Aims/hypothesis: We determined whether hepatic fat content and plasma adiponectin concentration regulate VLDL 1 production. Methods: A multicompartment model was used to simultaneously determine the kinetic parameters of triglycerides (TGs) and apolipoprotein B (ApoB) in VLDL 1 and VLDL 2 after a bolus of [ 2 H 3 ]leucine and [ 2 H 5 ]glycerol in ten men with type 2 diabetes and in 18 non-diabetic men. Liver fat content was determined by proton spectroscopy and intra-abdominal fat content by MRI. Results: Univariate regression analysis showed that liver fat content, intra-abdominal fat volume, plasma glucose, insulin and HOMA-IR (homeostasis model assessment of insulin resistance) correlated with VLDL 1 TG and ApoB production. However, only liver fat and plasma glucose were significant in multiple regression models, emphasising the critical role of substrate fluxes and lipid availability in the liver as the driving force for overproduction of VLDL 1 in subjects with type 2 diabetes. Despite negative correlations with fasting TG levels, liver fat content, and VLDL 1 TG and ApoB pool sizes, adiponectin was not linked to VLDL 1 TG or ApoB production and thus was not a predictor of VLDL 1 production. However, adiponectin correlated negatively with the removal rates of VLDL 1 TG and ApoB. Conclusions/interpretation: We propose that the metabolic effect of insulin resistance, partly mediated by depressed plasma adiponectin levels, increases fatty acid flux from adipose tissue to the liver and induces the accumulation of fat in the liver. Elevated plasma glucose can further increase hepatic fat content through multiple pathways, resulting in overproduction of VLDL 1 particles and leading to the characteristic dyslipidaemia associated with type 2 diabetes.

To determine causes of interindividual variation in insulin requirements, we recruited 20 type 2 diabetic patients with stable glucose control and insulin doses for >1 year on combination therapy with bedtime NPH insulin and metformin. Insulin absorption (increase in free and total insulin over 8 h after a subcutaneous dose of regular insulin) and actions of intravenous (6-h 0.3 mU · kg -1 · min -1 euglycemic insulin clamp combined with [3-3 H]glucose) and subcutaneous (glucose infusion rate required to maintain isoglycemia and suppression of free fatty acids [FFAs]) insulin, liver fat content (proton spectroscopy), visceral fat (magnetic resonance imaging), weight, and body composition were determined. We found the following variation in parameters: insulin dose range 10-176 U (mean 42 U, fold variation 17.6؋) or 0.13-1.39 U/kg (0.44 U/kg, 10.7؋), absorbed insulin 10.6؋, action of subcutaneous insulin to suppress FFAs 7.5؋ and to stimulate glucose metabolism (M value) 11.5؋, body weight 67-127 kg (91 kg, 1.9؋), liver fat 2-28% (12%, 14؋), and visceral fat 179-2,053 ml (1,114 ml, 11.5؋). The amount of insulin absorbed, measured as either free or total insulin, was significantly correlated with its ability to suppress FFAs and stimulate glucose metabolism but not with the insulin dose per se. The actions of absorbed insulin were, on the other hand, significantly correlated with the daily insulin dose (r = 0.70 for action on FFAs, P < 0.001, and r = -0.61 for M value, P < 0.005). Actions of subcutaneous and intravenous insulin to suppress FFAs were significantly correlated (r = 0.82, P < 0.001, R 2 = 67%). Of the measures of adiposity, the percent hepatic fat was the parameter best correlated with the daily insulin dose (r = 0.76, P < 0.001). The percent hepatic fat was also significantly correlated with the ability of intravenous insulin to suppress endogenous glucose production (r = 0.72, P < 0.005). We conclude that the major reason for interindividual variation in insulin requirements in type 2 diabetes is the variation in insulin action. Variation in hepatic fat content may influence insulin requirements via an effect on the sensitivity of endogenous glucose production to insulin. Diabetes 49:749-758, 2000

Liver fat content is significantly increased in subjects with the metabolic syndrome as compared with those without the syndrome, independently of age, gender, and body mass index. Of other markers, serum C-peptide is the strongest correlate of liver fat.

We determined whether interindividual variation in hepatic insulin sensitivity could be attributed to variation in liver fat content (LFAT) independent of obesity. We recruited 30 healthy nondiabetic men whose LFAT (determined by proton spectroscopy); intraabdominal, sc, and total (determined by magnetic resonance imaging) fat; and insulin sensitivity of endogenous glucose rate of production (R(a)) and suppression of serum FFA [euglycemic insulin clamp combined with [3-(3)H]glucose (0-300 min); insulin infusion rate, 0.3 mU/kg.min, 120-300 min] were measured. The men were divided into groups of low (mean +/- SD, 1.7 +/- 0.2%) and high (10.5 +/- 2.0%) LFAT based on their median fat content. The low and high LFAT groups were comparable with respect to age (44 +/- 2 vs. 42 +/- 2 yr), body mass index (25 +/- 1 vs. 26 +/- 1 kg/m(2) ), waist to hip ratio (0.953 +/- 0.013 vs. 0.953 +/- 0.013), maximal oxygen uptake (35.6 +/- 1.5 vs. 33.5 +/- 1.5 ml/kg.min), and intraabdominal, sc, and total fat. The high compared with the low LFAT group had several features of insulin resistance, including fasting hyperinsulinemia (7.3 +/- 0.6 vs. 5.3 +/- 0.6 mU/liter; P< 0.02, high vs. low LFAT) hypertriglyceridemia (1.4 +/- 0.2 vs. 0.9 +/- 0.1 mmol/liter; P < 0.02), a low high density lipoprotein (HDL) cholesterol concentration (1.4 +/- 0.1 vs. 1.6 +/- 0.1 mmol/liter; P < 0.05), and a higher ambulatory 24-h systolic blood pressure (130 +/- 3 vs. 122 +/- 3 mm Hg; P < 0.05). Basal glucose R(a) and serum FFA were comparable between the groups, whereas insulin suppression of glucose R(a) [51 +/- 8 vs. 20 +/- 12 mg/m(2).min during 240-300 min (P < 0.05) or -55 +/- 7 vs. -85 +/- 12% below basal (P < 0.05, high vs. low LFAT)] and of serum FFA (299 +/- 33 vs. 212 +/- 13 micromol/liter; 240-300 min; P < 0.02) were impaired in the high compared with the low LFAT group. Insulin stimulation of glucose Rd were comparable in the men with high LFAT (141 +/- 12 mg/m(2).min) and those with low LFAT (156 +/- 14 mg/m(2).min; P = NS). Fat accumulation in the liver is, independent of body mass index and intraabdominal and overall obesity, characterized by several features of insulin resistance in normal weight and moderately overweight subjects.

Despite the high prevalence of nonalcoholic fatty liver disease (NAFLD), little is known of its pathogenesis based on study of human liver samples. By the use of Affymetrix GeneChips (17,601 genes), we investigated gene expression in the human liver of subjects with extreme steatosis due to NAFLD without histological signs of inflammation (liver fat 66.0 +/- 6.8%) and in subjects with low liver fat content (6.4 +/- 2.7%). The data were analyzed by using sequence-based reannotation of Affymetrix probes and a robust model-based normalization method. We identified genes involved in hepatic glucose and lipid metabolism, insulin signaling, inflammation, coagulation, and cell adhesion to be significantly associated with liver fat content. In addition, genes involved in ceramide signaling (MAP2K4) and metabolism (UGCG) were found to be positively associated with liver fat content. Genes involved in lipid metabolism (PLIN, ACADM), fatty acid transport (FABP4, CD36), amino acid catabolism (BCAT1), and inflammation (CCL2) were validated by real-time PCR and were found to be upregulated in subjects with high liver fat content. The data show that multiple changes in gene expression characterize simple steatosis.