Elevated circulating adiponectin levels in liver cirrhosis are associated with reduced liver function and altered hepatic hemodynamics

Adiponectin is a novel adipocytokine negatively correlated with parameters of the metabolic syndrome, such as body mass index (BMI), body fat mass (BFM), and circulating insulin levels. Furthermore, metabolic actions directly on the liver have been described. The aim of the present study was to characterize circulating adiponectin levels, hepatic turnover, and the association of adiponectin with key parameters of hepatic as well as systemic metabolism in cirrhosis, a catabolic disease. Circulating adiponectin levels and hepatic turnover were investigated in 20 patients with advanced cirrhosis. Hepatic hemodynamics [portal pressure, liver blood flow, hepatic vascular resistance, indocyanine green (ICG) half-life], body composition, resting energy expenditure, hepatic free fatty acids (FFA) and glucose turnover, and circulating levels of hormones (catecholamines, insulin, glucagon) and proinflammatory cytokines (IL-1beta, TNF-alpha, IL-6) were also assessed. Circulating adiponectin increased dependently on the clinical stage in cirrhosis compared with controls (15.2 +/- 1.7 vs. 8.2 +/- 1.1 microg/ml, respectively, P < 0.01), whereas hepatic extraction decreased. Adiponectin was negatively correlated with parameters of hepatic protein synthesis (prothrombin time: r = -0.62, P = 0.003; albumin: r = -0.72, P < 0.001) but not with transaminases or parameters of lipid metabolism. In addition, circulating adiponectin increased with portal pressure (r = 0.67, P = 0.003), hepatic vascular resistance (r = 0.60, P = 0.008), and effective hepatic blood flow (ICG half-life: r = 0.69, P = 0.001). Adiponectin in cirrhosis was not correlated with BMI, BFM, parameters of energy metabolism, insulin levels, hepatic FFA and glucose turnover, and circulating proinflammatory cytokines. These results demonstrate that 1) adiponectin plasma levels in cirrhosis are significantly elevated, 2) the liver is a major source of adiponectin extraction, and 3) adiponectin levels in cirrhosis do not correlate with parameters of body composition or metabolism but exclusively with reduced liver function and altered hepatic hemodynamics.     

Effect of liver fat on insulin clearance

A fatty liver is associated with fasting hyperinsulinemia, which could reflect either impaired insulin clearance or hepatic insulin action. We determined the effect of liver fat on insulin clearance and hepatic insulin sensitivity in 80 nondiabetic subjects [age 43 +/- 1 yr, body mass index (BMI) 26.3 +/- 0.5 kg/m(2)]. Insulin clearance and hepatic insulin resistance were measured by the euglycemic hyperinsulinemic (insulin infusion rate 0.3 mU.kg(-1).min(-1) for 240 min) clamp technique combined with the infusion of [3-(3)H]glucose and liver fat by proton magnetic resonance spectroscopy. During hyperinsulinemia, both serum insulin concentrations and increments above basal remained approximately 40% higher (P < 0.0001) in the high (15.0 +/- 1.5%) compared with the low (1.8 +/- 0.2%) liver fat group, independent of age, sex, and BMI. Insulin clearance (ml.kg fat free mass(-1).min(-1)) was inversely related to liver fat content (r = -0.52, P < 0.0001), independent of age, sex, and BMI (r = -0.37, P = 0.001). The variation in insulin clearance due to that in liver fat (range 0-41%) explained on the average 27% of the variation in fasting serum (fS)-insulin concentrations. The contribution of impaired insulin clearance to fS-insulin concentrations increased as a function of liver fat. This implies that indirect indexes of insulin sensitivity, such as homeostatic model assessment, overestimate insulin resistance in subjects with high liver fat content. Liver fat content correlated significantly with fS-insulin concentrations adjusted for insulin clearance (r = 0.43, P < 0.0001) and with directly measured hepatic insulin sensitivity (r = -0.40, P = 0.0002). We conclude that increased liver fat is associated with both impaired insulin clearance and hepatic insulin resistance. Hepatic insulin sensitivity associates with liver fat content, independent of insulin clearance.     

Correlation between Serum Resistin Level and Adiposity in Obese Individuals

Objective: Resistin is associated with insulin resistance in mice and may play a similar role in humans. The aim of our study was to examine the relationship of serum resistin level to body composition, insulin resistance, and related obesity phenotypes in humans. Research Methods and Procedures: Sixty‐four young (age 32 ± 10 years), obese (BMI 32.9 ± 5.6), nondiabetic subjects taking no medication, and 15 lean (BMI 21.1 ± 1.3) volunteers were studied cross‐sectionally. Thirty‐five of the subjects were also reevaluated after 1.5 years on a weight reduction program entailing dieting and exercise; changes of serum resistin were compared with changes of BMI, body composition, fat distribution, and several indices of insulin sensitivity derived from plasma glucose and serum insulin levels measured during 75‐g oral glucose tolerance test. Results: In a cross‐sectional analysis, serum resistin was significantly higher in obese subjects than in lean volunteers (24.58 ± 12.93 ng/mL; n = 64 vs. 12.83 ± 8.30 ng/mL; n = 15; p < 0.01), and there was a correlation between resistin level and BMI, when the two groups were combined (ρ = 0.35, p < 0.01). Although cross‐sectional analysis in obese subjects revealed no correlation between serum resistin and parameters related to adiposity or insulin resistance, longitudinal analysis revealed change in serum resistin to be positively correlated with changes in BMI, body fat, fat mass, visceral fat area, and mean glucose and insulin (ρ = 0.39, 0.40, 0.44, 0.50, 0.40, and 0.50; p = 0.02, 0.03, 0.02, <0.01, 0.02, and <0.01, respectively). Discussion: Resistin appears to be related to human adiposity and to be a possible candidate factor in human insulin resistance.     

Fatty liver in type 2 diabetes mellitus: relation to regional adiposity,fatty acids,and insulin resistance

The current study was undertaken to examine metabolic and body composition correlates of fatty liver in type 2 diabetes mellitus (DM). Eighty-three men and women with type 2 DM [mean body mass index (BMI): 34 +/- 0.5 kg/m2] and without clinical or laboratory evidence of liver dysfunction had body composition assessments of fat mass (FM), visceral adipose tissue (VAT), liver and spleen computed tomography (CT) attenuation (ratio of liver to spleen), muscle CT attenuation, and thigh adiposity; these assessments were also performed in 12 lean and 15 obese nondiabetic volunteers. Insulin sensitivity was measured with a euglycemic insulin infusion (40 mU. m-2. min-1) combined with systemic indirect calorimetry to assess glucose and lipid oxidation, and with infusions of [2H2]glucose for assessment of endogenous glucose production. A majority of those with type 2 DM (63%) met CT criteria for fatty liver, compared with 20% of obese and none of the lean nondiabetic volunteers. Fatty liver was most strongly correlated with VAT (r = -0.57, P < 0.0001) and less strongly but significantly associated with BMI (r = -0.42, P < 0.001) and FM (r = -0.37, P < 0.001), but only weakly associated with subcutaneous adiposity (r = -0.29; P < 0.01). Fatty liver was also correlated with subfascial adiposity of skeletal muscle (r = -0.44; P < 0.01). Volunteers with type 2 DM and fatty liver were substantially more insulin resistant those with type 2 DM but without fatty liver (P < 0.001) and had higher levels of plasma free fatty acids (P < 0.01) and more severe dyslipidemia (P < 0.01), a pattern observed in both genders. Plasma levels of cytokines were increased in relation to fatty liver (r = -0.34; P < 0.01). In summary, fatty liver is relatively common in overweight and obese volunteers with type 2 DM and is an aspect of body composition related to severity of insulin resistance, dyslipidemia, and inflammatory markers.     

Acquired obesity is associated with increased liver fat, intra-abdominal fat, and insulin resistance in young adult monozygotic twins

We determined whether acquired obesity is associated with increases in liver or intra-abdominal fat or impaired insulin sensitivity by studying monozygotic (MZ) twin pairs discordant and concordant for obesity. We studied nineteen 24- to 27-yr-old MZ twin pairs, with intrapair differences in body weight ranging from 0.1 to 24.7 kg [body mass index (BMI) range 20.0-33.9 kg/m2], identified from a population-based FinnTwin16 sample. Fat distribution was determined by magnetic resonance imaging, percent body fat by dual-energy X-ray absorptiometry, liver fat by proton spectroscopy, insulin sensitivity by measuring the fasting insulin concentration, and whole body insulin sensitivity by the euglycemic insulin clamp technique. Intrapair differences in BMI were significantly correlated with those in intra-abdominal fat (r = 0.82, P < 0.001) and liver fat (r = 0.57, P = 0.010). Intrapair differences in fasting insulin correlated with those in subcutaneous abdominal (r = 0.60, P = 0.008), intra-abdominal (r = 0.75, P = 0.0001) and liver (r = 0.49, P = 0.048) fat. Intrapair differences in whole body insulin sensitivity correlated with those in subcutaneous abdominal (r = -0.72, P = 0.001) and intra-abdominal (r = -0.55, P = 0.015) but not liver (r = -0.20, P = 0.20) fat. We conclude that acquired obesity is associated with increases in intra-abdominal and liver fat and insulin resistance, independent of genetic factors.     

Physical training reverses the increased activity of the hepatic ketone body synthesis pathway in chronically diabetic rats

This study was designed to examine whether the training-induced improvement in the plasma concentration of ketone bodies in experimental diabetes mellitus could be explained by changes in the activity of the hepatic ketone body synthesis pathway and/or the plasma free fatty acid levels. Diabetes mellitus was induced by an intravenous injection of streptozotocin (50 mg/kg), and training was carried out on a treadmill. The plasma concentration of beta-hydroxybutyric acid was increased (P < 0.001) in sedentary diabetic rats, and this was partly reversed by training (P < 0.001). The plasma concentration of free fatty acids was increased (P < 0.001) in sedentary diabetic rats, and this was reversed to normal by training (P < 0.001). Diabetes was also associated with an increased activity of the hepatic ketone body synthesis pathway. When the data are expressed as per total liver, physical training decreased the activity of the hepatic ketone body synthesis pathway by 18% in nondiabetic rats (P < 0.05) and by 22% in diabetic rats (P < 0.01), the activity present in trained diabetic rats being not statistically different from that of sedentary control rats. These data suggest that the beneficial effects of physical training on the plasma beta-hydroxybutyric acid levels in the diabetic state are probably explained in part by a decrease in the activity of the hepatic ketone body synthesis pathway and in part by a decrease in plasma free fatty acid levels.     

Short-term pioglitazone treatment prevents free fatty acid-induced hepatic insulin resistance in normal rats: possible role of the resistin and adiponectin

We have evaluated the effects of a 2 week treatment with pioglitazone (Pio, 4mg/kg x d) on hepatic and peripheral insulin sensitivity, plasma adiponectin, and resistin concentrations in lipid-infused rats. Lipid infusion caused a large (60% in 4h) decrease in whole-body insulin sensitivity. Hepatic and peripheral insulin resistance contributed about equally to the whole-body insulin resistance. Pio treatment significantly improved whole-body insulin sensitivity due to normalization of hepatic insulin action, whereas peripheral insulin action remained unchanged and inhibited. Basal plasma resistin levels were approximately 4-fold lower in Pio-treated than in untreated rats. During lipid infusion, resistin levels rose in both Pio-treated and untreated rats, but remained significantly lower in Pio-treated than in untreated rats (P<0.01). Dot-blot analyses revealed a marked decrease in resistin protein levels in the liver of Pio-treated rats. Resistin levels were higher in muscle tissue in lipid group compared with control and Pio-treated rats (P<0.05). Fasting plasma adiponectin levels were 1.5-fold higher in Pio-treated than in untreated rats. We conclude that short-term treatment of rats with Pio prevented lipid-induced hepatic insulin resistance and that Pio mediated lowering of blood resistin and raising of adiponectin levels may have contributed to that effect.     

Abdominal fat distribution and peripheral and hepatic insulin resistance in type 2 diabetes mellitus

We examined the relationship between peripheral/hepatic insulin sensitivity and abdominal superficial/deep subcutaneous fat (SSF/DSF) and intra-abdominal visceral fat (VF) in patients with type 2 diabetes mellitus (T2DM). Sixty-two T2DM patients (36 males and 26 females, age = 55 +/- 3 yr, body mass index = 30 +/- 1 kg/m2) underwent a two-step euglycemic insulin clamp (40 and 160 mU. m(-2). min(-1)) with [3-3H]glucose. SSF, DSF, and VF areas were quantitated with magnetic resonance imaging at the L(4-5) level. Basal endogenous glucose production (EGP), hepatic insulin resistance index (basal EGP x FPI), and total glucose disposal (TGD) during the first and second insulin clamp steps were similar in male and female subjects. VF (159 +/- 9 vs. 143 +/- 9 cm2) and DSF (199 +/- 14 vs. 200 +/- 15 cm(2)) were not different in male and female subjects. SSF (104 +/- 8 vs. 223 +/- 15 cm2) was greater (P < 0.0001) in female vs. male subjects despite similar body mass index (31 +/- 1 vs. 30 +/- 1 kg/m2) and total body fat mass (31 +/- 2 vs. 33 +/- 2 kg). In male T2DM, TGD during the first insulin clamp step (1st TGD) correlated inversely with VF (r = -0.45, P < 0.01), DSF (r = -0.46, P < 0.01), and SSF (r = -0.39, P < 0.05). In males, VF (r = 0.37, P < 0.05), DSF (r = 0.49, P < 0.01), and SSF (r = 0.33, P < 0.05) were correlated positively with hepatic insulin resistance. In females, the first TGD (r = -0.45, P < 0.05) and hepatic insulin resistance (r = 0.49, P < 0.05) correlated with VF but not with DSF, SSF, or total subcutaneous fat area. We conclude that visceral adiposity is associated with both peripheral and hepatic insulin resistance, independent of gender, in T2DM. In male but not female T2DM, deep subcutaneous adipose tissue also is associated with peripheral and hepatic insulin resistance.     

Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity

Fatty liver is frequent in the apolipoprotein B (apoB)-defective genetic form of familial hypobetalipoproteinemia (FHBL), but interindividual variability in liver fat is large. To explain this, we assessed the roles of metabolic factors in 32 affected family members with apoB-defective FHBL and 33 related and unrelated normolipidemic controls matched for age, sex, and indices of adiposity. Two hour, 75 g oral glucose tests, with measurements of plasma glucose and insulin levels, body mass index, and waist-hip ratios were obtained. Abdominal subcutaneous, intraperitoneal (IPAT), and retroperitoneal adipose tissue masses were quantified by MR imaging, and hepatic fat was quantified by MR spectroscopy. Mean +/- SD liver fat percentage values of FHBL and controls were 14.8 +/- 12.0 and 5.2 +/- 5.9, respectively (P = 0.001). Means for these measures of obesity and insulin action were similar in the two groups. Important determinants of liver fat percentage were FHBL-affected status, IPAT, and area under the curve (AUC) insulin in both groups, but the strongest predictors were IPAT in FHBL (partial R(2) = 0.55, P < 0.0002) and AUC insulin in controls (partial R(2) = 0.59, P = 0.0001). Regression of liver fat percentage on IPAT fat was significantly greater for FHBL than for controls (P < 0.001). In summary, because apoB-defective FHBL imparts heightened susceptibility to liver triglyceride accumulation, increasing IPAT and insulin resistance exert greater liver fat-increasing effects in FHBL.     

Intramyocellular lipid and insulin resistance: differential relationships in European and African Americans

Insulin resistance has been associated with the accumulation of fat within skeletal muscle fibers as intramyocellular lipid (IMCL). Here, we have examined in a cross-sectional study the interrelationships among IMCL, insulin sensitivity, and adiposity in European Americans (EAs) and African Americans (AAs). In 43 EA and 43 AA subjects, we measured soleus IMCL content with proton-magnetic resonance spectroscopy, insulin sensitivity with hyperinsulinemic-euglycemic clamp, and body composition with dual-energy X-ray absorptiometry. The AA and EA subgroups had similar IMCL content, insulin sensitivity, and percent fat, but only in EA was IMCL correlated with insulin sensitivity (r = -0.47, P < 0.01), BMI (r = 0.56, P < 0.01), percent fat (r = 0.35, P < 0.05), trunk fat (r = 0.47, P < 0.01), leg fat (r = 0.40, P < 0.05), and waist and hip circumferences (r = 0.54 and 0.55, respectively, P < 0.01). In a multiple regression model including IMCL, race, and a race by IMCL interaction, the interaction was found to be a significant predictor (t = 1.69, DF = 1, P = 0.0422). IMCL is related to insulin sensitivity and adiposity in EA but not in AA, suggesting that IMCL may not function as a pathophysiological factor in individuals of African descent. These results highlight ethnic differences in the determinants of insulin sensitivity and in the pathogenesis of the metabolic syndrome trait cluster.     

Resistin and adiponectin levels in subjects with coronary artery disease and type 2 diabetes

BACKGROUND: Resistin and adiponectin are implicated in insulin resistance and atherosclerosis. The objective of this study was to evaluate the association between plasma resistin levels and the presence of coronary artery disease (CAD) or diabetes compared to the controls. In a cross-sectional study, we measured glucose, fasting lipid panel, resistin, adiponectin, insulin, C-reactive protein (CRP) and TNF-alpha in 57 subjects with CAD, 58 subjects with diabetes compared to 45 normal control subjects. Results: Subjects with CAD compared to the control subjects had increased insulin resistance index (39+/-32 vs. 13.45+/-12.73 with p<0.0001), CRP levels (3.8+/-4.03 vs. 2.0+/-2.0 with p<0.05) and decreased levels of adiponectin (12.5+/-4.8 vs. 17.26+/-10.4 with p<0.0003). Subjects with diabetes compared to the controls had had increased insulin resistance index (69+/-19 vs. 13.45+/-12.73 with p<0.001), CRP levels (4.1+/-4.8 vs. 2.0+/-2.0 with p<0.01) and decreased levels of adiponectin (11.58+/-4.8 vs. 17.26+/-10.4 with p<0.001). Compared to the controls, there was no significant difference in the levels of resistin in subjects with CAD (4.92+/-3.2 vs. 4.1+/-2.4) as well as diabetes (4.92+/-3.2 vs. 4.6+/-2.6). Both CRP and resistin levels correlate with TNF-alpha (r=0.557, p<0.000001; r=0.84, p<0.000001). Conclusions: The present study shows decreased plasma adiponectin levels in subjects with diabetes as well as in subjects with CAD is similar to the literature. Plasma levels of resistin in subjects with CAD or diabetes are similar to the controls. However, there was a strong correlation of resistin levels with inflammatory markers. This suggests resistin as an inflammatory marker associated with CAD.     

Fatty liver in familial hypobetalipoproteinemia: triglyceride assembly into VLDL particles is affected by the extent of hepatic steatosis

Familial hypobetalipoproteinemia (FHBL) subjects may develop fatty liver. Liver fat was assessed in 21 FHBL with six different apolipoprotein B (apoB) truncations (apoB-4 to apoB-89) and 14 controls by magnetic resonance spectroscopy (MRS). Liver fat percentages were 16.7 +/- 11.5 and 3.3 +/- 2.9 (mean +/- SD) (P = 0.001). Liver fat percentage was positively correlated with body mass index, waist circumference, and areas under the insulin curves of 2 h glucose tolerance tests, suggesting that obesity may affect the severity of liver fat accumulation in both groups. Despite 5-fold differences in liver fat percentage, mean values for obesity and insulin indexes were similar. Thus, for similar degrees of obesity, FHBL subjects have more hepatic fat. VLDL-triglyceride (TG)-fatty acids arise from plasma and nonplasma sources (liver and splanchnic tissues). To assess the relative contributions of each, [2H2]palmitate was infused over 12 h in 13 FHBL subjects and 11 controls. Isotopic enrichment of plasma free palmitate and VLDL-TG-palmitate was determined by mass spectrometry. Non-plasma sources contributed 51 +/- 15% in FHBL and 37 +/- 13% in controls (P = 0.02). Correlations of liver fat percentage and percent VLDL-TG-palmitate from liver were r = 0.89 (P = 0.0001) for FHBL subjects and r = 0.69 (P = 0.01) for controls. Thus, apoB truncation-producing mutations result in fatty liver and in altered assembly of VLDL-TG.     

Effects of insulin therapy on liver fat content and hepatic insulin sensitivity in patients with type 2 diabetes

We determined whether insulin therapy changes liver fat content (LFAT) or hepatic insulin sensitivity in type 2 diabetes. Fourteen patients with type 2 diabetes (age 51+/-2 yr, body mass index 33.1+/-1.4 kg/m2) treated with metformin alone received additional basal insulin for 7 mo. Liver fat (proton magnetic resonance spectroscopy), fat distribution (MRI), fat-free and fat mass, and whole body and hepatic insulin sensitivity (6-h euglycemic hyperinsulinemic clamp combined with infusion of [3-(3)H]glucose) were measured. The insulin dose averaged 75+/-10 IU/day (0.69+/-0.08 IU/kg, range 24-132 IU/day). Glycosylated hemoglobin A1c (Hb A1c) decreased from 8.9+/-0.3 to 7.4+/-0.2% (P<0.001). Whole body insulin sensitivity increased from 2.21+/-0.38 to 3.08+/-0.40 mg/kg fat-free mass (FFM).min (P<0.05). This improvement could be attributed to enhanced suppression of hepatic glucose production (HGP) by insulin (HGP 1.04+/-0.28 vs. 0.21+/-0.19 mg/kg FFM.min, P<0.01). The percent suppression of HGP by insulin increased from 72+/-8 to 105+/-11% (P<0.01). LFAT decreased from 17+/-3 to 14+/-3% (P<0.05). The change in LFAT was significantly correlated with that in hepatic insulin sensitivity (r=0.56, P<0.05). Body weight increased by 3.0+/-1.1 kg (P<0.05). Of this, 83% was due to an increase in fat-free mass (P<0.01). Fat distribution and serum adiponectin concentrations remained unchanged while serum free fatty acids decreased significantly. Conclusions: insulin therapy improves hepatic insulin sensitivity and slightly but significantly reduces liver fat content, independent of serum adiponectin.     

Increased insulin sensitivity in patients with anorexia nervosa: the role of adipocytokines

Anorexia nervosa (AN) is characterized by self-induced starvation leading to severe weight and fat loss. In the present study, we measured fasting plasma levels of adiponectin, leptin, resistin, insulin and glucose in 10 women with a restrictive type of AN and in 12 healthy women (C). Insulin sensitivity was determined according to homeostasis model assessment of insulin resistance (HOMA-R). Plasma resistin, leptin and insulin levels were significantly decreased, whereas plasma adiponectin levels were significantly increased in patients with AN compared to the C. HOMA-R was significantly decreased in patients with AN compared to the C group. Plasma adiponectin and leptin concentrations negatively and positively correlated with the body mass index and percentage body fat in both groups. Plasma adiponectin levels were negatively related to plasma insulin levels in the AN group only. In conclusion, we demonstrated that AN is associated with significantly decreased plasma leptin and resistin levels, markedly increased plasma adiponectin levels and increased insulin sensitivity. Plasma leptin and adiponectin levels were related to the body size and adiposity. Hyperadiponectinemia could play a role in increased insulin sensitivity of patients with AN. Neither body size and adiposity nor insulin sensitivity are the major determinants of plasma resistin levels in AN.     

Early undernutrition induces glucagon resistance and insulin hypersensitivity in the liver of suckling rats

Developing brains are vulnerable to nutritional insults. Early undernutrition alters their structure and neurochemistry, inducing long-term pathological effects whose causal pathways are not well defined. During suckling, the brain uses glucose and ketone bodies as substrates. Milk is a high-fat low-carbohydrate diet, and the liver must maintain high rates of gluconeogenesis and ketogenesis to address the needs of these substrates. Insulin and glucagon play major roles in this adaptation: throughout suckling, their blood concentrations are low and high, respectively, and the liver maintains low insulin sensitivity and increased glucagon responsiveness. We propose that disturbances in the endocrine profile and available plasma substrates along with undernutrition-related changes in brain cortex capacity for ketone utilization may cause further alterations in some brain functions. We explored this hypothesis in 10-day-old suckling rats whose mothers were severely food restricted from the 14th day of gestation. We measured the plasma/serum concentrations of glucose, ketone body, insulin and glucagon, and hepatic insulin and glucagon responses. Undernutrition led to hypoglycemia and hyperketonemia to 84% (P < 0.001) and 144% (P < 0.001) of control values, respectively. Liver responsiveness to insulin and glucagon became increased and reduced, respectively; intraperitoneal glucagon reduced liver glycogen by 90% (P < 0.01) in control and by 35% (P < 0.05) in restricted. Cortical enzymes of ketone utilization remained unchanged, but their carrier proteins were altered: monocarboxylate transporter (MCT) 1 increased: 73 ± 14, controls; 169 ± 20, undernourished (P < 0.01; densitometric units); MCT2 decreased: 103 ± 3, controls; 37 ± 4, undernourished (P < 0.001; densitometric units). All of these changes, coinciding with the brain growth spurt, may cause some harmful effects associated with early undernutrition.     

Hyperthyroidism is associated with higher plasma endothelin-1 concentrations

The objective of this study was to determine the change of plasma endothelin (ET)-1 concentrations and insulin resistance index after therapy for hyperthyroidism. We studied 20 patients with hyperthyroidism (15 women and 5 men; age, 34.0 +/- 2.8 years), and 31 patients with euthyroid goiters as controls (27 women, 4 men; age, 37.0 +/- 2.4 years). All hyperthyroid patients were treated with antithyroid drugs. The patients received evaluations before and after normalization of thyroid function. The evaluations included body mass index (BMI), body fat, and measurement of circulating concentrations of thyroid hormones, glucose, insulin, and ET-1. Hyperthyroid subjects had higher plasma ET-1 concentrations than the control group (P < 0.001). No significant differences in serum glucose and insulin concentrations or insulin resistance index estimated by the R value of the homeostasis model assessment (HOMA-R) were noted between the groups. Plasma ET-1 concentrations decreased after correction of hyperthyroidism compared with pretreatment (P = 0.006). Serum glucose concentrations decreased after correction of hyperthyroidism (P = 0.005). Moreover, both body weight-adjusted insulin concentrations and the HOMA-R index were also decreased after correction of hyperthyroidism compared with pretreatment (P = 0.026 and P = 0.019, respectively). Pearson's correlation revealed that plasma ET-1 levels positively correlated with serum triiodothyronine (T3) and free thyroxine (FT4) levels. Serum insulin levels and the HOMA-R index positively correlated with BMI and body fat. The HOMA-R index also positively correlated with serum T3 and FT4 levels. Neither insulin levels nor the HOMA-R index correlated with ET-1 levels. Hyperthyroidism is associated with higher plasma ET-1 concentrations. In addition, correction of hyperthyroidism is also associated with a decrease of plasma ET-1 levels as well as the insulin resistance index calculated by HOMA-R.     

Normal insulin sensitivity and IMCL content in overweight humans are associated with higher fasting lipid oxidation

Intramyocellular lipid (IMCL) storage is considered a local marker of whole body insulin resistance; because increments of body weight are supposed to impair insulin sensitivity, this study was designed to assess IMCL content, lipid oxidation, and insulin action in individuals with a moderate increment of body fat mass and no family history of diabetes. We studied 14 young, nonobese women with body fat <30% (n = 7) or >30% (n = 7) and 14 young, nonobese men with body fat <25% (n = 7) or >25% (n = 7) by means of the euglycemic-insulin clamp to assess whole body glucose metabolism, with indirect calorimetry to assess lipid oxidation, by localized (1)H NMR spectroscopy of the calf muscles to assess IMCL content, and with dual-energy X-ray absorptiometry to assess body composition. Subjects with higher body fat had normal insulin-stimulated glucose disposal (P = 0.80), IMCL content in both soleus (P = 0.22) and tibialis anterior (P = 0.75) muscles, and plasma free fatty acid levels (P = 0.075) compared with leaner subjects in association with increased lipid oxidation (P < 0.05), resting energy expenditure (P = 0.046), resting oxygen consumption (P = 0.049), and plasma leptin levels (P < 0.01) in the postabsorptive condition. In conclusion, in overweight subjects, preservation of insulin sensitivity was combined with increased lipid oxidation and maintenance of normal IMCL content, suggesting that abnormalities of these factors may mutually determine the development of insulin resistance associated with weight gain.     

Clinical characteristics of OGTT-derived hepatic- and muscle insulin resistance in healthy young men

[Purpose]

Insulin inhibits glucose release in the liver but increases glucose absorption in muscles. When insulin cannot properly control glucose, it negatively affects glucose metabolism and, furthermore, contributes to the onset of metabolic syndrome and chronic disease. Therefore, this study''s goal is to understand the clinical characteristics of hepatic insulin resistance and muscle insulin sensitivity in healthy young men.

[Methods]

Twenty-eight healthy young men (age 23.3 ± 0.5; mean ± SE) participated in this study. Liver function and blood lipids were measured by blood sampling from brachial vein after participants fasted the previous day. Hepatic insulin resistance and muscle insulin sensitivity were evaluated using two-hour OGTT along with surrogate index related to insulin sensitivity. The VO_2max was evaluated using cycle ergometer. Systemic insulin sensitivity was evaluated using two-hour euglycemic hyperinsulinemic clamp method.

[Results]

Hepatic insulin resistance showed a significant correlation with body fat (r = 0.609, p < 0.05). Also, hepatic insulin resistance showed a significant correlation with GOT (r = 0.467), GPT (r = 0.434), and γ-GTP (r = 0.375), reflecting liver functions, as well as showing a significant correlation with hs-CRP (r = 0.492, p < 0.05). On the other hand, muscle insulin sensitivity had no correlation with neither body fat nor liver function index (p > 0.05), and among surrogate indexes, it showed a significant correlation with Avignon (r = -0.493) and Matsuda index (r = -0.577). Glucose infusion rate, using the clamp method, showed a significant correlation with muscle insulin sensitivity (r = 0.448, p < 0.05). The VO_2max had a significant correlation with hepatic insulin resistance (r = -0.435, p < 0.05) and muscle insulin sensitivity (r = 0.474, p < 0.05), respectively.

[Conclusion]

For young men in their 20''s, the OGTT-based hepatic insulin sensitivity was an indicator of hepatic function and body fat but muscle insulin sensitivity was related to peripheral insulin sensitivity. Also, for young men, higher VO_2max indicated lower hepatic insulin resistance and higher muscle insulin sensitivity.     

Liver fat reduction with niacin is influenced by DGAT-2 polymorphisms in hypertriglyceridemic patients

Niacin reduces plasma triglycerides, but it may increase free fatty acids and insulin resistance during long-term treatment. We examined the effect of extended-release niacin on liver fat content in Chinese patients with dyslipidemia and whether the common diacylglycerol acyltransferase-2 (DGAT2) polymorphisms influenced this effect. The 39 patients (baseline liver fat content: 12.8 ± 7.6%, triglycerides: 3.30 ± 1.67 mmol/l) were treated with niacin, gradually increasing the dose to 2 g/day for a total of 23 weeks. The liver fat content and visceral/subcutaneous fat was measured before and after treatment. Subjects were genotyped for the DGAT2 rs3060 and rs101899116 polymorphisms. There were significant (P < 0.001) reductions in plasma triglycerides (-34.9 ± 37.6%), liver fat content (-47.2 ± 32.8%), and visceral fat (-6.3 ± 15.8%, P < 0.05) after niacin treatment. Mean body weight decreased by 1.46 ± 2.7% (1.17 ± 2.44 kg, P < 0.001) during the study, but liver fat changes remained significant after adjustment for age, gender, and body weight changes [mean absolute change (95% CI): -6.1% (-8.0, -4.3), P < 0.001]. The DGAT2 variant alleles were associated with a smaller reduction in liver fat content in response to niacin after adjustment for other covariates (P < 0.01). These findings suggest that niacin treatment may reduce liver fat content in Chinese patients with dyslipidemia and that the mechanism may involve inhibition of DGAT2. However, the findings might have been confounded by the small but significant reductions in body weight during the study. Future large randomized controlled trials are needed to verify these findings.     

Long-time alcohol intake modifies resistin secretion and expression of resistin gene in adipose tissue

Elevated serum resistin is implicated in insulin resistance associated with obesity and type 2 diabetes mellitus. Alcohol consumption interferes with the nutritional status, metabolic and hormonal activity of the drinker. Impact of ethanol intake on resistin level and resistin metabolic effects is unknown. Effect of long-time (28 days) ad libitum moderate alcohol (6% ethanol solution) intake on serum resistin and resistin mRNA level in adipose tissue of rats (A) was compared to control (C) and pair-fed (PF) animals. PF rats were fed the same caloric amount as A rats on previous day. Alcohol consumption resulted in reduction of food and energy intake, decreased body mass gain, epididymal fat pads mass and smaller adipocytes (vs. C rats). Alcohol intake significantly increased serum resistin and glucose, insulinemia remained unchanged. Systemic insulin resistance was not proved by HOMA, QUICKI and McAuley indexes, but impaired insulin effect on glucose transport in isolated adipocytes was present. Elevated serum resistin was positively correlated with glycemia (r = 0.88, p < 0.01) and negatively with fat cell size (r = -0.73, p < 0.05). High resistin level as the consequence of long-time alcohol intake could contribute to smaller adipocytes, higher glycemia, attenuation of insulin-stimulated glucose transport in adipocytes. Diminished resistin gene expression in adipose tissue of A and PF rats was present.