatment led to increased lactoferrin secretion (398 +/- 193 vs. 280.1 +/- 104.9 ng/ml, P < 0.0001). Lactoferrin decreased nuclear factor-kappabeta activation and IL-6, IL-8, and macrophage chemoattractant protein-1 expression under LPS challenge.. Decreased circulating lactoferrin levels may play a role in chronic low level inflammation-associated insulin resistance.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Chemokine CCL2; Chronic Disease; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Humans; Inflammation; Insulin Resistance; Interleukin-6; Interleukin-8; Lactoferrin; Linear Models; Lipopolysaccharides; Male; Middle Aged; Neutrophils; White People

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

Although many studies have shown that the metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) both are associated with chronic inflammatory state and are risk factors for coronary artery disease (CAD), it is still unclear which condition is a more important contributor to the increased production of inflammatory chemokines. The purpose of this study was to assess monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) levels and their association with insulin resistance and adiponectin concentrations in CAD patients, who were categorized as having T2DM, MS, or neither.. CAD male patients were categorized into three groups: 24 non-obese patients with T2DM (D), 24 obese patients with MS (M) and 24 patients without T2DM or MS (W). 20 healthy subjects were selected as controls (C). Insulin resistance was assessed by the HOMA-IR method, but serum MCP-1, IL-8, and adiponectin levels were measured by xMAP technology.. Serum levels of MCP-1 and IL-8 in D and M groups were increased in comparison with W and C groups (p<0.001, p<0.01), but the increase in the M group was significantly higher than that in the D group (p<0.05, p<0,001), besides MCP-1 and IL-8 concentrations were correlated with HOMA-IR indexes (r=0.52; r=0.49, p<0.0001) and adiponectin levels (r=-0.59, p<0.0001). The M group demonstrated a diminution in the adiponectin level (p<0.01) and pronounced increase of HOMA-IR in comparison with the other three groups (p<0.01).. Obese CAD patients with MS have a more pronounced increase of MCP-1, IL-8 and HOMA-IR and more decreased adiponectin levels than non-obese CAD patients without MS.

Topics: Adiponectin; Adult; Aged; Biomarkers; Chemokine CCL2; Coronary Artery Disease; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Interleukin-8; Male; Metabolic Syndrome; Middle Aged; Obesity; Risk Factors

Several adipocytokines have been implicated in the pathogenesis non-alcoholic fatty liver disease (NAFLD).. To assess adipocytokines in NAFLD patients and controls.. A total of 95 patients (26 non-alcoholic steatohepatitis (NASH), 19 simple steatosis (SS), 38 obese controls and 12 non-obese controls) were included. Fasting serum insulin, glucose, visfatin, resistin, adiponectin, tumour necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8) and IL-6 were determined. Univariate and multivariate analyses were used to compare groups and determine associations.. Serum TNF-alpha and IL-8 were higher in NAFLD patients when compared with both obese and non-obese controls. Analysis involving all patients revealed a significant correlation between serum TNF-alpha and IL-8 (P < 6.319e-08), and between IL-6 and IL-8 (P < 5.271e-15). Homeostatic model assessment scores negatively correlated with adiponectin in NAFLD (P < 0.0032). Serum visfatin was higher in all three obese groups than in non-obese controls (P < 0.02, P < 0.002 and P < 0.008). Visfatin in NASH patients was lower than SS and obese controls. Although TNF-alpha was associated with NAFLD (P < 0.02), it was interdependent on visfatin. In comparison to SS, four factors were independently associated with NASH: age, alanine aminotransferase, IL-8 and adiponectin (P < 0.05). Multivariate analysis indicated that TNF-alpha was the only independent predictor of fibrosis in NASH (P < 0.0004).. These findings support a complex interaction between adipocytokines and the pathogenesis of NAFLD.

Topics: Adipokines; Adiponectin; Adult; Aged; Biopsy; Blood Glucose; Case-Control Studies; Cohort Studies; Cytokines; Fasting; Fatty Liver; Female; Humans; Immunoenzyme Techniques; Insulin; Insulin Resistance; Interleukin-6; Interleukin-8; Linear Models; Liver; Liver Cirrhosis; Male; Middle Aged; Multivariate Analysis; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Tumor Necrosis Factor-alpha

Topics: Adipokines; Hepatitis C; Humans; Insulin Resistance; Interleukin-8; Leptin; Liver

Insulin resistance in skeletal muscle is an early event in the development of diabetes, with obesity being one of the major contributing factors. In vitro, conditioned medium (CM) from differentiated human adipocytes impairs insulin signaling in human skeletal muscle cells, but it is not known whether insulin resistance is reversible and which mechanisms may underlie this process. CM induced insulin resistance in human myotubes at the level of insulin-stimulated Akt and GSK-3 phosphorylation. In addition, insulin-resistant skeletal muscle cells exhibit enhanced production of reactive oxygen species and ceramide as well as a downregulation of myogenic transcription factors such as myogenin and MyoD. However, insulin resistance was not paralleled by increased apopotosis. Regeneration of myotubes for 24 or 48 h after induction of insulin resistance restored normal insulin signaling. However, the expression level of myogenin could not be reestablished. In addition to decreasing myogenin expression, CM also decreased the release of IL-6 and IL-8 and increased monocyte chemotactic protein-1 (MCP-1) secretion from skeletal muscle cells. Although regeneration of myotubes reestablished normal secretion of IL-6, the release of IL-8 and MCP-1 remained impaired for 48 h after withdrawal of CM. In conclusion, our data show that insulin resistance in skeletal muscle cells is only partially reversible. Although some characteristic features of insulin-resistant myotubes normalize in parallel to insulin signaling after withdrawal of CM, others such as IL-8 and MCP-1 secretion and myogenin expression remain impaired over a longer period. Thus, we propose that the induction of insulin resistance may cause irreversible changes of protein expression and secretion in skeletal muscle cells.

Topics: Adipocytes; Adult; Apoptosis; Ceramides; Chemokine CCL2; Child; Culture Media, Conditioned; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoblotting; Insulin Resistance; Interleukin-6; Interleukin-8; Male; Middle Aged; Muscle, Skeletal; Myoblasts, Skeletal; MyoD Protein; Myogenin; Nitric Oxide; Reactive Oxygen Species; Signal Transduction

In this study we measured serum concentrations of proinflammatory interleukin-6, interleukin-8, and interleukin-18 as well as anti-inflammatory interleukin-10 in 30 pregnant women with normal glucose tolerance, in 32 women with abnormal results of a 50-g glucose challenge test, and in 57 patients with gestational diabetes mellitus. Patients with gestational diabetes had significantly higher IL-6 (median 1.0 [0.7-1.5] vs. 0.7 [0.4-0.8] pg/ml, p=0.001), IL-8 (2.1 [1.1-4.2] pg/ml vs. 0.7 [0.4-0.9] pg/ml, p<0.0001), and IL-18 (249.3 [188.5-318.7] pg/ml vs. 186.7 [139.9-243.9] pg/ml, p=0.005) as well as lower IL-10 levels than healthy pregnant women (0.6 [0.5-1.5] pg/ml vs. 2.9 [1.8-3.2] pg/ml, p<0.0001). After adjusting for glucose, insulin, and BMI values, the differences in IL-8 and IL-18 became insignificant, whereas the differences in IL-6 and IL-10 levels remained highly significant (p<0.0001). The subjects with abnormal glucose challenge test results had higher IL-6 levels (0.9 [0.7-1.3] pg/ml, p=0.005) and similar levels of other cytokines as compared with the women with normal glucose tolerance. Our results suggest an impaired balance between circulating pro- and anti-inflammatory cytokines in patients with gestational diabetes; however, a significant contribution of maternal obesity to the increased levels of IL-8 and IL-18 should be underlined.

Topics: Adult; Anthropometry; Body Mass Index; Cytokines; Diabetes, Gestational; Female; Glucose Intolerance; Homeostasis; Humans; Insulin; Insulin Resistance; Interleukin-10; Interleukin-18; Interleukin-6; Interleukin-8; Poland; Pregnancy

Studies have shown clear associations of abdominal obesity with lipid and glucose metabolism and cytokine levels in a number of different population groups. However, no such studies have been performed in an African population in which visceral adipose tissue levels have been shown to be lower than in European subjects.. Cross-sectional analysis in 124 African women.. Fasting serum samples were taken from all subjects and anthropometric measurements obtained. Blood levels of glucose, insulin, total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglyceride, interleukin (IL)-6, IL-8 and IL-18 were measured. Subjects were separated into normal and abnormal glucose tolerant groups and into tertiles according to waist circumference (WC). Insulin resistance was assessed using the homeostasis model assessment (HOMA).. Abnormal glucose-tolerant subjects had higher WC, glucose and HOMA levels than the normal glucose-tolerant group. Increased WC was associated with higher triglyceride, insulin and HOMA levels and lower HDL levels. Multiple regression analyses showed that WC associated positively with HOMA and serum triglyceride levels and negatively with HDL levels. IL18 was a positive but weak determinant of the HOMA level and BMI correlated positively with serum IL-6 concentrations.. Although previous studies have shown that African subjects have a lower visceral adipose depot size than European subjects, abdominal obesity is still associated with insulin resistance and dyslipidaemia. The association between abdominal obesity and metabolic dysfunction within this population is not dependent upon IL-6, IL-8 or IL-18.

Topics: Abdominal Fat; Adult; Aged; Anthropometry; Blood Glucose; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cross-Sectional Studies; Cytokines; Female; Humans; Insulin; Insulin Resistance; Interleukin-18; Interleukin-6; Interleukin-8; Lipids; Middle Aged; Obesity; Regression Analysis; South Africa; Triglycerides

Insulin resistance and central obesity are often associated with hypertension. The metabolic syndrome is a cluster of these common clinical disorders, and is related with an increased risk for cardiovascular diseases. A number of pro-inflammatory cytokines derived from adipose tissues have been thought to contribute to the development of insulin resistance and accelerated atherosclerosis. Among them, TNF-alpha has been most widely studied; it not only suppresses the insulin signaling, but also elicits vascular inflammation. Indeed, inhibition of TNF-alpha was found to improve insulin resistance in obese rats and reduce the progression of atherosclerosis in apolipoprotein E knockout mice, respectively. These observations demonstrate that TNF-alpha could play a central role in the pathogenesis of insulin resistance and accelerated atherosclerosis in the metabolic syndrome. Considering that the primary goals of treatment for hypertensive patients with the metabolic syndrome are prevention of the development of diabetes and cardiovascular events, anti-hypertensive drugs that have abilities to block the TNF-alpha signaling would be desirable as a first-line therapy for these patients. In the process of the search for such a unique anti-hypertensive drug, we have recently found that azelnidipine, a newly developed and commercially used long-acting dihydropyridine-based calcium antagonist (DHP), inhibited TNF-alpha-induced activator protein-1 activation and interleukin-8 expression in human umbilical vein endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation. The concentration of azelnidipine that was found effective in these in vitro-experiments is well within the therapeutic range. Since endothelial cells do not possess voltage-operated L-type calcium channels, these observations suggest that the beneficial effects of azelnidipine are not likely due to calcium channel blocking property, but due to its unique anti-oxidative ability. Furthermore, we have very recently found that serum levels of monocyte chemoattractant protein-1, a biomarker for subclinical atherosclerosis, were significantly decreased by the treatment of azelnidipine in patients with essential hypertension. In this paper, we would like to hypothesize that due to its unique TNF-alpha signal modulatory, anti-oxidative property, azelnidipine may be a promising DHP that targets diabetes and cardiovascular diseases in hypertensive patients with the metabolic synd

Topics: Antihypertensive Agents; Antioxidants; Arteriosclerosis; Azetidinecarboxylic Acid; Biomarkers; Calcium; Cardiovascular Diseases; Cells, Cultured; Chemokine CCL2; Diabetes Mellitus; Dihydropyridines; Endothelium, Vascular; Humans; Hypertension; Insulin Resistance; Interleukin-8; Models, Biological; Reactive Oxygen Species; Transcription Factor AP-1; Tumor Necrosis Factor-alpha; Umbilical Veins

PAI-1, an important inhibitor of fibrinolysis, is increased in obese subjects and has been shown to be an independent risk factor for cardiovascular disease. In the present study, we investigated the association between circulating levels of PAI-1 and locally produced PAI-1 in adipose tissue and body fat distribution and adipokines (TNF-alpha, TNF receptors, IL-6, IL-8) in patients with and without HIV-associated lipodystrophy syndrome (HALS).. Eighteen men with HALS and 18 men with HIV but without HALS were investigated. DEXA and computed tomography scan were performed to determine total body fat and visceral adipose tissue mass. Insulin sensitivity was determined by the euglycaemic clamp technique. Plasma levels of PAI-1 and cytokines were determined. In addition, PAI-1, TNF-alpha, IL-6 and IL-8 mRNA levels in subcutaneous adipose tissue were measured by real-time reverse transcriptase polymerase chain reaction.. HALS patients were characterized by a 3-fold increased visceral adipose tissue (P < 0.001) and reduced limb fat (P < 0.01) as compared with non-HALS patients but with no difference in total fat mass between the groups. Plasma PAI-1 was increased in HALS patients (16.7 ng mL(-1) vs. 8.2 ng mL(-1), P < 0.05). Plasma PAI-1 was positively correlated with BMI (r = 0.74, P < 0.01), plasma TNF-alpha level (r = 0.64, P < 0.01), sTNFR-I (r = 0.38, P < 0.05), and visceral fat (r = 0.67, P < 0.01). Moreover, plasma PAI-1 was negatively associated with insulin sensitivity (r = -0.57, P < 0.01) and the percentage of limb fat (r = -0.57, P < 0.01). A positive correlation was found between plasma PAI-1 and TNF-alpha mRNA level. No association was, however, found between plasma PAI-1 and PAI-1 mRNA level in adipose tissue.. Plasma PAI-1 is increased in HALS patients and it is suggested that dysregulation of the TNF-system (high TNFalpha and high sTNFR1) may play a role in up-regulating PAI-1 in HALS.

Topics: Adipose Tissue; Adult; Body Mass Index; Cytokines; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin Resistance; Interleukin-6; Interleukin-8; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Receptors, Tumor Necrosis Factor; RNA, Messenger; Serine Proteinase Inhibitors; Tumor Necrosis Factor-alpha

We previously demonstrated that trans-10, cis-12 conjugated linoleic acid (CLA) reduced the triglyceride content of human adipocytes by activating mitogen-activated protein kinase kinase/extracellular signal-related kinase (MEK/ERK) signaling via interleukins (IL) 6 and 8. However, the upstream mechanism is unknown. Here we show that CLA increased (>or=6 h) the secretion of IL-6 and IL-8 in cultures containing both differentiated adipocytes and stromal vascular (SV) cells, non-differentiated SV cells, and adipose tissue explants. CLA isomer-specific induction of IL-6 and tumor necrosis factor-alpha was associated with the activation of nuclear factor kappaB (NFkappaB) as evidenced by 1) phosphorylation of IkappaBalpha, IkappaBalpha kinase, and NFkappaB p65, 2) IkappaBalpha degradation, and 3) nuclear translocation of NFkappaB. Pretreatment with selective NFkappaB inhibitors and the MEK/ERK inhibitor U0126 blocked CLA-mediated IL-6 gene expression. Trans-10, cis-12 CLA suppression of insulin-stimulated glucose uptake at 24 h was associated with decreased total and plasma membrane glucose transporter 4 proteins. Inhibition of NFkappaB activation or depletion of NFkappaB by RNA interference using small interfering NFkappaB p65 attenuated CLA suppression of glucose transporter 4 and peroxisome proliferator-activated receptor gamma proteins and glucose uptake. Collectively, these data demonstrate for the first time that trans-10, cis-12 CLA promotes NFkappaB activation and subsequent induction of IL-6, which are at least in part responsible for trans-10, cis-12 CLA-mediated suppression of peroxisome proliferator-activated receptor gamma target gene expression and insulin sensitivity in mature human adipocytes.

Topics: Active Transport, Cell Nucleus; Adipocytes; Butadienes; Cell Differentiation; Cell Membrane; Cell Nucleus; Cells, Cultured; Cytokines; Cytoplasm; Deoxyglucose; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Fatty Acids; Glucose; Glucose Transporter Type 4; Humans; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Interleukin-6; Interleukin-8; Linoleic Acids, Conjugated; MAP Kinase Kinase Kinases; Microscopy, Fluorescence; Microscopy, Phase-Contrast; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Models, Biological; NF-kappa B; Nitriles; Phosphoproteins; Phosphorylation; PPAR gamma; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Small Interfering; Time Factors; Transcription Factor RelA; Transfection; Triglycerides; Tumor Necrosis Factor-alpha

Topics: Adiponectin; Adipose Tissue; Anti-Inflammatory Agents; Atherosclerosis; Endothelial Cells; Humans; Insulin Resistance; Interleukin-8; Receptors, Adiponectin; Receptors, Cell Surface; Tumor Necrosis Factor-alpha

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

To study the association between anthropometric and metabolic parameters as well as the effect of weight loss on plasma levels of the adipose tissue-derived cytokines interleukin-8 (IL-8), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in abdominal obese men.. Nineteen obese (mean body mass index (BMI): 38.6+/-0.6 kg/m(2)) and ten lean men (mean BMI: 23.4+/-0.4 kg/m(2)) were included in the study. The obese subjects received a 4.2 MJ/day diet for 8 weeks, followed by 8 weeks on energy restriction (6.2 MJ/day) and 8 weeks on a weight-maintenance diet.. A dual energy X-ray absorptiometry (DEXA)-scan was performed to estimate body composition. Plasma levels of IL-8, IL-6 and TNF-alpha were measured by a specific ELISA method. Insulin sensitivity was assessed by the homeostasis model assessment method (HOMA).. Plasma levels of IL-8 and IL-6 were 30-40% higher in obese as compared with lean subjects (P<0.05), whereas no group difference in TNF-alpha was observed. During the intervention, obese subjects obtained a 30% reduction in fat mass (P<0.001), fasting insulin (P<0.05) and HOMA (P<0.05). Plasma levels of TNF-alpha and IL-6 were decreased by 25-30% (P<0.001) but IL-8 was increased by 30% (P<0.001) after weight loss. IL-8 and IL-6 were correlated with measures of insulin resistance, and changes in IL-6 but not IL-8 were correlated with the improvement in insulin sensitivity after weight loss.. Plasma levels of IL-8 and IL-6 were found to be increased and were correlated with measures of insulin resistance in abdominal obese male subjects. Weight loss was associated with changes in the circulating levels of IL-8, IL-6 and TNF-alpha indicating that these cytokines are influenced by weight loss.

Topics: Adult; Anthropometry; Humans; Insulin Resistance; Interleukin-6; Interleukin-8; Male; Middle Aged; Obesity; Thinness; Tumor Necrosis Factor-alpha; Weight Loss

Human immunodeficiency virus (HIV)-associated lipodystrophy syndrome (HALS) is a side effect of highly active antiretroviral therapy of HIV-infected patients; however, the mechanism of the lipodystrophy and insulin resistance seen in this syndrome remains elusive. Adiponectin, an adipocyte-specific protein, is thought to play an important role in regulating insulin sensitivity. We investigated circulating levels and gene expression of adiponectin in subcutaneous abdominal adipose tissue (AT) from 18 HIV-infected patients with HALS compared with 18 HIV-infected patients without HALS. Implications of cytokines for adiponectin levels were investigated by determining circulating levels of TNF-alpha, IL-6, and IL-8 as well as gene expression of these cytokines in AT. HALS patients exhibited 40% reduced plasma adiponectin levels (P < 0.05) compared with non-HALS subjects. Correspondingly, adiponectin mRNA levels in AT were reduced by >50% (P = 0.06). HALS patients were insulin resistant, and a positive correlation was found between plasma adiponectin and insulin sensitivity (r = 0.55, P < 0.01) and percent limb fat (r = 0.61, P < 0.01). AT mRNA of TNF-alpha, IL-6, and IL-8 was increased in AT of HALS subjects (P < 0.05), and both AT TNF-alpha mRNA and plasma TNF-alpha were negatively correlated to plasma adiponectin (P < 0.05). Finally, TNF-alpha was found in vitro to inhibit human AT adiponectin mRNA by 80% (P < 0.05). In conclusion, HALS patients have reduced levels of plasma adiponectin and adiponectin mRNA in AT. Increased cytokine mRNA in AT is hypothesized to exert an inhibitory effect on adiponectin gene expression and, consequently, to play a role in the reduced plasma adiponectin levels found in HALS patients.

Topics: Acquired Immunodeficiency Syndrome; Adiponectin; Adipose Tissue; Adult; Antiretroviral Therapy, Highly Active; Body Composition; Body Mass Index; Cholesterol; Gene Expression; HIV-Associated Lipodystrophy Syndrome; Humans; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Interleukin-6; Interleukin-8; Male; Middle Aged; Proteins; RNA, Messenger; Tumor Necrosis Factor-alpha

Several studies have shown a relationship between interleukin (IL) 6 levels and insulin resistance. We here show that human subcutaneous adipose cells, like 3T3-L1 cells, are target cells for IL-6. To examine putative mechanisms and cross-talk with insulin, 3T3-L1 adipocytes were cultured for different times with IL-6 and tumor necrosis factor alpha (TNF-alpha). IL-6, in contrast to TNF-alpha, did not increase pS-307 of insulin-receptor substrate (IRS)-1 or JNK activation. However, IL-6, like TNF-alpha exerted long term inhibitory effects on the gene transcription of IRS-1, GLUT-4, and peroxisome proliferator-activated receptor gamma. This effect of IL-6 was accompanied by a marked reduction in IRS-1, but not IRS-2, protein expression, and insulin-stimulated tyrosine phosphorylation, whereas no inhibitory effect was seen on the insulin receptor tyrosine phosphorylation. Consistent with the reduced GLUT-4 mRNA, insulin-stimulated glucose transport was also significantly reduced by IL-6. An important interaction with TNF-alpha was found because TNF-alpha markedly increased IL-6 mRNA and protein secretion. These results show that IL-6, through effects on gene transcription, is capable of impairing insulin signaling and action but, in contrast to TNF-alpha, IL-6 does not increase pS-307 (or pS-612) of IRS-1. The link between IL-6 and insulin resistance in man was further corroborated by the finding that the expression of IL-6, like that of TNF-alpha and IL-8, was markedly increased ( approximately 15-fold) in human fat cells from insulin-resistant individuals. We conclude that IL-6 can play an important role in insulin resistance in man and, furthermore, that it may act in concert with other cytokines that also are up-regulated in adipose cells in insulin resistance.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue; Adult; Animals; Biological Transport; Blotting, Northern; Cytokines; Dose-Response Relationship, Drug; Glucose; Glucose Transporter Type 4; Humans; Insulin Receptor Substrate Proteins; Insulin Resistance; Interleukin-6; Interleukin-8; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; Mice; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Monosaccharide Transport Proteins; Muscle Proteins; Phosphoproteins; Phosphorylation; Proteins; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Time Factors; Transcription Factors; Transcription, Genetic; Tumor Necrosis Factor-alpha; Tyrosine; Up-Regulation