No abstract

To investigate the direct relationship of oxidative stress with obesity and insulin resistance in men, we measured the plasma levels of 8-epi-prostaglandin F2alpha (PGF2alpha) in 14 obese and 17 nonobese men and evaluated their relationship with body mass index; body fat weight; visceral, sc, and total fat areas, measured by computed tomography; and glucose infusion rate during a euglycemic hyperinsulinemic clamp study. Obese men had significantly higher plasma concentrations of 8-epi-PGF2alpha than nonobese men (P < 0.05). The plasma levels of 8-epi-PGF2alpha were significantly correlated with body mass index (r = 0.408; P < 0.05), body fat weight (r = 0.467; P < 0.05), visceral (r = 0.387; P < 0.05) and total fat area (r = 0.359; P < 0.05) in all (obese and nonobese) men. There was also a significant correlation between the plasma levels of 8-epi-PGF2alpha and glucose infusion rate in obese men (r = -0.552; P < 0.05) and all men (r = -0.668; P < 0.01). In all subjects, the plasma levels of 8-epi-PGF2alpha were significantly correlated with fasting serum levels of insulin (r = 0.487; P < 0.01). In brief, these findings showed that the circulating levels of 8-epi-PGF2alpha are related to adiposity and insulin resistance in men. Although correlation does not prove causation, the results of this study suggest that obesity is an important factor for enhanced oxidative stress and that this oxidative stress triggers the development of insulin resistance in men.

Dubin-Johnson syndrome (DJS) is an autosomal recessive disease characterized by conjugated hyperbilirubinemia. Previous studies of the defects in the human canalicular multispecific organic anion transporter gene (MRP2/cMOAT) in patients with DJS have suggested that the gene defects are responsible for DJS. In this study, we determined the exon/intron structure of the human MRP2/cMOAT gene and further characterized mutations in patients with DJS. The human MRP2/cMOAT gene contains 32 exons, and it has a structure that is highly conserved with that of another ATP-binding-cassette gene, that for a multidrug resistance-associated protein. We then identified three mutations, including two novel ones. All mutations identified to date are in the cytoplasmic domain, which includes the two ATP-binding cassettes and the linker region, or adjacent putative transmembrane domain. Our results confirm that MRP2/cMOAT is the gene responsible for DJS. The finding that mutations are concentrated in the first ATP-binding-cassette domain strongly suggests that a disruption of this region is a critical route to loss of function.

Patients with chronic hepatitis C frequently have serum and hepatic iron overload, but the mechanism is unknown. Recently identified hepcidin, exclusively synthesized in the liver, is thought to be a key regulator for iron homeostasis and is induced by infection and inflammation. This study was conducted to determine the hepatic hepcidin expression levels in patients with various liver diseases. We investigated hepcidin mRNA levels of liver samples by real-time detection-polymerase chain reaction; 56 were hepatitis C virus (HCV) positive, 34 were hepatitis B virus (HBV) positive, and 42 were negative for HCV and HBV (3 cases of autoimmune hepatitis, 7 alcoholic liver disease, 13 primary biliary cirrhosis, 9 nonalcoholic fatty liver disease, and 10 normal liver). We analyzed the relation of hepcidin to clinical, hematological, histological, and etiological findings. Hepcidin expression levels were strongly correlated with serum ferritin (P < 0.0001) and the degree of iron deposit in liver tissues (P < 0.0001). Hepcidin was also correlated with hematological parameters (vs. hemoglobin, P = 0.0073; vs. serum iron, P = 0.0012; vs. transferrin saturation, P < 0.0001) and transaminase levels (P = 0.0013). The hepcidin-to-ferritin ratio was significantly lower in HCV + patients than in HBV + patients (P = 0.0129) or control subjects (P = 0.0080). In conclusion, hepcidin expression levels in chronic liver diseases were strongly correlated with either the serum ferritin concentration or degree of iron deposits in the liver. When adjusted by either serum ferritin values or hepatic iron scores, hepcidin indices were significantly lower in HCV + patients than in HBV + patients, suggesting that hepcidin may play a pivotal role in the pathogenesis of iron overload in patients with chronic hepatitis C.

OBJECTIVE -The purpose of this study was to investigate the association between visceral adiposity or triglyceride (TG) metabolism and insulin resistance in metabolically obese, normal weight (MONW) Japanese individuals with normal glucose tolerance.RESEARCH DESIGN AND METHODS -We evaluated body fat areas, lipid profiles, and the glucose infusion rate (GIR) during a euglycemic-hyperinsulinemic clamp study in 20 MONW subjects (BMI Ͻ25 kg/m 2 and visceral fat areas 100 cm 2 ) with normal glucose tolerance. Body fat areas were measured by computed tomography scans. Control data were obtained from 20 normal subjects (BMI Ͻ25 kg/m 2 and visceral fat areas Ͻ100 cm 2 ).RESULTS -MONW subjects showed a significant increase in fasting serum levels of TG (P Ͻ 0.01) and a decrease in GIR (P Ͻ 0.01) compared with normal subjects. There were significant correlations between visceral fat areas (r ϭ Ϫ0.563, P Ͻ 0.01) or serum levels of TG (r ϭ Ϫ0.474, P Ͻ 0.05) and GIR in MONW subjects. Multiple regression analyses showed that visceral fat areas (F ϭ 7.702, P Ͻ 0.02) and serum levels of TG (F ϭ 7.114, P Ͻ 0.05) were significantly associated with GIR in all (MONW and normal) subjects.CONCLUSIONS -Increased visceral fat and serum levels of TG are associated with insulin resistance in Japanese MONW subjects with normal glucose tolerance. Excess visceral fat and elevated TG levels may play important roles in the development of insulin resistance in Japanese MONW subjects with normal glucose tolerance. Diabetes Care 26:2341-2344, 2003R ecent reports described the existence of individuals with normal body weight but with a cluster of obesity-related characteristics (1,2). They are characterized by excess visceral fat, insulin resistance, and hyperinsulinemia and have been called metabolically obese, normal weight (MONW) subjects. Ethnic differences should be considered for identifying MONW subjects. In the Japanese population, nonobese (BMI Ͻ25 kg/ m 2 ) subjects with increased visceral fat areas (100 cm 2 ) fulfill the criteria for categorizing them in the MONW group (2-6). Regarding the association of the MONW state with diabetes, higher prevalence of hyperglycemia has been observed in MONW subjects than in normal individuals (3,4).Previous studies have demonstrated that visceral fat areas are associated with insulin resistance in Japanese subjects with normal glucose tolerance and impaired glucose tolerance and in nonobese Japanese patients with type 2 diabetes (7-9). Visceral fat accumulation is also associated with serum triglyceride (TG) levels, and the disturbance of TG metabolism precedes the development of insulin resistance in nonobese Japanese type 2 diabetic patients (9,10). However, the relationships of visceral adiposity and TG metabolism with insulin resistance in Japanese MONW subjects with normal glucose tolerance have not been evaluated. To clarify these points, in the present study, we investigated the relationship between visceral fat areas or serum levels of TG and insulin resistance in Japanese MONW subjects wit...