Diabetes In Japanese Subjects Research Articles

Improving diagnostic accuracy of 3 Screen ICA ELISA kit in the identification of Japanese type 1 diabetes.

This study aimed to investigate the clinical utility of 3 Screen ICA ELISA in identifying immune-mediated type 1 diabetes in Japanese subjects. We compared the positivity of 3 Screen ICA were compared with autoantibodies against GAD, IA-2, and ZnT8 in 638 patients with type 1 diabetes and 159 healthy control subjects. With a cut-off value of 20.0 index, 67.4% of acute-onset type 1 diabetic patients, 71.8% of slowly progressive type 1 diabetic (SPIDDM) patients, and none of the fulminant type 1 diabetic patients showed 3 Screen ICA levels above this threshold. The prevalence of 3 Screen ICA was 14.2% higher in acute-onset type 1 diabetes and 1.6% higher in SPIDDM than in GADA. 3 Screen ICA-positive cases were found in 4.8% of cases of individual autoantibody-negative acute-onset type 1 diabetes and 3.8% of SPIDDM, indicating improved diagnostic sensitivity with the 3 Screen ICA. Among individual autoantibody-negative patients, the sum of each autoantibody level was significantly lower in fulminant type 1 diabetes than in acute onset type 1 diabetes and in SPIDDM (P < 0.0001). Additionally, 84.2% of patients negative for individual autoantibodies but positive for 3 Screen ICA had a sum of individual autoantibody levels of ≥4.7 U/mL. Furthermore, 3 Screen ICA levels were significantly higher in patients with type 1 diabetes with other autoimmune diseases than in those without (P < 0.0001). Our findings suggest that the 3 Screen ICA ELISA may be a valuable screening tool for Japanese patients with type 1 diabetes, potentially increasing the diagnostic sensitivity and accuracy beyond the existing GADA, IA-2A, and ZnT8A tests.

Relationship between Serum Antioxidative Vitamin Concentrations and Type 2 Diabetes in Japanese Subjects

A high intake of green leafy vegetables rich in antioxidative nutrients such as vitamin C and β-carotene may protect against the risk of type 2 diabetes. Measurement of the circulating nutrient concentrations can indicate the nutrient status more directly, and vitamin C and carotenoids are recognized as good biomarkers for the intake of fruits and vegetables. The aim of this study was to investigate the relationships between serum antioxidative vitamin concentrations and type 2 diabetes in Japanese subjects. The study subjects comprised 506 men and 493 women who first underwent anti-aging health checks at Tokai University Tokyo Hospital. Serum concentration of vitamin (V) A, VC, α-tocoferol, β-carotene, VB12, folate, ferritin and homocysteine, and fasting plasma glucose and HbA1c were used for analysis. Low levels of β-carotene and VC were significantly associated with dysglycemia. Diabetic subjects showed significantly decreased β-carotene and VC levels, and multivariate analyses suggested that low levels of β-carotene and VC were factors related to diabetes. Low levels of β-carotene and VC are significantly related to dysglycemia/type 2 diabetes, and encouraging people at a higher risk of diabetes to take more green vegetables may be useful as a dietary intervention to improve the antioxidative vitamin status and dysglycemia.

Decreased β-Cell Function Is Associated with Reduced Skeletal Muscle Mass in Japanese Subjects without Diabetes.

BackgroundDecreased insulin secretion has a great impact on the incidence of type 2 diabetes in Japanese subjects. It is not clear whether β-cell function is related to muscle mass in subjects without diabetes. We investigated the relationship between β-cell function and skeletal muscle mass in Japanese subjects without diabetes.MethodsThe study included 1098 subjects (538 men and 560 women) aged 40 to 79 years, without diabetes (fasting glucose lower than 126 mg/dL and glycosylated hemoglobin lower than 6.5%), who consulted Osaka Medical College Health Science Clinic for a medical examination. Appendicular muscle mass was measured by bioelectrical impedance analysis. Appendicular muscle mass index was calculated as appendicular muscle mass divided by height squared (kg/m2). The homeostatic model assessment of β-cell function was used to assess β-cell function. The homeostatic model assessment of insulin resistance was used as a measure of insulin resistance. The association between appendicular muscle mass index and clinical parameters of β-cell function and insulin resistance was examined.ResultsLog-transformed homeostatic model assessment of β-cell function and Log-transformed homeostatic model assessment of insulin resistance showed a normal distribution. In both men and women, there was a significant positive correlation between appendicular muscle mass index and clinical parameters of β-cell function and insulin resistance. Tertile analysis, following stratification according to appendicular muscle mass index, found that low appendicular muscle mass index was significantly associated with the Log homeostatic model assessment of β-cell function and Log-transformed homeostatic model assessment of insulin resistance.ConclusionThis study shows that decreased β cell function is associated with reduced skeletal muscle mass in Japanese subjects without diabetes.

Development of new diabetes risk scores on the basis of the current definition of diabetes in Japanese subjects [Rapid Communication

To develop diabetes risk score (RS) based on the current definition of diabetes, we retrospectively analyzed consecutive 4,159 health examinees who were non-diabetic at baseline. Diabetes, diagnosed by fasting plasma glucose (FPG) ≥7.0 mmol/L, 2hPG ≥11.1 mmol/L and/or HbA1c ≥6.5% (48 mmol/mol), developed in 279 of them during the mean period of 4.9 years. A full RS (RSFull), a RS without 2hPG (RS-2hPG) and a non-invasive RS (RSNI) were created on the basis of multivariate Cox proportional model by weighted grading based on hazard ratio in half the persons assigned. The RSs were verified in the remaining half of the participants. Positive family history (FH), male sex, smoking and higher age, systolic blood pressure (SBP), FPG, 2hPG and HbA1c were independent predictors for RSFull. For RS-2hPG, 7 independent predictors, exclusive of 2hPG and smoking but inclusive of elevated triglycerides (TG) comparing to RSFull, were selected. FH, male sex, and higher age, SBP and HbA1c were independent predictors in RSNI. In the validation cohort, C-statistic (95%CI) of RSFull, RS-2hPG and RSNI were 0.80 (0.76-0.84), 0.75 (0.70-0.78) and 0.68 (0.63-0.72), respectively, which were significantly different from each other (P <0.01). Absolute percentage difference between predicted probability and observed diabetes were 1.9%, 0.7% and 0.9%, by the three scores, respectively, and not significantly different from each other. In conclusion, diabetes defined by the current criteria was predicted by the new diabetes risk scores with reasonable accuracy. Nonetheless, RSFull with a postchallenge glucose value performed superior to RS-2hPG and RSNI.

Association of genetic variants of the incretin-related genes with quantitative traits and occurrence of type 2 diabetes in Japanese

BackgroundNone of the high frequency variants of the incretin-related genes has been found by genome-wide association study (GWAS) for association with occurrence of type 2 diabetes in Japanese. However, low frequency and rare and/or high frequency variants affecting glucose metabolic traits remain to be investigated. MethodWe screened all exons of the incretin-related genes (GCG, GLP1R, DPP4, PCSK1, GIP, and GIPR) in 96 patients with type 2 diabetes and investigated for association of genetic variants of these genes with quantitative metabolic traits upon test meal with 38 young healthy volunteers and with the occurrence of type 2 diabetes in Japanese subjects comprising 1303 patients with type 2 diabetes and 1014 controls. ResultTwo mutations of GIPR, p.Thr3Alafsx21 and Arg183Gln, were found only in patients with type 2 diabetes, and both of them were treated with insulin. Of ten tagSNPs, we found that risk allele C of SNP393 (rs6235) of PCSK1 was nominally associated with higher fasting insulin and HOMA-R (P=0.034 and P=0.030), but not with proinsulin level, incretin level or BMI. The variant showed significant association with occurrence of type 2 diabetes after adjustment for age, sex, and BMI (P=0.0043). ConclusionRare variants of GIPR may contribute to the development of type 2 diabetes, possibly through insulin secretory defects. Furthermore, the genetic variant of PCSK1 might influence glucose homeostasis by altered insulin resistance independently of BMI, incretin level or proinsulin conversion, and may be associated with the occurrence of type 2 diabetes in Japanese.

Characteristics of sleep-disordered breathing in Japanese patients with type 2 diabetes mellitus

Sleep-disordered breathing (SDB), especially sleep apnea-hypopnea syndrome, is often observed in patients with type 2 diabetes mellitus; but there are only a few studies on SDB in Japanese diabetic subjects. We investigated the prevalence of SDB in diabetic patients; associations between severity of sleep apnea (SA) and clinical factors, visceral fat, and adiponectin; and associations between type of SA and clinical factors. In the present study, 40 Japanese diabetic patients underwent overnight cardiorespiratory monitoring, and night and morning measurements of serum adiponectin concentrations. Sleep apnea was detected in Japanese diabetic patients at a high prevalence (77.5%). The following variables were associated with SDB: age, body mass index, estimated visceral fat area, and nocturnal reduction in serum adiponectin concentrations. The prevalence of central sleep apnea (CSA, ≥5/h) was 32.3% among diabetic SDB patients. Diabetic SDB patients with CSA had higher hemoglobin, increased intima-media thickness, and higher plasma brain natriuretic peptide levels than those without CSA (<5/h). In conclusion, our study demonstrated a high prevalence of SDB in Japanese diabetic patients, which correlated with visceral fat area and adiponectin. A high frequency of CSA was noted in diabetic SDB patients, together with high hemoglobin, high brain natriuretic peptide, and increased intima-media thickness. The present results of prevalence of SDB may be relevant to the higher incidence of cardiovascular disease in diabetic patients, which need to be clarified in future studies.

Prevention of psychiatric illness in the elderly, I: Path to prevention of dementia

Prevention of psychiatric illness in the elderly, I: Path to prevention of dementia

A Variant in the KCNQ1 Gene Predicts Future Type 2 Diabetes and Mediates Impaired Insulin Secretion

OBJECTIVETwo independent genome-wide association studies for type 2 diabetes in Japanese subjects have recently identified common variants in the KCNQ1 gene that are strongly associated with type 2 diabetes. Here we studied whether a common variant in KCNQ1 would influence BMI as well as insulin secretion and action and predict future type 2 diabetes in subjects from Sweden and Finland.RESEARCH DESIGN AND METHODSRisk of type 2 diabetes conferred by KCNQ1 rs2237895 was studied in 2,830 type 2 diabetic case subjects and 3,550 control subjects from Sweden (Malmö Case-Control) and prospectively in 16,061 individuals from the Malmö Preventive Project (MPP). Association between genotype and insulin secretion/action was assessed cross- sectionally in 3,298 nondiabetic subjects from the Prevalence, Prediction and Prevention of Diabetes (PPP)-Botnia Study and longitudinally in 2,328 nondiabetic subjects from the Botnia Prospective Study (BPS). KCNQ1 expression (n = 18) and glucose-stimulated insulin secretion (n = 19) were measured in human islets from nondiabetic cadaver donors.RESULTSThe C-allele of KCNQ1 rs2237895 was associated with increased risk of type 2 diabetes in both the Malmö Case-Control (odds ratio 1.23 [95% CI 1.12–1.34]; P = 5.6 × 10−6) and the prospective (1.14 [1.06–1.22]; P = 4.8 × 10−4) studies. Furthermore, the C-allele was associated with decreased insulin secretion (corrected insulin response [CIR] P = 0.013; disposition index [DI] P = 0.013) in the PPP-Botnia Study and in the BPS at baseline (CIR P = 3.6 × 10−4; DI P = 0.0058) and after follow-up (CIR P = 0.0018; DI P = 0.0030). C-allele carriers showed reduced glucose-stimulated insulin secretion in human islets (P = 2.5 × 10−6).CONCLUSIONSA common variant in the KCNQ1 gene is associated with increased risk of future type 2 diabetes in Scandinavians, which partially can be explained by an effect on insulin secretion.

Common coding variant in the TCF7L2 gene and study of the association with type 2 diabetes in Japanese subjects

Genetic variants of the transcription factor 7-like 2 (TCF7L2) gene affect the risk of type 2 diabetes in populations with multiple ethnic groups. However, a comprehensive survey of this gene has not been done for a Japanese population. Thus, we conducted this gene-based association study, in which the common genetic variants were analyzed. Using 24 Japanese type 2 diabetic subjects, we first screened a 9.5 kb region, which included the entire coding sequence, to assess potential functional variants of TCF7L2. Sequencing revealed a common coding variant (Pro477Thr) in exon 14 of TCF7L2 that was not enrolled in the public SNP database. Nineteen SNPs and the microsatellite DG10S478 were genotyped across the gene in 2,877 unrelated Japanese subjects. This independent screen identified the previously reported rs7903146 with a strongest association (allele P = 0.0001, odds ratio = 1.59 [95% confidence interval 1.25-2.01]), but there was no significant association between Pro477Thr and type 2 diabetes (allele P = 0.64). Expression of the Pro477Thr variant did not alter TCF7L2 expression in 30 lymphoblast cells. Although a genotypic effect of Pro477Thr on expression of TCF7L2 was not apparent, Pro477Thr was identified as a common variant of TCF7L2 in 2,877 Japanese subjects. Further functional studies are required to determine the possible effect of this coding variant on type 2 diabetes.

Prevalence of Alzheimer's disease with diabetes in the Japanese population

AbstractBackground: The aim of the present study was to estimate the prevalence of impaired cognitive function and Alzheimer's disease (AD) in diabetic subjects from Japan.Methods: In the present study, 386 Japanese diabetic subjects aged more than 50 years were initially screened with the ‘brief screening test’ for AD, and were diagnosed with AD and vascular dementia (VaD) according to the criteria of the NINCDS‐ADRDA and the NINDS‐AIREN. We compared the prevalence of dementia in diabetic patients with that in ordinary subjects, and analyzed the association of the status of diabetes with dementia including AD and VaD.Results: Forty‐six (11.9%) patients were diagnosed with dementia, including 13 (3.4%) patients with AD and nine (2.3%) patients with VaD. Of the 221 subjects aged more than 65 years, 39 (17.6%) patients had dementia, including 13 (5.9%) patients with AD and eight (3.6%) patients with VaD. Compared with ordinary subjects, the prevalence of dementia in the present study was more frequent than the prevalence of dementia for the general population in almost each age group examined. There was also a greater prevalence of AD and VaD in subjects aged over 65 years in the present study. In the present study, AD subjects had significantly higher levels of fasting plasma glucose (FPG; 247.5 ± 116.3 mg/dL; P &lt; 0.05) and glycosylated hemoglobin (HbA1c; 8.8 ± 1.9%; P &lt; 0.01) compared with non‐demented subjects. In AD patients, the odds ratios of FPG and HbA1c were also significantly higher (1.02 and 2.07, respectively; both P &lt; 0.01).Conclusion: The present study shows that diabetes can be associated with impaired cognitive function, particularly AD, in Japanese subjects.

Association of the Glu298Asp polymorphism of the eNOS Gene with ischemic heart disease in Japanese diabetic subjects

We analysed the association of the Glu298Asp polymorphism of the endothelial nitric oxide synthase (eNOS) gene with ischemic heart disease (IHD) and albuminuria in 337 Japanese diabetes patients. Restriction fragment length polymorphism analysis of Glu298Asp of the eNOS gene was performed by amplification of genomic DNA isolated from whole blood followed by digestion with the restriction enzyme BanII. Individuals with IHD were identified by review of medical records and were identified based on apparent ischemic change of electrocardiography, significant stenosis of coronary artery, or a history of myocardial infarction, coronary artery bypass surgery, or catheter intervention. Albuminuria was confirmed by a positive test on at least two separate examinations. Of the 337 subjects analysed for polymorphisms of the eNOS gene, 45 with the GluAsp and five with the AspAsp genotype were combined into 1 group (GluAsp or AspAsp group). Among these 50 subjects, 16 (32%) had IHD, and among 287 subjects with the GluGlu genotype, 38 (13.2%) had IHD. The number of subjects with IHD was significantly greater in the GluAsp or AspAsp group than in the GluGlu group ( P = 0.0006). There was no difference in the frequency of albuminuria among the genotypes. The GluAsp or AspAsp genotype of the Glu298Asp polymorphism was significantly associated with IHD, but not albuminuria in these Japanese diabetic subjects.

P-60 Pitavastatin improves lipid profiles and reduces high-sensitivity CRP in Japanese diabetic subjects with hypercholesterolemia (KISHIMEN multi-center prospective study)-subanalysis of diabetic subjects

P-60 Pitavastatin improves lipid profiles and reduces high-sensitivity CRP in Japanese diabetic subjects with hypercholesterolemia (KISHIMEN multi-center prospective study)-subanalysis of diabetic subjects

Factors associated with lower Mini Mental State Examination scores in elderly Japanese diabetes mellitus patients

Cognitive impairment in elderly diabetic patients has generated considerable interest recently; however, the mechanism of the impairment remains to be elucidated. In the current study, factors associated with cognitive dysfunction in old diabetic patients were explored. A Mini Mental State Examination (MMSE) was performed on 907 of 1173 registered elderly Japanese diabetic subjects. To characterize the clinical features of diabetes, we examined indices of glycemic control, lipid metabolism, blood pressure and complications. Single regression analysis adjusted for age showed that shorter height, higher GDS 15 scores, lower serum albumin, history of cerebrovascular disease, the existence of diabetic nephropathy, no smoking habit, no drinking habit, and no occupation were associated with lower MMSE scores. Multiple regression analysis demonstrated that age (odds ratio (OR) = 1.079; 95% confidence interval (CI) = 1.011–1.150), GDS 15 scores (OR = 1.139; 95% CI = 1.045–1.243), serum albumin (OR = 0.336; 95% CI = 0.174–0.745), and history of cerebrovascular disease (OR = 3.011; 95% CI = 1.578–5.748) were the variables significantly associated with having lower MMSE scores.

Association Studies of Variants in the Genes Involved in Pancreatic β-Cell Function in Type 2 Diabetes in Japanese Subjects

Because impaired insulin secretion is characteristic of type 2 diabetes in Asians, including Japanese, the genes involved in pancreatic beta-cell function are candidate susceptibility genes for type 2 diabetes. We examined the association of variants in genes encoding several transcription factors (TCF1, TCF2, HNF4A, ISL1, IPF1, NEUROG3, PAX6, NKX2-2, NKX6-1, and NEUROD1) and genes encoding the ATP-sensitive K(+) channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) with type 2 diabetes in a Japanese cohort of 2,834 subjects. The exon 16 -3c/t variant rs1799854 in ABCC8 showed a significant association (P = 0.0073), and variants in several genes showed nominally significant associations (P < 0.05) with type 2 diabetes. Although the E23K variant rs5219 in KCNJ11 showed no association with diabetes in Japanese (for the K allele, odds ratio [OR] 1.08 [95% CI 0.97-1.21], P = 0.15), 95% CI around the OR overlaps in meta-analysis of European populations, suggesting that our results are not inconsistent with the previous studies. This is the largest association study so far conducted on these genes in Japanese and provides valuable information for comparison with other ethnic groups.

Factors responsible for deteriorating glucose tolerance in newly diagnosed type 2 diabetes in Japanese men

Hyperglycemia frequently continues to worsen even after the diagnosis of overt diabetes. The aim of this study is to evaluate the factors contributing to increasing glucose intolerance after onset of type 2 diabetes in Japanese subjects. Five hundred fifty newly diagnosed type 2 diabetic patients were classified into 3 degrees of hyperglycemia based on plasma glucose levels estimated by 75-g oral glucose tolerance test: diabetes mellitus with isolated fasting hyperglycemia (DM/IFH), DM with isolated postchallenge hyperglycemia (DM/IPH), and DM with fasting and postchallenge hyperglycemia (DM/FPH). In addition, the DM/IFH and DM/IPH groups were subdivided to clarify the determinants of fasting and postchallenge hyperglycemia. Insulin secretion was evaluated by insulinogenic index, and insulin sensitivity was evaluated by composite index of insulin sensitivity (ISI composite). The insulinogenic index in DM/IFH was highest of the 3 groups ( P < .0001). The insulinogenic index in DM/IPH was higher than in DM/FPH ( P < .0001). The international sensitivity index composite in DM/IPH was highest of the 3 groups ( P < .05). Although impaired early-phase insulin secretion plays the crucial role in deterioration from DM/IFH to DM/FPH in Japanese subjects, impaired early-phase insulin secretion and decreased insulin sensitivity both are factors in deterioration from DM/IPH to DM/FPH. In addition, comparison of subgroups of DM/IFH and DM/IPH shows that although decreased early-phase insulin secretion plays the more significant role in postchallenge hyperglycemia in Japanese subjects, insulin sensitivity is the more important factor in fasting hyperglycemia.

Functional polymorphism in Z-DNA–forming motif of promoter of SLC11A1 gene and type 1 diabetes in Japanese subjects: Association study and meta-analysis

The association of the polymorphism of the Z-DNA–forming repeats in the promoter region of SLC11A1 (solute carrier family 11 member 1), formerly designated NRAMP1 (natural resistance associated macrophage protein 1), with type 1 diabetes was studied in a total of 244 Japanese subjects. Three alleles were detected in Japanese subjects. In diabetic patients, allele 2 was less frequent and allele 3 was more frequent, albeit not significantly, than in control subjects. Allele 2 was significantly ( P < .024) less frequent whereas allele 3 was more, albeit not significantly, frequent in the younger onset group than in the control subjects. In patients with a susceptible HLA allele, DRB1*0405 or DRB1*0901, the frequency of allele 2 was significantly ( P < .013) lower and that of allele 3 tended to be higher than that in patients without either DRB1*0405 or DRB1*0901. The protective effect of allele 2 against type 1 diabetes and other autoimmune diseases was confirmed by meta-analysis (summary odds ratio, 0.71, 95% confidence interval, 0.53-0.96). Because allele 2 was shown to be associated with low expression of SLC11A1 and protection against another autoimmune disease, rheumatoid arthritis, the negative association of allele 2 with autoimmune type 1 diabetes in the present study suggests that a less active immune system in subjects with allele 2 may protect individuals from autoimmune diseases.

PAX4 gene variations predispose to ketosis-prone diabetes

Ketosis-prone diabetes (KPD) is a rare form of type 2 diabetes, mostly observed in subjects of west African origin (west Africans and African-Americans), characterized by fulminant and phasic insulin dependence, but lacking markers of autoimmunity observed in type 1 diabetes. PAX4 is a transcription factor essential for the development of insulin-producing pancreatic beta-cells. Recently, a missense mutation (Arg121Trp) of PAX4 has been implicated in early and insulin deficient type 2 diabetes in Japanese subjects. The phenotype similarities between KPD and Japanese carriers of Arg121Trp have prompted us to investigate the role of PAX4 in KPD. We have screened 101 KPD subjects and we have found a new variant in the PAX4 gene (Arg133Trp), specific to the population of west African ancestry, and which predisposes to KPD under a recessive model. Homozygous Arg133Trp PAX4 carriers were found in 4% of subjects with KPD but not in 355 controls or 147 subjects with common type 2 or type 1 diabetes. In vitro, the Arg133Trp variant showed a decreased transcriptional repression of target gene promoters in an alpha-TC1.6 cell line. In addition, one KPD patient was heterozygous for a rare PAX4 variant (Arg37Trp) that was not found in controls and that showed a more severe biochemical phenotype than Arg133Trp. Clinical investigation of the homozygous Arg133Trp carriers and of the Arg37Trp carrier demonstrated a more severe alteration in insulin secretory reserve, during a glucagon-stimulation test, compared to other KPD subjects. Together these data provide the first evidence that ethnic-specific gene variants may contribute to the predisposition to this particular form of diabetes and suggest that KPD, like maturity onset diabetes of the young, is a rare, phenotypically defined but genetically heterogeneous form of type 2 diabetes.

Promoter polymorphism of SLC11A1 (formerly NRAMP1) confers susceptibility to autoimmune type 1 diabetes mellitus in Japanese.

Defective function of antigen-presenting cells has been postulated to be one of the non-HLA-linked susceptibility factors for type 1 diabetes mellitus, though the underlying genetic factors remain unclear. SLC11A1 (formerly NRAMP1), a divalent cation transporter, plays a crucial role in macrophage activation. We performed a case-control study in 224 healthy and 95 type 1 diabetic Japanese subjects, examining the length polymorphisms in the promoter region (-377 to -222) of SLC11A1, which may influence transcriptional activity. Alleles designated 2, 3, and 7 have been identified in Japanese subjects. The frequency of allele 7 was significantly higher in subjects with type 1 diabetes (9.47%) than in the healthy controls (4.46%). The difference is more marked in the subpopulation of Japanese subjects with type 1 diabetes; diabetic subjects with at least one protective HLA class II allele and those without any susceptibility HLA class II haplotypes, DR4-DQ4 or DR9-DQ9, had a much higher allele 7 frequency than controls. These findings suggest that the novel promoter polymorphism of SLC11A1 influences the susceptibility to type 1 diabetes in Japanese subjects.

Role of urotensin II gene in genetic susceptibility to Type 2 diabetes mellitus in Japanese subjects.

Urotensin II is a potent vasoactive hormone and the urotensin II gene (UTS2) is localized to 1p36-p32, one of the regions reported to show possible linkage with Type 2 diabetes in Japanese subjects. The aim of this study is to investigate a possible contribution of SNPs in the UTS2 gene to the development of Type 2 diabetes. We surveyed SNPs in the UTS2 gene in 152 Japanese subjects with Type 2 diabetes mellitus and two control Japanese cohorts: one consisting of 122 elderly subjects who met stringent criteria for being non-diabetic, including being older than 60 years of age with no evidence of diabetes (HbA(1c)<5.6%), and another 268 subjects with normal glucose tolerance. We identified two SNPs with amino acid substitutions, designated T21M and S89N. The allele frequency of 89N was higher in Type 2 diabetic patients than in both elderly normal subjects (p=0.0018) and subjects with normal glucose tolerance (p=0.0011), whereas the allele frequency of T21M was essentially identical in these three groups. Furthermore, in the subjects with normal glucose tolerance, 89N was associated with higher insulin concentrations on oral glucose tolerance test, suggesting reduced insulin sensitivity in subjects with 89N. These results strongly suggest that the S89N polymorphism in the UTS2 gene is associated with the development of Type 2 diabetes, via insulin sensitivity, in Japanese subjects.

The absence of evidence for major effects of the frequent SNP +299G>A in the resistin gene on susceptibility to insulin resistance syndrome associated with Japanese type 2 diabetes

Resistin, specifically secreted from adipocytes, antagonizes insulin and represents a promising candidate gene for type 2 diabetes. We reported that a frequent single nucleotide polymorphism (SNP) +299G>A in this gene is not associated with type 2 diabetes. To determine whether this SNP affects insulin resistance syndrome associated with type 2 diabetes, we examined its effects on susceptibility to obesity, hyperlipidemia and hypertension in type 2 diabetic subjects and on susceptibility to type 2 diabetes by interaction with other frequent genes involved in lipid metabolism, namely, β3-adrenergic receptor (b3AR) Trp64Arg, phosphodiesterase 3B (PDE3B) c.1389G>A or lysosomal acid lipase (LAL) Thr-6Pro. The 99 type 2 diabetic and 99 control subjects were typed by PCR direct sequencing or PCR-RFLP. No differences in frequencies of obesity, hyperlipidemia and hypertension were found between the type 2 diabetic subjects with G/G and those with G/A or A/A genotypes of the resistin SNP. When the combination of the resistin SNP with each of b3AR, PDE3B and LAL SNPs was assessed, no association with type 2 diabetes was evident. Therefore, the frequent SNP +299G>A in the resistin gene is unlikely to have major effects on susceptibility to insulin resistance syndrome associated with type 2 diabetes in Japanese subjects.