Liver steatosis,but not fibrosis,is associated with insulin resistance in nonalcoholic fatty liver disease

Background To address the hypothesis that liver steatosis causes systemic insulin resistance, we sought to determine the liver histological feature that most strongly contributes to insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). Methods Liver biopsy specimens were obtained from 131 patients with clinically suspected NAFLD. The stage, grade of nonalcoholic steatohepatitis (NASH), and level of steatosis were scored and analyzed in relation to the homeostasis model assessment of insulin resistance (HOMA-IR) and the metabolic clearance rate (MCR), measured using the glucose clamp method. Results In the univariate analysis, the degree of hepatic steatosis (r = 0.458, P < 0.001), stage (r = 0.360, P < 0.001), and grade (r = 0.349, P < 0.01) of NASH were significantly correlated with the HOMA-IR. Multiple regression analysis adjusting for age, sex, body mass index, and each histological score showed that steatosis was significantly and independently associated with HOMA-IR (coefficient = 1.42, P < 0.001), but not with the stage (coefficient = 0.33, P = 0.307) or grade (coefficient = 0.67, P = 0.134) of NASH. Similar independent relationships were observed between steatosis and MCR, but the relationship was weaker (coefficient = −0.98, P = 0.076). Conclusions Steatosis of the liver, but not the stage or the grade of NASH, is associated with insulin resistance in patients with NAFLD.     

Offspring birthweight is not associated with paternal insulin resistance

Aims/hypothesis Low birthweight is associated with insulin resistance and other insulin resistance-related phenotypes: diabetes, hypertension, and vascular disease in later life. The underlying mechanism is unclear. The foetal insulin hypothesis proposes that a single genetic predisposition to beta cell dysfunction/insulin resistance results in both reduced insulin-dependent foetal growth in utero, hence low birthweight, and predisposition to type 2 diabetes. The aim of this study was to test whether, as predicted by the foetal insulin hypothesis, there is an association between measures of paternal insulin resistance and offspring birthweight.Subjects and Methods The Exeter Family Study of Childhood Health (EFSOCH) is a community-based study within central Exeter (UK), established to test the foetal insulin hypothesis prospectively. Associations were tested between offspring birthweight and paternal insulin resistance, calculated by homeostasis model assessment analysis in 986 families using data relating to singleton, non-diabetic, UK white pregnancies. Ethics approval was given by the North and East Devon local ethics committee.Results Offspring birthweight was not significantly correlated with log paternal insulin resistance (r=0, p=0.91), log HDL cholesterol concentration (r=−0.02, p=0.47) or log triglyceride concentration (r=0, p=0.99) when corrected for paternal BMI and common confounders. Multiple linear regression analysis confirmed that paternal insulin resistance was not an independent predictor of offspring birthweight.Conclusions/interpretation Results from a young, adult, non-diabetic population do not support the foetal insulin hypothesis as an explanation for the association of low birthweight with insulin resistance.     

Lower cardiovagal tone and baroreflex sensitivity associated with hepatic insulin resistance and promote cardiovascular disorders in Tibetan minipigs induced by a high fat and high cholesterol diet

Aims

A long-term high-fat/cholesterol (HFC) diet leads to hepatic insulin resistance (IR), which is associated with autonomic dysfunction and cardiovascular diseases risk increasing. However, whether this occurs in Tibetan minipigs remains unknown. We tested that a long-term HFC diet caused hepatic IR and promote cardiovascular disorders in Tibetan minipigs, and are associated with the reduction of cardiovagal tone and baroreflex sensitivity (BRS).

Liver steatosis is associated with insulin resistance in skeletal muscle rather than in the liver in Japanese patients with non‐alcoholic fatty liver disease

Aims/Introduction

To examine the association between liver histological features and organ-specific insulin resistance indices calculated from 75-g oral glucose tolerance test data in patients with non-alcoholic fatty liver disease.

Materials and Methods

Liver biopsy specimens were obtained from 72 patients with non-alcoholic fatty liver disease, and were scored for steatosis, grade and stage. Hepatic and skeletal muscle insulin resistance indices (hepatic insulin resistance index and Matsuda index, respectively) were calculated from 75-g oral glucose tolerance test data, and metabolic clearance rate was measured using the euglycemic hyperinsulinemic clamp method.

Results

The degree of hepatic steatosis, and grade and stage of non-alcoholic steatohepatitis were significantly correlated with Matsuda index (steatosis r = −0.45, P < 0.001; grade r = −0.54, P < 0.001; stage r = −0.37, P < 0.01), but not with hepatic insulin resistance index. Multiple regression analyses adjusted for age, sex, body mass index and each histological score showed that the degree of hepatic steatosis (coefficient = −0.22, P < 0.05) and grade (coefficient = −0.40, P < 0.01) were associated with Matsuda index, whereas the association between stage and Matsuda index (coefficient = −0.07, P = 0.593) was no longer significant. A similar trend was observed for the association between steatosis and metabolic clearance rate (coefficient = −0.62, P = 0.059).

Conclusions

Liver steatosis is associated with insulin resistance in skeletal muscle rather than in the liver in patients with non-alcoholic fatty liver disease, suggesting a central role of fatty liver in the development of peripheral insulin resistance and the existence of a network between the liver and skeletal muscle.     

Down-regulation of hepatic stearoyl-CoA desaturase 1 expression by angiotensin II receptor blocker in the obese fa/fa Zucker rat: possible role in amelioration of insulin resistance and hepatic steatosis

Background  It has been reported that angiotensin II type 1 receptor blocker (ARB) can ameliorate hepatic steatosis and insulin resistance. Stearoyl-CoA desaturase 1 (SCD-1), which catalyzes the cellular synthesis of monounsaturated fatty acids, affects lipid metabolism. In this study, we investigated whether SCD-1 gene expression is affected by ARB treatment. Methods  Obese fa/fa Zucker rats fed a high-fat diet were treated with a potent ARB and olmesartan, and the resulting changes in the components of serum and liver were studied. Gene expression of hepatic SCD-1 was assayed using real-time PCR. Results  The serum glucose and insulin levels and hepatic TG content of the obese Zucker rats fed a high-fat diet were reduced after olmesartan administration, while the serum adiponectin level was increased. Real-time PCR revealed an increase of SCD-1 gene expression in the liver of these rats, followed by a reduction after olmesartan administration. The ratio of stearic acid (C18:0) to oleic acid (C18:1) in the liver was increased by olmesartan, indicating a reduction in the in vivo activity of SCD-1. Conclusions  ARB ameliorates hepatic steatosis and insulin resistance in obese fa/fa Zucker rats fed a high-fat diet. Gene expression of SCD-1 is decreased by olmesartan, suggesting that the beneficial effect is due partly to suppression of the key enzyme for hepatic lipid metabolism by ARB.     

Myocardial autophagy activation and suppressed survival signaling is associated with insulin resistance in fructose-fed mice

Fructose intake is linked with the increasing prevalence of insulin resistance and there is now evidence for a specific insulin-resistant cardiomyopathy. The aim of this study was to determine the cardiac-specific myocardial remodeling effects of high fructose dietary intake. Given the links between insulin signaling, reactive oxygen species generation and autophagy induction, we hypothesized that autophagy contributes to pathologic remodeling in the insulin-resistant heart, and in particular may be a feature of high fructose diet-induced cardiac phenotype. Male C57Bl/6 mice were fed a high fructose (60%) diet or nutrient-matched control diet for 12 weeks. Systemic and myocardial insulin-resistant status was characterized. Superoxide production (lucigenin) and cellular growth and death signaling pathways were examined in myocardial tissue. Myocardial structural remodeling was evaluated by measurement of heart weight indices and histological analysis of collagen deposition (picrosirius red). Fructose-fed mice exhibited hyperglycemia and glucose intolerance, but plasma insulin and blood pressure were unchanged. High fructose intake suppressed the myocardial Akt cell survival signaling coincident with increased cardiac superoxide generation (21% increase, p < 0.05). Fructose feeding induced elevated autophagy (LC3B-II: LC3B-I ratio: 46% increase, p < 0.05) but not apoptosis signaling (unchanged Bax-1:Bcl-2 ratio). Despite a 28% increase in interstitial fibrosis, no difference in heart weight was observed in fructose-fed mice. We provide the first evidence that myocardial autophagy activation is associated with systemic insulin resistance, and that high level fructose intake inflicts direct cardiac damage. Upregulated autophagy is associated with elevated cardiac superoxide production, suppressed cell survival signaling and fibrotic infiltration in fructose-fed mice. The novel finding that autophagy contributes to cardiac pathology in insulin resistance identifies a new therapeutic target for diabetic cardiomyopathy.     

Serum leptin as a mediator of the influence of insulin resistance on hepatic steatosis in youths with excess adiposity

Background and aimsThe relationship between insulin resistance (IR) and hepatic steatosis (fatty liver) is well known; however, the extent to which the satiety hormone leptin acts as a confounder or mediator in this relationship is uncertain. We examined whether the association between IR and hepatic steatosis is mediated by leptin in Colombian adolescents with excess adiposity.Methods and resultsA total of 122 adolescents (mean age: 13.4 years; 68% girls) participated in the study. We assessed body composition, hepatic steatosis (as defined by the controlled attenuation parameter [CAP]), cardiometabolic risk factors (body mass index, waist circumference, body composition), biochemical variables (leptin, insulin, glucose, lipid profile, cardiometabolic Z-score, transaminases, etc.), and physical fitness (cardiorespiratory fitness and grip strength). Partial correlation, regression, and mediation analyses were conducted using the Barron and Kenny framework.ResultsNinety-two youths (75.4%) had IR. Mediation analysis revealed a positive relationship between Homeostasis Model Assessment-IR (HOMA-IR) and CAP (β_dir = 3.414, 95% confidence interval [CI]: 1.012 to 5.816, p < 0.001), which was attenuated when leptin was included in the model, thus indicating that leptin mediates this relationship (β_ind = 1.074, 95% CI: 0.349 to 2.686, p < 0.001). The percentage of the total effect mediated by leptin was 21%. Regarding sex, the mediation effect of leptin remains significant among boys (β_ind = 0.962, 95% CI: 0.009 to 2.615, p < 0.001), but not in girls (β_ind = 0.991, 95% CI: 1.263 to 5.483, p = 0.477).ConclusionsThe findings are clinically relevant to consider leptin levels as a surrogate marker of insulin sensitivity when assessing youths with excess adiposity and/or suspected Nonalcoholic hepatic steatosis or nonalcoholic fatty liver disease (NAFLD).     

Association of chronic hepatitis B virus infection with insulin resistance and hepatic steatosis

Background and Aim: Chronic viral infections such as human immunodeficiency virus and hepatitis C virus (HCV) may decrease tissue response to insulin, thereby causing insulin resistance. In addition, insulin resistance is associated with hepatic steatosis. However, whether these phenomena hold true for chronic hepatitis B virus (HBV) infection remains largely unknown. The present study therefore aimed to investigate the association of chronic HBV infection with insulin resistance and hepatic steatosis. Methods: A total of 507 subjects (243 men and 264 women; mean age 46.56 years) less than 60 years‐old attending a health examination center were enrolled in the study. All the subjects were negative for antibodies against HCV and consumed less than 140 g alcohol/week. Demographic, anthropometric, clinical, and laboratory data were obtained from each subject. Insulin resistance index was determined using homeostasis model assessment (HOMA‐IR). Hepatic steatosis was identified by ultrasound examination. Results: Of the 507 subjects, 50 (9.9%) were positive for hepatitis B surface antigen (HBsAg) and designated HBV carriers. All variables were comparable between HBV carriers and non‐HBV carriers, except that HBV carriers had significantly higher serum alanine aminotransferase and aspartate aminotransferase levels (P < 0.05). By multivariate linear regression, HBV carriers were not associated with insulin resistance. In addition, multivariate regression analyses showed that HBV carriers were not associated with the presence of ultrasonographic fatty liver. Conclusions: Chronic HBV infection seems not to be associated with insulin resistance or hepatic steatosis in HBV carriers.     

Retinol-binding protein 4 is associated with components of the metabolic syndrome, but not with insulin resistance, in men with type 2 diabetes or coronary artery disease

Aims/hypothesis Retinol-binding protein 4 (RBP4) has recently been reported to be associated with insulin resistance and the metabolic syndrome. This study tested the hypothesis that RBP4 is a marker of insulin resistance and the metabolic syndrome in patients with type 2 diabetes or coronary artery disease (CAD) or in non-diabetic control subjects without CAD. Methods Serum RBP4 was measured in 365 men (126 with type 2 diabetes, 143 with CAD and 96 control subjects) and correlated with the homeostasis model assessment of insulin resistance index (HOMA-IR), components of the metabolic syndrome and lipoprotein metabolism. RBP4 was detected by ELISA and validated by quantitative Western blotting. Results RBP4 concentrations detected by ELISA were shown to be strongly associated with the results gained in quantitative Western blots. There were no associations of RBP4 with HOMA-IR or HbA_1c in any of the groups studied. In patients with type 2 diabetes there were significant positive correlations of RBP4 with total cholesterol, LDL-cholesterol, VLDL-cholesterol, plasma triacylglycerol and hepatic lipase activity. In patients with CAD, there were significant associations of RBP4 with VLDL-cholesterol, plasma triacylglycerol and hepatic lipase activity, while non-diabetic control subjects without CAD showed positive correlations of RBP4 with VLDL-cholesterol and plasma triacylglycerol. Conclusions/interpretation RBP4 does not seem to be a valuable marker for identification of the metabolic syndrome or insulin resistance in male patients with type 2 diabetes or CAD. Independent associations of RBP4 with pro-atherogenic lipoproteins and enzymes of lipoprotein metabolism indicate a possible role of RBP4 in lipid metabolism.     

Smoking is associated with steatosis and severe fibrosis in chronic hepatitis C but not B

Objective. The results of retrospective studies suggest an association between smoking, insulin resistance, steatosis and fibrosis in patients with chronic hepatitis C (CHC); no data are available for chronic hepatitis B (CHB). The purpose of this study was to evaluate the relationship, if any, of such factors on liver fibrosis in a cohort of patients with CHB and CHC. Material and methods. The study prospectively included 271 consecutive patients with CHB (n=95) or CHC (n=176) who had undergone liver biopsies. Each patient completed a questionnaire on smoking habits; anthropometric measurements and laboratory examinations were carried out and histological lesions were recorded. Results. In CHC patients, severe fibrosis was independently associated with a higher body mass index (BMI) (OR: 1.180, 95% CI: 1.028–1.354; p=0.019), heavy smoking (OR: 3.923, 95% CI: 1.356–11.348; p=0.012), higher alanine aminotransferase (ALAT) levels (OR: 1.010, 95% CI: 1.003–1.017; p=0.005) and alkaline phosphatase (ALP) levels (OR: 1.016, 95% CI: 1.001–1.030; p=0.03) and presence of necroinflammation (OR: 11.165, 95% CI: 1.286–96.970; p=0.029). Moreover, steatosis was independently associated with high gamma-glutamyl transpeptidase (GGT) values, heavy smoking and presence of necroinflammation. In CHB patients, no association between smoking habits and fibrosis or steatosis was noted. Conclusions. Heavy smoking is associated with severe fibrosis in CHC but not CHB. Heavy smoking is also significantly associated with steatosis in CHC and this could be the link between smoking and fibrosis progression.     

Free fatty acids are associated with insulin resistance but not coronary artery atherosclerosis in rheumatoid arthritis

Background

Free fatty acids (FFAs) affect insulin signaling and are implicated in the pathogenesis of insulin resistance and atherosclerosis. Inflammatory cytokines such as interleukin-6 (IL-6) increase lipolysis and thus levels of FFAs. We hypothesized that increased IL-6 concentrations are associated with increased FFAs resulting in insulin resistance and atherosclerosis in rheumatoid arthritis (RA).

Methods

Clinical variables, serum FFAs and inflammatory cytokines, homeostasis model assessment for insulin resistance (HOMA-IR), and coronary artery calcium were measured in 166 patients with RA and 92 controls. We compared serum FFAs in RA and controls using Wilcoxon rank sum tests and further tested for multivariable association by adjusting for age, race, sex and BMI. Among patients with RA, we assessed the relationship between serum FFAs and inflammatory cytokines, HOMA-IR, and coronary artery calcium scores using Spearman correlation and multivariable regression analyses.

Results

Serum FFAs did not differ significantly in patients with RA and controls (0.56 mmol/L [0.38–0.75] and 0.56 mmol/L [0.45–0.70] respectively, p = 0.75). Presence of metabolic syndrome was associated with significantly increased serum FFAs in both RA and controls (p = 0.035 and p = 0.025). In multivariable regression analysis that adjusted for age, race, sex and BMI, serum FFAs were associated with HOMA-IR (p = 0.011), CRP (p = 0.01), triglycerides (p = 0.005) and Framingham risk score (p = 0.048) in RA, but not with IL-6 (p = 0.48) or coronary artery calcium score (p = 0.62).

Conclusions

Serum FFAs do not differ significantly in patients with RA and controls. FFAs may contribute to insulin resistance, but are not associated with IL-6 and coronary atherosclerosis in RA.     

Reduced whole-body lipid oxidation is associated with insulin resistance, but not with intramyocellular lipid content in offspring of type 2 diabetic patients

Aims/hypothesis Intramyocellular lipid accumulation and insulin resistance are thought to be due to reduced lipid oxidation in a human model of high risk of developing type 2 diabetes.Methods We studied 32 offspring of type 2 diabetic parents and 32 control individuals by means of DXA, indirect calorimetry, insulin clamp and ¹H MRS of the calf muscles, and differences between and within study groups were analysed before and after segregation by quartiles of fasting lipid oxidation.Results In comparison with control subjects, the offspring showed impaired insulin sensitivity, which was associated with higher fasting intramyocellular lipid content (Spearmans rho –0.35; p=0.04), but fasting lipid oxidation did not differ between groups (1.21±0.46 vs. 1.25±0.37 mg·kg^–1 lean body mass per min; p=0.70). Nevertheless, offspring in the lowest quartile of lipid oxidation had the most severe impairment of insulin sensitivity and a strong association was shown between lipid oxidation and insulin sensitivity within quartiles (Spearmans rho 0.47; p=0.01); this was not observed within the control group (Spearmans rho 0.13; p=0.47). Intramyocellular lipid content was not significantly different within quartiles of lipid oxidation in either of the groups.Conclusions/interpretation Insulin sensitivity improved across increasing quartiles of fasting lipid oxidation in the offspring group, but remained constant in the control group, supporting the hypothesis that impaired fat oxidation is a primary pathogenic factor of insulin resistance in people with a genetic background for type 2 diabetes. Despite their association with impaired insulin sensitivity, soleus and tibialis anterior intramyocellular lipid content remained constant across increasing quartiles of fasting lipid oxidation within both groups.     

Basal lipolysis, not the degree of insulin resistance, differentiates large from small isolated adipocytes in high-fat fed mice

Aims/hypothesis  Adipocytes in obesity are characterised by increased cell size and insulin resistance compared with adipocytes isolated from lean patients. However, it is not clear at present whether hypertrophy actually does drive adipocyte insulin resistance. Thus, the aim of the present study was to metabolically characterise small and large adipocytes isolated from epididymal fat pads of mice fed a high-fat diet (HFD). Methods  C57BL/6J mice were fed normal chow or HFD for 8 weeks. Adipocytes from epididymal fat pads were isolated by collagenase digestion and, in HFD-fed mice, separated into two fractions according to their size by filtration through a nylon mesh. Viability was assessed by lactate dehydrogenase and 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium assays. Basal and insulin-stimulated d-[U-¹⁴C]glucose incorporation and lipolysis were measured. Protein levels and mRNA expression were determined by western blot and real-time RT-PCR, respectively. Results  Insulin-stimulated D-[U-¹⁴C]glucose incorporation into adipocytes isolated from HFD-fed mice was reduced by 50% compared with adipocytes from chow-fed mice. However, it was similar between small (average diameter 60.9 ± 3.1 μm) and large (average diameter 83.0 ± 6.6 μm) adipocytes. Similarly, insulin-stimulated phosphorylation of protein kinase B and AS160 were reduced to the same extent in small and large adipocytes isolated from HFD-mice. In addition, insulin failed to inhibit lipolysis in both adipocyte fractions, whereas it decreased lipolysis by 30% in adipocytes of chow-fed mice. In contrast, large and small adipocytes differed in basal lipolysis rate, which was twofold higher in the larger cells. The latter finding was associated with higher mRNA expression levels of Atgl (also known as Pnpla2) and Hsl (also known as Lipe) in larger adipocytes. Viability was not different between small and large adipocytes. Conclusions/interpretation  Rate of basal lipolysis but not insulin responsiveness is different between small and large adipocytes isolated from epididymal fat pads of HFD-fed mice.     

雷帕霉素对KKAy小鼠体重及胰岛素抵抗的影响

目的 探讨雷帕霉素对KKAy小鼠体重及胰岛素抵抗(IR)的影响.方法 16周KKAy小鼠34只,随机分为对照组(NC组,12只)、雷帕霉素治疗组(R组,12只)、胰岛素治疗组(Ins组,10只),6只同龄C57BL与5只KKAy小鼠作为治疗前对照.结果 治疗前KKAy小鼠体重、血糖、TG明显高于C57BL小鼠(体重36.2±1.9 g vs 29.3±1.0 g;血糖13.4±1.7 mmol/L vs 7.8±0.5 mmol/L;TG1.59±0.16 mmol/L vs 0.75±0.09 mmol/L;P均＜0.01).治疗4周后R组体重(33.7±2.3 g),低于NC组(38.2±1.5 g)和Ins组(37.4±1.1 g),差异有统计学意义(P均＜0.05);R组血糖(17.2±7.3 nmol/L),低于NC组(29.1±3.2 mmol/L),差异有统计学意义(P＜0.05);治疗8周后R组体重(32.2±3.1 g),低于NC组(39.3±2.8 g),差异有统计学意义(P＜0.05);血糖(18.2±3.7 mmol/L),低于NC组(24.4±5.1 mmol/L),差异无统计学意义(P=0.06).胰岛素敏感试验表明R组在注射胰岛素60 min后,血糖降幅明显大于NC组(4.88±0.73 mmol/L vs 2.65±2.12 mmol/L,P＜0.05).结论 雷帕霉素可减轻KKAy小鼠体重、改善IR、降低血糖.     

Significance of serum leptin and adiponectin levels in Egyptian patients with chronic hepatitis C virus associated hepatic steatosis and fibrosis

AIM: To study serum levels of leptin and adiponectin in patients with chronic hepatitis C virus infection genotype-4 (HCV-4) related steatosis and fibrosis. METHODS: We prospectively studied 45 untreated men with chronic HCV-4, with proven steatosis (group I, 30 patients), and fibrosis (group II, 15 patients), on liver biopsy. In addition, 15 healthy men (group III), matched for age, and body mass index were included. However, we excluded another five patients with steatohepatitis, and six patients with cirrhosis. We measured total serum leptin and adiponectin levels, as potential predictors for liver steatosis and fibrosis. Also, a correlation between these adipokines and various clinical and laboratory data were evaluated. All subjects were selected from Tropical and Internal medicine departments, Menoufiya University Hospital, Menoufiya, Egypt, during the period from February 2010 to August 2011. RESULTS: In group I, severity of hepatic steatosis was mild, moderate, and severe, in 19 patients (63.5%), 8 patients (26.5%), and 3 patients (10%), respectively. In contrast, in group II, hepatic fibrosis was found to be in stage 1, 2, and 3, in 6 patients (40%), in 6 patients (40%), and in 3 patients (20%), respectively. On comparing group I with group II, there was a significant decrease in serum adiponectin levels (131.4 ± 7.91 pg/mL vs 436 ± 9.75 pg/mL, P < 0.001), while there was no significant difference between both groups regarding serum leptin levels (34.69 ± 7.69 ng/mL vs 35.17 ± 1.06 ng/mL, P > 0.05). However, in the same group, when compared with group III, there was a significant increase in serum leptin levels (34.69 ± 7.69 ng/mL vs 10.69 ± 0.84 ng/mL, P < 0.001), while there was a significant decrease in serum adiponectin levels (131.4 ± 7.91 pg/mL vs 342.4 ± 44.48 pg/mL, P < 0.001). In contrast, in group II, when compared with group III, there was a significant increase in serum leptin and adiponectin levels (35.17 ± 1.06 ng/mL vs 10.69 ± 0.84 ng/mL, P < 0.001, and 436 ± 9.75 pg /mL vs 342.4 ± 44.48 pg/mL, P < 0.05, respectively), while there was no significant difference between both groups regarding serum creatinine (0.83 ± 0.34 vs 0.89 ± 0.24, P > 0.05). On the other hand, serum leptin was not correlated with serum adiponectin in group I and in group II (r = 0.09, P > 0.05, and r = -0.1, P > 0.05, respectively). However, serum adiponectin was significantly negatively correlated with serum aspartate transaminase in group I, but no correlation detected in group II (r =-0.39, P > 0.05, and r = -0.03, P > 0.05). CONCLUSION: In male patients with chronic HCV-4, serum adiponectin levels are elevated in hepatic fibrosis, but decreased in steatosis. Therefore, in contrast to leptin, adiponectin may be used as a non-invasive marker.     

Perivascular fatty tissue at the brachial artery is linked to insulin resistance but not to local endothelial dysfunction

Aims/hypothesis  Different ectopic fat depots, such as visceral or hepatic fat, are known to affect whole body insulin sensitivity. It has recently been hypothesised that differences in perivascular adipose tissue (PVAT) mass around resistance vessels may also contribute to insulin resistance, possibly via direct vascular effects leading to reduced capillary cross-sectional area in the muscle, which in turn affects muscular blood flow and glucose uptake. Based on this, the aim of the present study was to test whether PVAT around conduit arteries (i.e. the brachial artery) influences NO bioavailability, expressed as flow-mediated dilation (FMD), or insulin sensitivity in humans in vivo. Methods  Insulin sensitivity was measured by OGTT in all 95 participants (59 women, 36 men; median age 47 years, range 19–66 years) and by the gold standard, a euglycaemic–hyperinsulinaemic clamp, in a randomly selected subgroup of 33 participants. Quantification of the different fat compartments, including PVAT around the brachial artery, was achieved by high-resolution magnetic resonance imaging (1.5 T). Blood flow and FMD were measured at the brachial artery using high-resolution (13 MHz) ultrasound, after 5 min of forearm occlusion. Results  PVAT was negatively correlated with insulin sensitivity and the post-ischaemic increase in blood flow. The association between PVAT and insulin sensitivity (r = −0.54, β = −0.37, p = 0.009) was independent of age, sex, visceral adipose tissue, liver fat, BMI and further cardiovascular risk factors. No correlation could be detected between PVAT and local endothelial function. However, we observed an independent association between PVAT and post-ischaemic increase in blood flow (r = −0.241; β = −1.69; p = 0.02). Conclusions/interpretation  PVAT seems to play an independent role in the pathogenesis of insulin resistance. This may be due to direct vascular effects influencing muscular blood flow.     

Hypolactasia is associated with insulin resistance in nonalcoholic steatohepatitis

AIM To assess lactase gene(LCT)-13910CT polymorphisms in Brazilian non-alcoholic fatty liver disease(NAFLD) and nonalcoholic steatohepatitis(NASH) patients in comparison with healthy controls.METHODS This was a transverse observational clinical study with NAFLD patients who were followed at the Hepatology Outpatient Unit of the Hospital das Clínicas, S?o Paulo, Brazil. The polymorphism of lactase non-persistence/lactase persistence(LCT-13910CT) was examined by PCR-restriction fragment length polymorphism technique in 102 liver biopsy-proven NAFLD patients(steatosis in 9 and NASH in 93) and compared to those of 501 unrelated healthy volunteers. Anthropometric, clinical, biochemical and liver histology data were analyzed. Continuous variables were compared using the t or Mann-Whitney tests, and categorical data were compared with the Fisher's exact test. Univariate logistic regression and multivariate logistic regression adjusted for gender and age were performed.RESULTS No differences in the LCT-13910 genotype frequencies were noted between the NAFLD patients(66.67% of the patients with steatosis were CC, 33.33% were CT, and none were TT; 55.91% of the patients with NASH were CC, 39.78% were CT, and 4.3% were TT; P = 0.941) and the healthy controls(59.12% were CC, 35.67% were CT, and 5.21% were TT) or between the steatosis and NASH patients. That is, the distribution of the lactase non-persistence/lactase persistence polymorphism(LCT-13910CT) in the patients with NAFLD was equal to that in the general population. In the NASH patients, the univariate analysis revealed that the lactase nonpersistence(low lactase activity or hypolactasia) phenotype was associated with higher insulin levels(23.47 ± 15.94 μU/m L vs 15.8 ± 8.33 μU/m L, P = 0.027) and a higher frequency of insulin resistance(91.84% vs 72.22%, P = 0.02) compared with the lactase persistence phenotype. There were no associations between the LCT genotypes and diabetes(P = 0.651), dyslipidaemia(P = 0.328), hypertension(P = 0.507) or liver histology in these patients. Moreover, in the NASH patients, hypolactasia was an independent risk factor for insulin resistance even after adjusting for gender and age [OR = 5.0(95%CI: 1.35-20; P = 0.017)].CONCLUSION The LCT-13910 genotype distribution in Brazilian NAFLD patients was the same as that of the general population, but hypolactasia increased the risk of insulin resistance in the NASH patients.     

Resistin is not associated with insulin sensitivity or the metabolic syndrome in humans

Aims/hypothesis The aim of this study was to further elucidate the relationship between resistin and insulin sensitivity, body fat distribution and the metabolic syndrome in humans.Methods We measured plasma resistin levels in 177 non-diabetic subjects (75 male, 102 female; age 32–75 years). BMI, waist circumference, blood pressure, lipids, glucose, plasminogen-activator inhibitor 1 (PAI-1), adiponectin and leptin levels were also measured. The insulin sensitivity index (S_I) was quantified using Bergmans minimal model. Intra-abdominal fat (IAF) and subcutaneous fat (SQF) areas were quantified by CT scan. Presence of metabolic syndrome criteria was determined using the National Cholesterol Education Program Adult Treatment Panel III guidelines.Results When subjects were divided into categories based on BMI (< or 27.5 kg/m²) and S_I (< or 7×10^–5 min^–1 [pmol/l]^–1), resistin levels did not differ between the lean, insulin-sensitive (n=53, 5.36±0.3 ng/ml), lean, insulin-resistant (n=67, 5.70±0.4 ng/ml) and obese, insulin-resistant groups (n=48, 5.94±0.4 ng/ml; ANOVA p=0.65). Resistin correlated with age (r=–0.22, p<0.01), BMI (r=0.16, p=0.03) and SQF (r=0.19, p=0.01) but not with S_I (p=0.31) or IAF (p=0.52). Resistin did not correlate with the number of metabolic syndrome criteria or any of the individual metabolic syndrome criteria. In contrast, adiponectin, PAI-1 and leptin each correlated with IAF, SQF and S_I. Additionally, the number of metabolic syndrome criteria correlated with adiponectin (r=–0.32, p<0.001), leptin (r=0.31, p<0.001) and PAI-1 (r=0.26, p=0.001).Conclusions/interpretation In contrast to other adipokines, resistin is only weakly associated with body fat and is unlikely to be a major mediator of insulin resistance or the metabolic syndrome in humans.