Pathway analysis of genome-wide association datasets of personality traits.

Although several genome-wide association (GWA) studies of human personality have been recently published, genetic variants that are highly associated with certain personality traits remain unknown, due to difficulty reproducing results. To further investigate these genetic variants, we assessed biological pathways using GWA datasets. Pathway analysis using GWA data was performed on 1089 Korean women whose personality traits were measured with the Revised NEO Personality Inventory for the 5-factor model of personality. A total of 1042 pathways containing 8297 genes were included in our study. Of these, 14 pathways were highly enriched with association signals that were validated in 1490 independent samples. These pathways include association of: Neuroticism with axon guidance [L1 cell adhesion molecule (L1CAM) interactions]; Extraversion with neuronal system and voltage-gated potassium channels; Agreeableness with L1CAM interaction, neurotransmitter receptor binding and downstream transmission in postsynaptic cells; and Conscientiousness with the interferon-gamma and platelet-derived growth factor receptor beta polypeptide pathways. Several genes that contribute to top-ranked pathways in this study were previously identified in GWA studies or by pathway analysis in schizophrenia or other neuropsychiatric disorders. Here we report the first pathway analysis of all five personality traits. Importantly, our analysis identified novel pathways that contribute to understanding the etiology of personality traits.

Lobeglitazone and pioglitazone as add-ons to metformin for patients with type 2 diabetes: a 24-week, multicentre, randomized, double-blind, parallel-group, active-controlled, phase III clinical trial with a 28-week extension.

We aimed to compare the efficacy and safety of lobeglitazone and pioglitazone as add-ons to metformin in patients with type 2 diabetes. Patients who were inadequately controlled by metformin were randomized and treated once daily with either lobeglitazone (0.5 mg, n = 128) or pioglitazone (15 mg, n = 125) for 24 weeks, with a 28-week extension trial of lobeglitazone treatment in patients who consented. The primary endpoint was the change in glycated haemoglobin (HbA1c) concentration from baseline to week 24. At week 24, the mean change from baseline in HbA1c was -0.74% for the lobeglitazone group and -0.74% for the pioglitazone group, with a mean difference of 0.01% [95% confidence interval (CI) of difference, -0.16 to 0.18]. The effects of lobeglitazone on lipid variables and the adverse events associated with lobeglitazone were similar to those observed with pioglitazone. Lobeglitazone was not inferior to pioglitazone as an add-on to metformin in terms of their efficacy and safety.

Efficacy and safety of glimepiride/metformin sustained release once daily vs. glimepiride/metformin twice daily in patients with type 2 diabetes.

AIMS: The study investigated the clinical equivalence in reducing haemoglobin A1c (A1C) between glimepiride/metformin sustained release (GM-SR) 2/500 mg, a fixed-dose combination, once daily and glimepiride/metformin (GM) 1/250 mg, a fixed-dose combination, twice daily in patients with type 2 diabetes (T2D). METHODS: A multicentre, randomised, double-blind, double-dummy study was conducted in 14 hospitals in Korea. Inclusion criteria were age 30-75 years, T2D diagnosis no longer than 10 years previously, A1C between 7% and 10%, and body mass index <40 kg/m(2) . A total of 207 subjects were randomised into the GM-SR group (n=101) or the GM group (n=106). Participants were assessed at baseline, 8 weeks and 16 weeks after treatment. RESULTS: After 16 weeks treatment, no difference in baseline-adjusted changes of A1C (primary efficacy variable) was observed between the two groups (-0.59% for GM-SR group vs. -0.61% for GM group, 95% CI: -0.17 to 0.21; p=0.84). In addition, there were no significant differences in secondary efficacy parameters between the two groups, including changes in A1C up to week 8, changes in fasting plasma glucose (FPG) and 2-h-postprandial plasma glucose up to week 8 and week 16, response rate, drug compliance and hypoglycaemic events. However, there was a difference in baseline-adjusted changes of FPG between the two groups (-1.01 mmol/l for GM-SR group vs. -1.52 mmol/l for GM group, p=0.01 in the intention to treat set). CONCLUSIONS: GM-SR 2/500 mg once daily was as effective as GM 1/250 mg twice daily in lowering A1C. In addition, no difference was noted in hypoglycaemic events between the two groups.

The lipid accumulation product as a useful index for identifying abnormal glucose regulation in young Korean women.

AIMS: The lipid accumulation product, a combination of waist circumference and triglycerides concentration, has been suggested as a better marker for abnormal glucose regulation than BMI. We aimed to compare the lipid accumulation product and BMI as useful markers for abnormal glucose regulation in young Korean women. METHODS: The lipid accumulation product was calculated using the formula [waist circumference (cm) - 58] × triglycerides (mmol/l). Glucose tolerance status was determined using a 75-g oral glucose tolerance test in 2810 Korean women aged 18-39 years from the general population. RESULTS: The prevalence of abnormal glucose regulation was 6.8% (isolated impaired fasting glucose 1.8%, isolated impaired glucose tolerance 4.0%; impaired fasting glucose + impaired glucose tolerance 0.4% and diabetes mellitus 0.6%). According to the quintile distributions of the lipid accumulation product and BMI, women with a lipid accumulation product quintile greater than their BMI quintile exhibited significantly greater areas under the curve and higher levels of 2-h post-load glucose, insulin, homeostasis model analysis of insulin resistance and lipid profiles than did women with a BMI quintile greater than their lipid accumulation product quintile. Multiple logistic regression revealed that the lipid accumulation product exhibited a higher odds ratio for abnormal glucose regulation than did BMI after adjusting for age, systolic blood pressure, HDL cholesterol, previous history of gestational diabetes and family history of diabetes (odds ratios 3.5 and 2.6 of the highest vs. the lowest quintiles of lipid accumulation product and BMI, respectively). CONCLUSIONS: The lipid accumulation product could be useful for identifying the young Korean women with abnormal glucose regulation.

Genetic polymorphisms in peroxisome proliferator-activated receptor gamma are associated with Type 2 diabetes mellitus and obesity in the Korean population.

AIMS: We examined whether the common polymorphisms of the peroxisome proliferator-activated receptor-gamma (PPARgamma) gene are associated with Type 2 diabetes or obesity in the Korean population. METHODS: We genotyped two common PPARgamma polymorphisms (Pro12Ala and 161C > T) and examined their association with the clinical phenotypes found in 684 patients with Type 2 diabetes mellitus and 291 non-diabetic control subjects. RESULTS: The 12Ala allele was less frequent in the Type 2 diabetic patients than in the non-diabetic control subjects (0.036 vs. 0.053, P = 0.024). The allele frequencies of the 161C > T polymorphism did not differ between the control and Type 2 diabetic group (0.158 vs. 0.173). In the non-diabetic controls, those with the T allele had lower BMI and fasting serum triglyceride (TG) concentrations than those with the C/C homozygote (22.7 +/- 2.9 vs. 23.8 +/- 3.2 kg/m2, P = 0.002; 1.45 +/- 0.81 vs. 1.65 +/- 0.83 mmol/l, P = 0.03, respectively). The 12Ala-161T haplotype was associated with a decreased risk for Type 2 diabetes (OR = 0.47, P = 0.009), whereas the 12Pro-161T haplotype was associated with lower BMI and lower fasting serum TG (22.5 +/- 2.8 vs. 23.7 +/- 3.2 kg/m2, P = 0.004; 1.41 +/- 0.87 vs. 1.64 +/- 0.79 mmol/l, P = 0.02, respectively). CONCLUSIONS: The PPARgamma 12Ala allele was associated with a reduced risk of Type 2 diabetes, whereas the PPARgamma 161T allele was associated with lower BMI and fasting serum TG concentrations in the Korean subjects. The subjects with 12Ala-161T haplotypes had a reduced risk of Type 2 diabetes.

Peripheral blood mitochondrial DNA content is related to insulin sensitivity in offspring of type 2 diabetic patients.

OBJECTIVE: To investigate whether the peripheral blood mtDNA (pb-mtDNA) content is decreased and linked to insulin resistance in the offspring of type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 82 offspring of type 2 diabetic patients and 52 age-, sex-, and BMI-matched normal subjects from the Mokdong, Korea, population were selected for this study by stratified, randomized sampling. Of the offspring of diabetic patients, 52 had normal glucose tolerance (NGT), 21 had impaired glucose tolerance (IGT), and 9 had newly diagnosed type 2 diabetes. The pb-mtDNA content was measured by real-time polymerase chain reaction with a mitochondria-specific fluorescent probe, normalized by a nuclear DNA, 285 rRNA gene. The associations between pb-mtDNA content and several parameters of insulin resistance were studied. RESULTS: The pb-mtDNA contents tended to be lower in the 82 offspring of type 2 diabetic patients (1,084.7 +/- 62.6 vs. 1,304.0 +/- 99.2 in the offspring and control subjects, respectively, P = 0.051) and was significantly lower in the combined NGT and IGT offspring group (NGT+IGT, 1,068.0 +/- 67.8, P < 0.05) than in the control subjects. In NGT+IGT offspring, the pb-mtDNA content was significantly correlated with logarithmically transformed insulin sensitivity (r = 0.253, P < 0.05) and was the main predictor of insulin sensitivity. CONCLUSIONS: Quantitative mtDNA status might be a hereditary factor associated with type 2 diabetes and could serve as an indicator for insulin sensitivity.

High signal intensity of the posterior pituitary gland on T1-weighted MR images. Correlation with plasma vasopressin concentration to water deprivation.

PURPOSE: To evaluate the effect of water deprivation on the signal intensity of the posterior pituitary gland on T1-weighted MR images and correlate the signal intensity with the plasma vasopressin concentration. MATERIAL AND METHODS: Fifteen rabbits were studied: Group 1 (n=10) was deprived of water for 9 days and Group 2 (n=5) was replenished water for 7 days after 7-day water deprivation. MR imaging and plasma vasopressin measurement by radioimmunoassay were made before and after water deprivation and replenishment. Sequential changes of the signal intensity ratio of the posterior lobe to the pons and plasma vasopressin concentration were correlated. RESULTS: Before water deprivation, the hyperintense posterior lobe was demonstrated in all rabbits. During water deprivation, the signal intensity ratio decreased and vasopressin concentration increased gradually. On the contrary, the signal intensity ratio increased and vasopressin concentration decreased with water replenishment. The signal intensity ratio correlated well with the plasma vasopressin concentration (p<0.05). CONCLUSION: There was a negative, linear correlation between the signal intensity ratio of the posterior pituitary gland on T1-weighted MR images and plasma vasopressin concentration to water deprivation. The results support that the high signal intensity of the posterior pituitary gland on T1-weighted MR images is attributed to the normal content of vasopressin-neurosecretory granules.

Direct relationship between elevated free testosterone and insulin resistance in hyperprolactinemic women.

Women with hyperprolactinemia have been reported to have hyperandrogenemia and/or insulin resistance. However, little is known about the association of hyperandrogenemia and insulin resistance in these women. To investigate whether hyperandrogenemia and/or insulin resistance occur in hyperprolactinemic women, and to assess the relationship between them, we measured basal androgen level and both glucose and insulin levels after oral glucose administration in 20 hyperprolactinemic women and 7 female control subjects. Free testosterone level was higher and estradiol level lower in hyperprolactinemic women than in control subjects (p < 0.05), whereas dehydroepiandrosterone sulfate (DHEAS) and total testosterone levels were similar (p > 0.05). Both fasting glucose and insulin levels didn't differ in the two groups (p > 0.05). However, both serum glucose and insulin levels, after a 75 g glucose load, were significantly increased in hyperprolactinemic women, (p = 0.001, p < 0.001, respectively). In simple linear regression analysis in hyperprolactinemic women, only free testosterone level had a positive correlation with the incremental area under the insulin curve (insulin-IAU) (r = 0.47, p < 0.05). In multiple stepwise regression analysis, free testosterone level, mean blood pressure and DHEAS level were associated significantly with insulin-IAU (beta = 0.98, p < 0.0001; beta = 0.58, p = 0.002; beta = -0.67, p < 0.003, respectively). These results suggest that insulin resistance is closely related to elevated free testosterone level in hyperprolactinemic women.