OBJECTIVE -Resistin, secreted from adipocytes, causes insulin resistance in rodents. We previously reported that the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at Ϫ420 increases type 2 diabetes susceptibility by enhancing promoter activity. We report here on the relation between plasma resistin and either SNP Ϫ420 genotype or factors related to insulin resistance. RESEARCH DESIGN AND METHODS-We cross-sectionally analyzed 2,078 community-dwelling Japanese subjects attending a yearly medical checkup. The SNP Ϫ420 genotype was determined by TaqMan analysis. Fasting plasma resistin was measured using an enzyme-linked immunosorbent assay kit.RESULTS -Plasma resistin was associated with the SNP Ϫ420 genotype (P Ͻ 0.0001), which was highest in G/G followed by C/G and C/C. Plasma resistin was higher in elderly individuals, female subjects, nondrinkers, and subjects with high blood pressure (P Ͻ 0.001, 0.003, Ͻ0.001, and 0.001, respectively). Simple regression analysis revealed that age, female sex, homeostasis model assessment of insulin resistance (HOMA-IR) index, systolic blood pressure, low HDL cholesterol, and high-sensitivity C-reactive protein (hs-CRP) were positively correlated with plasma resistin (P Ͻ 0.001, 0.003, Ͻ0.001, 0.004, Ͻ0.001, and 0.003, respectively). Multiple regression analysis adjusted for age, sex, and BMI revealed that plasma resistin was an independent factor for HOMA-IR, low HDL cholesterol, and hs-CRP (P ϭ 0.001, Ͻ0.001, and 0.006, respectively).CONCLUSIONS -Plasma resistin was associated with SNP Ϫ420 and was correlated with insulin resistance, low serum HDL cholesterol, and high hs-CRP in the Japanese general population.

The effect of genetic polymorphism of human organic anion transporting polypeptide C (OATP-C) on the lipid-lowering response to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors was assessed. A retrospective study was conducted on 66 patients who underwent treatment of hyperlipidemia with HMG-CoA reductase inhibitors in a municipal hospital in a community-based cohort of Ehime prefecture in the southern part of Japan. Plasma lipid concentrations before and after administration were analyzed in patients in relation to the 521T/C (Val-174-->Ala) polymorphism in the OATP-C gene (TT: n=44 (66.7%), TC: n=20 (30.3%), CC: n=0 (0.0%), undetermined: n=2 (3.0%)). Total cholesterol level was significantly lowered after treatment with HMG-CoA reductase inhibitors in all patients (p<0.001); moreover, subjects with the 521C allele showed an attenuated total-cholesterol-lowering effect compared with those homozygous for the 521T allele (-22.3+/-8.7% vs. -16.5+/-10.5%, p<0.05). These data suggest that the 521T/C polymorphism of the OATP-C gene modulates the lipid-lowering efficacy of HMG-CoA reductase inhibitors.

The association of low muscle strength with cardio-metabolic risks remains controversial. The present study included 742 men aged 70 ± 9 years and 937 women aged 70 ± 8 years from a rural village. We examined the cross-sectional relationship between relative muscle strength defined by handgrip strength (HGS)/body weight (BW) ratio, and metabolic syndrome (MetS) based on the modified criteria of the National Cholesterol Education Program's Adult Treatment Panel (NCEP-ATP) III report and its components. Of these, 203 men (27.4%) and 448 women (47.8%) had MetS. In men, increasing quartile of HGS/BW ratio was significantly and independently associated with high waist circumference {odds ratio, 0.31; 95% confidence interval (CI), 0.24-0.41} and elevated triglyceridemia (0.71, 0.59-0.86). In women, it was also significantly and independently associated with high waist circumference (0.41; 0.36-0.48), high blood pressure (0.78; 0.66-0.92), Low HDL-cholesterolemia (0.84; 0.73-0.98) and elevated triglyceridemia (0.65; 0.53-0.79). In both genders, the prevalence of MetS significantly decreased in relation to increasing HGS/BW ratio. After adjustment for age, smoking status, drinking status, LDL-C, estimated glomerular filtration ratio (eGFR), and medication, the respective odds ratio (95% CI) for the quartile of HGS/BW ratio for MetS was 1.00, 0.54 (0.34-0.85), 0.32 (0.19-0.53), and 0.16 (0.09-0.29) in men, and 1.00, 0.76 (0.50-1.16), 0.33 (0.22-0.51), and 0.16 (0.10-0.25) in women. These results suggest that HGS/BW ratio was significantly and negatively associated with an increased risk of cardio-metabolic disorders in Japanese-community dwelling persons.

OBJECTIVE— The present study was conducted to confirm possible associations between candidate genes from genome-wide association studies and type 2 diabetes in Japanese diabetic patients and a community-based general population. A total of 11 previously reported single-nucleotide polymorphisms (SNPs) from the TCF7L2 , CDKAL1 , HHEX , IGF2BP2 , CDKN2A/B , SLC30A8 , and KCNJ11 genes were analyzed. RESEARCH DESIGN AND METHODS— Candidate SNPs were genotyped in 506 type 2 diabetic patients and 402 control subjects and meta-analyzed with six previous association studies in Japanese patients. Associations with fasting plasma insulin levels were investigated in a general population sample ( n = 1,963, 61 ± 13 years). RESULTS— In our case-control subjects, susceptibility to type 2 diabetes was replicated in TCF7L2 (rs12255372), CDKAL1 (rs7756992, rs7754840), HHEX (rs7923837), IGF2BP2 (rs4402960 and rs1470579), CDKN2A/B (rs10811661), and SLC30A8 (rs13266634). In addition to these polymorphisms, meta-analysis confirmed the association of type 2 diabetes susceptibility with KCNJ11 rs5219, TCF7L2 rs7903146, and HHEX rs1111875. The TCF7L2 rs12255372 polymorphism showed the highest odds ratio (OR) for type 2 diabetes (OR 1.714 [1.298–2.263]). Odds ratio of other polymorphisms ranged from 1.13 to 1.41. The risk allele of CDKAL1 rs7756992 was significantly associated with lower insulin levels in type 2 diabetic patients after adjustment for other confounding factors. CONCLUSIONS— Type 2 diabetes susceptibility of seven candidate genes was confirmed in Japanese. Conservation of susceptible loci for type 2 diabetes was independent of ethnic background.