The effect of lowering the threshold for diagnosis of impaired fasting glucose.

PURPOSE: The aim of this study was to evaluate the effect of lowering the fasting plasma glucose (FPG) criteria for impaired fasting glucose (IFG) on the prevalence of IFG and the risk for the development of diabetes associated with IFG in Koreans. MATERIALS AND METHODS: A total of 7,211 subjects who had normal glucose tolerance (NGT) or IFG were recruited. Subjects were evaluated at baseline and after two years follow up. Clinical data including total cholesterol, FPG and blood pressure were examined. RESULTS: Lowering the criteria for IFG from 6.1 mmol/L (110 mg/dL) to 5.6 mmol/L (100 mg/dL) increased the prevalence of IFG from 6.6% (494 subjects) to 24.4% (1829 subjects). After the 2 years follow up period, 91 subjects (1.3%) developed diabetes. Twenty one (0.3%) subjects developed diabetes among 5,382 NGT subjects and 70 (3.8%) subjects developed diabetes among 1,829 IFG (5.6-7.0 mmol/L) subjects. Lowering the IFG threshold from 6.1 mmol/L to 5.6 mmol/L resulted in a 18.4% decrease in specificity and 23.9% increase in sensitivity for predicting diabetes. The baseline FPG for predicting the development of diabetes after 2 years at a point on the receiver operating characteristic curve that was closest to the ideal 100% sensitivity and 100% specificity was 5.7 mmol/L (103 mg/dL). CONCLUSION: Lowering the FPG criterion of IFG should have benefits in predicting new onset type 2 diabetes mellitus in Koreans. The economic and health benefits of applying the new IFG criteria should be evaluated in future studies.

Rosiglitazone improves insulin sensitivity with increased serum leptin levels in patients with type 2 diabetes mellitus.

Rosiglitazone (RSG) is known to be an agonist for the peroxisome proliferator-activated receptor-gamma (PPARgamma) and promotes differentiation of pre-adipocytes into adipocytes. Leptin is highly correlated with adiposity, while the activation of PPARgamma is known to inhibit Lep gene expression and leptin release. This study was performed to evaluate the relationship between changes in circulating leptin levels, insulin sensitivity and regional adiposity after RSG treatment. Two hundred fifty-one type 2 diabetic patients (176 men and 75 women) who had been treated with sulfonylurea and/or metformin received 4 mg of RSG daily, in addition to the previous medications. Before and after RSG treatment (average duration 5.6+/-0.9 months), indices of insulin resistance, metabolic parameters, and serum leptin and adiponectin levels were measured. Abdominal subcutaneous fat thickness (SFT(max)) and visceral fat thickness were measured by sonography. After RSG treatment, HOMA-IR index decreased significantly (2.82+/-1.94 vs. 2.01+/-1.58), while BMI and SFT(max) increased, and leptin (4.72+/-3.77 vs. 5.69+/-4.30 ng/ml) and adiponectin levels (7.54+/-10.20 vs. 12.89+/-10.13 microg/ml) increased. The increase in serum leptin correlated with an increase in SFT(max) (r=0.511, p<0.001) and with a reduction in HOMA-IR (r=-0.368, p<0.001). The correlation of Delta leptin with Delta HOMA-IR and with Delta SFT(max) was higher in females and among insulin-resistant subjects. In conclusion, RSG improves the insulin sensitivity with increased serum leptin levels in patients with type 2 diabetes mellitus, which is related to an increase in subcutaneous adiposity.

The increase in abdominal subcutaneous fat depot is an independent factor to determine the glycemic control after rosiglitazone treatment.

OBJECTIVE: The goal was to investigate the interrelationships between the hypoglycemic effects of rosiglitazone and the changes in the regional adiposity of type 2 diabetic patients. DESIGN AND METHODS: We added rosiglitazone (4 mg/day) to 173 diabetic patients (111 males and 62 females) already taking a stable dose of conventional antidiabetic medications except for thiazolidinediones. The abdominal fat distribution was assessed by ultrasonography at baseline and 12 weeks later. Using ultrasonographic images, the s.c. and visceral fat thickness (SFT and VFT respectively) were measured. RESULTS: Rosiglitazone treatment for 3 months improved the glycemic control. However, the response to rosiglitazone was no more than 36.4%; the deterioration of the glycemic control was found in 16.8% of subjects. In addition, rosiglitazone treatment significantly increased the body fat mass, especially the s.c. fat. However that did not alter the visceral fat content. The percentage changes in fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) concentrations after treatment were inversely correlated with the increase in SFT (r=-0.327 and -0.353, P<0.001 respectively) and/or body weight (r=-0.316 and -0.327, P<0.001 respectively). Multiple regression analysis revealed that the improvement in the FPG after rosiglitazone treatment was correlated with the baseline FPG (P<0.001) and the change in the SFT (P=0.019), and the reduction in the HbA1c was related with the baseline FPG (P=0.003) and HbA1c (P<0.001) and the changes in the SFT (P=0.010) or VFT (P=0.013). CONCLUSIONS: The increase in the s.c. fat depot after rosiglitazone treatment may be an independent factor that determines the hypoglycemic efficacy.

Rosiglitazone protects human neuroblastoma SH-SY5Y cells against MPP+ induced cytotoxicity via inhibition of mitochondrial dysfunction and ROS production.

1-Methyl-4-phenylpyridinium ion (MPP(+)), an inhibitor of mitochondrial complex I, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome with elevation of intracellular reactive oxygen species (ROS) level and apoptotic death. Rosiglitazone, a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, has been known to show various non-hypoglycemic effects, including anti-inflammatory, anti-atherogenic, and anti-apoptotic. In the present study, we investigated the protective effects of rosiglitazone on MPP(+) induced cytotoxicity in human neuroblastoma SH-SY5Y cells, as well as underlying mechanism. Our results suggested that the protective effects of rosiglitazone on MPP(+) induced apoptosis may be ascribed to its anti-oxidative properties, anti-apoptotic activity via inducing expression of SOD and catalase and regulating the expression of Bcl-2 and Bax. These data indicated that rosiglitazone might provide a valuable therapeutic strategy for the treatment of progressive neurodegenerative disease such as Parkinson's disease.

Decrement of postprandial insulin secretion determines the progressive nature of type-2 diabetes.

OBJECTIVE: Type-2 diabetes is a progressive disease. However, little is known about whether decreased fasting or postprandial pancreatic beta-cell responsiveness is more prominent with increased duration of diabetes. The aim of this study was to evaluate the relationship between insulin secretion both during fasting and 2 h postprandial, and the duration of diabetes in type-2 diabetic patients. DESIGN: Cross-sectional clinical investigation. METHODS: We conducted a meal tolerance test in 1466 type-2 diabetic patients and calculated fasting (M0) and postprandial (M1) beta-cell responsiveness. RESULTS: The fasting C-peptide, postprandial C-peptide, M0, and M1 values were lower, but HbA1c values were higher, in patients with diabetes duration > 10 years than those in other groups. There was no difference in the HbA1c levels according to the tertiles of their fasting C-peptide level. However, in a group of patients with highest postprandial C-peptide tertile, the HbA1c values were significantly lower than those in other groups. After adjustment of age, sex, and body mass index (BMI), the duration of diabetes was found to be negatively correlated with fasting C-peptide (gamma = -0.102), postprandial C-peptide (gamma = -0.356), M0 (gamma = -0.263), and M1 (gamma = -0.315; P < 0.01 respectively). After adjustment of age, sex, and BMI, HbA1c was found to be negatively correlated with postprandial C-peptide (gamma = -0.264), M(0) (gamma = -0.379), and M1 (gamma = -0.522), however, positively correlated with fasting C-peptide (gamma = 0.105; P < 0.01 respectively). In stepwise multiple regression analysis, M0, M1, and homeostasis model assessment for insulin resistance (HOMA-IR) emerged as predictors of HbAlc after adjustment for age, sex, and BMI (R2 = 0.272, 0.080, and 0.056 respectively). CONCLUSIONS: With increasing duration of diabetes, the decrease of postprandial insulin secretion is becoming more prominent, and postprandial beta-cell responsiveness may be a more important determinant for glycemic control than fasting beta-cell responsiveness.

The long-term effects of rosiglitazone on serum lipid concentrations and body weight.

OBJECTIVE: Although rosiglitazone, an insulin sensitizer, is known to have beneficial effects on high density lipoprotein cholesterol (HDL-C) concentrations and low density lipoprotein (LDL) particle size, it has unwanted effects on total cholesterol (TC) and LDL cholesterol (LDL-C) concentrations and body weight in some short-term studies. The aim of this study was to evaluate the long-term effects of rosiglitazone on serum lipid levels and body weight. DESIGN: Open labelled clinical study. PATIENTS AND MEASUREMENTS: We prospectively evaluated fasting serum glucose, haemoglobin A(1c) (HbA(1c)), lipid profiles and body weight at baseline and every 3 months after the use of rosiglitazone (4 mg/day) for 18 months in 202 type 2 diabetic patients. RESULTS: TC levels increased maximally at 3 months and decreased thereafter. However, overall, TC levels remained significantly higher at 18 months than those at baseline. LDL-C levels from the 3-month to the 12-month timepoint were significantly higher than those at baseline. However, after 15 months, LDL-C concentrations were not significantly different from basal LDL-C concentrations. HDL-C levels increased after the first 3 months and these levels were maintained. The increment of change in HDL-C was more prominent in patients with low basal HDL-C concentrations than in patients with high basal HDL-C concentrations. Body weight increased after the first 3 months and these levels were maintained. CONCLUSIONS: HDL-C and body weight increased and remained elevated for the duration of the study. There was an initial increase in LDL-C but this attenuated and by the end of the study was not significantly elevated above baseline levels.

Adiponectin protects human neuroblastoma SH-SY5Y cells against acetaldehyde-induced cytotoxicity.

Acetaldehyde, an inhibitor of mitochondrial function, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome with elevation of the intracellular reactive oxygen species (ROS) level and apoptosis. Adiponectin, secreted from adipose tissue, mediates systemic insulin sensitivity with liver and muscle as target organs. In this study, we investigated the protective effects of adiponectin on acetaldehyde-induced apoptosis in human neuroblastoma SH-SY5Y cells and attempted to examine its mechanism. Acetaldehyde-induced apoptosis was moderately reversed by adiponectin treatment. Our results suggest that the protective effects of adiponectin on acetaldehyde-induced apoptosis may be ascribed to ability to induce the expression of anti-oxidant enzymes and to regulate Bcl-2 and Bax expression. These data indicate that adiponectin may provide a useful therapeutic strategy for the prevention of progressive neurodegenerative disease such as Parkinson's disease.

The 11482G >A polymorphism in the perilipin gene is associated with weight gain with rosiglitazone treatment in type 2 diabetes.

OBJECTIVE: The aim of this study was to examine the effects of perilipin gene (PLIN) polymorphisms on weight gain with rosiglitazone treatment in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 160 type 2 diabetic patients were treated with rosiglitazone (4 mg/day) for 12 weeks in addition to their previous medications, which were unchanged. Four single nucleotide polymorphisms (SNPs) at the PLIN locus were genotyped: PLIN 6209T>C, PLIN 11482G>A, PLIN 13041A>G, and PLIN 14995A>T. RESULTS: Although fasting plasma glucose and HbA(1c) levels decreased; mean body weight increased significantly after rosiglitazone treatment. Among the four SNPs tested, only the PLIN 11482G>A polymorphism was associated with weight gain from rosiglitazone treatment. In addition, there was a significant difference in the increase in the body weight among the genotypes. Patients with the 11482A/A genotype showed less increase in body weight than those with other genotypes. CONCLUSIONS: These data suggest that genetic variations in the perilipin gene can affect weight gain associated with rosiglitazone treatment in patients with type 2 diabetes.

Adiponectin protects human neuroblastoma SH-SY5Y cells against MPP+-induced cytotoxicity.

1-Methyl-4-phenylpyridinium ion (MPP+), an inhibitor of mitochondrial complex I, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome characterized by elevation of intracellular reactive oxygen species level and apoptotic death. Adiponectin, secreted from adipose tissue, mediates systemic insulin sensitivity with liver and muscle as target organs. Adiponectin can also suppress superoxide generation in endothelial cells. In the present study, we investigated the protective effects of adiponectin on MPP+-induced cytotoxicity in human neuroblastoma SH-SY5Y cells, as well as the underlying mechanism. Our results suggest that the protective effects of adiponectin on MPP+-induced apoptosis may be ascribed to its anti-oxidative properties, anti-apoptotic activity via inducing expression of SOD and catalase, and regulation of Bcl-2 and Bax expression. These data indicated that adiponectin might provide a useful therapeutic strategy for the treatment of progressive neurodegenerative diseases such as Parkinson's disease.

Rosiglitazone relieves acute ethanol-induced hangover in Sprague-Dawley rats.

AIMS: To assess the efficacy of rosiglitazone in blocking ethanol-induced hangover in rats. METHODS: Rats injected with ethanol (4 g/kg body weight) were subjected to social interaction tests. Levels of aldehyde dehydrogenase 2 (ALD2), involved in an anti-hangover mechanism, were measured by semi-quantitative RT-PCR and western blot analysis. RESULTS: Rosiglitazone caused an upregulation of mitochondrial ALD2, thus significantly detoxifying acetaldehyde. CONCLUSIONS: Rosiglitazone alleviated the symptoms of ethanol-induced hangover by inducing ALD2 expression; this result was reconfirmed by eliminating the effect of rosiglitazone by injecting cyanamide, an ALD2 inhibitor.

The association of total and differential white blood cell count with metabolic syndrome in type 2 diabetic patients.

AIMS: We investigated the relation between total and differential white blood cell (WBC) count and metabolic syndrome (MS) in type 2 diabetic patients. METHODS: Eight-hundred and twenty-two patients (males 430, females 392, BMI 25.4+/-3.2 kg/m2, duration of diabetes 5.7+/-6.8 years) were enrolled in this study. We measured total WBC count and differential count, anthropometry, blood pressure, fasting glucose, insulin and lipid profiles. RESULTS: The number of components of MS and prevalence of MS were increased from 1st quartile to 4th quartile of WBC count. Total WBC, neutrophil, lymphocyte, monocyte and eosinophil counts were increased with the increase of number of components of MS except basophil count. Total WBC, neutrophil, lymphocyte, monocyte and eosinophil counts were higher in the patients with MS features than those without MS features. WBC count was positively correlated with waist circumference (gamma=0.134), systolic blood pressure (gamma=0.082), diastolic blood pressure (gamma=0.083), triglyceride (gamma=0.241), insulin (gamma=0.222), and HOMA-IR (gamma=0.225), and negatively with HDL cholesterol (gamma=-0.146) (p<0.05, respectively). CONCLUSIONS: Chronic inflammation, as indicated by a higher WBC count, may be related with the increased number of components of MS in type 2 diabetic patients.

Rosiglitazone protects human neuroblastoma SH-SY5Y cells against acetaldehyde-induced cytotoxicity.

Acetaldehyde, an inhibitor of mitochondrial function, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome with elevation of the intracellular reactive oxygen species level and apoptosis. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, has been known to show various non-hypoglycemic effects, including anti-inflammatory, anti-atherogenic, and anti-apoptotic. In this study, we investigated the protective effects of rosiglitazone on acetaldehyde-induced apoptosis in human neuroblastoma SH-SY5Y cells and attempted to examine its mechanism. Acetaldehyde-induced apoptosis was moderately reversed by rosiglitazone treatment. Our results suggest that the protective effects of rosiglitazone on acetaldehyde-induced apoptosis may be ascribed to ability to induce the expression of anti-oxidant enzymes and to regulate Bcl-2 and Bax expression. These data indicate that rosiglitazone may provide a useful therapeutic strategy for the prevention of progressive neurodegenerative disease such as Parkinson's disease.