Rimei Nishimura

Genetic association of glutathione peroxidase-1 with coronary artery calcification in type 2 diabetes: a case control study with multi-slice computed tomography

BackgroundAlthough oxidative stress by accumulation of reactive oxygen species (ROS) in diabetes has become evident, it remains unclear what genes, involved in redox balance, would determine susceptibility for development of atherosclerosis in diabetes. This study evaluated the effect of genetic polymorphism of enzymes producing or responsible for reducing ROS on coronary artery calcification in type 2 diabetes (T2D).MethodsAn index for coronary-arteriosclerosis, coronary artery calcium score (CACS) was evaluated in 91 T2D patients using a multi-slice computed tomography. Patients were genotyped for ROS-scavenging enzymes, Glutathione peroxidase-1 (GPx-1), Catalase, Mn-SOD, Cu/Zn-SOD, as well as SNPs of NADPH oxidase as ROS-promoting elements, genes related to onset of T2D (CAPN10, ADRB3, PPAR gamma, FATP4). Age, blood pressure, BMI, HbA1c, lipid and duration of diabetes were evaluated for a multivariate regression analysis.ResultsCACS with Pro/Leu genotype of the GPx-1 gene was significantly higher than in those with Pro/Pro (744 ± 1,291 vs. 245 ± 399, respectively, p = 0.006). In addition, genotype frequency of Pro/Leu in those with CACS ≥ 1000 was significantly higher than in those with CACS < 1000 (45.5% vs. 18.8%; OR = 3.61, CI = 0.97–13.42; p = 0.045) when tested for deviation from Hardy-Weinbergs equilibrium. Multivariate regression analyses revealed that CACS significantly correlated with GPx-1 genotypes and age.ConclusionThe presence of Pro197Leu substitution of the GPx-1 gene may play a crucial role in determining genetic susceptibility to coronary-arteriosclerosis in T2D. The mechanism may be associated with a decreased ability to scavenge ROS with the variant GPx-1.

Comparison of vildagliptin twice daily vs. sitagliptin once daily using continuous glucose monitoring (CGM): Crossover pilot study (J-VICTORIA study)

BackgroundNo previous studies have compared the DPP-4 inhibitors vildagliptin and sitagliptin in terms of blood glucose levels using continuous glucose monitoring (CGM) and cardiovascular parameters.MethodsTwenty patients with type 2 diabetes mellitus were randomly allocated to groups who received vildagliptin then sitagliptin, or vice versa. Patients were hospitalized at 1 month after starting each drug, and CGM was used to determine: 1) mean (± standard deviation) 24-hour blood glucose level, 2) mean amplitude of glycemic excursions (MAGE), 3) fasting blood glucose level, 4) highest postprandial blood glucose level and time, 5) increase in blood glucose level after each meal, 6) area under the curve (AUC) for blood glucose level ≥180 mg/dL within 3 hours after each meal, and 7) area over the curve (AOC) for daily blood glucose level <70 mg/dL. Plasma glycosylated hemoglobin (HbA1c), glycoalbumin (GA), 1,5-anhydroglucitol (1,5AG), immunoreactive insulin (IRI), C-peptide immunoreactivity (CPR), brain natriuretic peptide (BNP), and plasminogen activator inhibitor-1 (PAI-1) levels, and urinary CPR levels, were measured.ResultsThe mean 24-hour blood glucose level was significantly lower in patients taking vildagliptin than sitagliptin (142.1 ± 35.5 vs. 153.2 ± 37.0 mg/dL; p = 0.012). In patients taking vildagliptin, MAGE was significantly lower (110.5 ± 33.5 vs. 129.4 ± 45.1 mg/dL; p = 0.040), the highest blood glucose level after supper was significantly lower (206.1 ± 40.2 vs. 223.2 ± 43.5 mg/dL; p = 0.015), the AUC (≥180 mg/dL) within 3 h was significantly lower after breakfast (484.3 vs. 897.9 mg/min/dL; p = 0.025), and urinary CPR level was significantly higher (97.0 ± 41.6 vs. 85.2 ± 39.9 μg/day; p = 0.008) than in patients taking sitagliptin. There were no significant differences in plasma HbA1c, GA, 1,5AG, IRI, CPR, BNP, or PAI-1 levels between patients taking vildagliptin and sitagliptin.ConclusionsCGM showed that mean 24-h blood glucose, MAGE, highest blood glucose level after supper, and hyperglycemia after breakfast were significantly lower in patients with type 2 diabetes mellitus taking vildagliptin than those taking sitagliptin. There were no significant differences in BNP and PAI-1 levels between patients taking vildagliptin and sitagliptin.Trial registrationUMIN000007687

Incidence of ESRD and survival after renal replacement therapy in patients with type 1 diabetes: a report from the allegheny county registry

BACKGROUND Little information is available regarding the long-term incidence of end-stage renal disease (ESRD) and survival after the introduction of renal replacement therapy (RRT) in patients with type 1 diabetes. METHODS We studied 1,075 patients with type 1 diabetes (onset age < 18 years) diagnosed between 1965 and 1979, who comprise the Allegheny County population-based registry. Onset of ESRD was defined as the introduction of RRT (dialysis or transplantation). RESULTS Of 1,075 registrants, the living status of 975 patients (90.7%) and complication status of 798 patients (74.2%) were ascertained as of January 1, 1999. During the observation period, 104 patients (13.0%) developed ESRD, for an incidence rate of 521/100,000 person-years (95% confidence interval, 424 to 629). The cumulative incidence of ESRD was 11.3% at 25 years of diabetes. A significant decline was observed in 20-year cumulative incidence rates of ESRD for patients diagnosed between 1965 and 1969, 1970 and 1974, and 1975 and 1979 (9.1%, 4.7%, and 3.6%, respectively; P = 0.006). Of 104 patients with ESRD, 29 patients (28%) received dialysis alone, 44 patients (42%) received dialysis followed by kidney transplantation, 26 patients (25%) underwent successful transplantation alone, and 5 patients (5%) underwent a failed kidney transplantation followed by dialysis therapy. The cumulative survival rate 10 years after the introduction of RRT was 51.2%. The cumulative survival rate of dialysis therapy followed by kidney transplantation was significantly greater than that of dialysis therapy alone (P < 0.001). No difference was detected in survival between pancreas-kidney transplant recipients and kidney-alone transplant recipients (P = 0.7). CONCLUSION The incidence of ESRD observed in this cohort has declined, probably reflecting the better glycemic and blood pressure control available since the early 1980s.

Prospective randomized study for optimal insulin therapy in type 2 diabetic patients with secondary failure

BackgroundThe large clinical trials proved that Basal-Bolus (BB) insulin therapy was effective in the prevention of diabetic complications and their progression. However, BB therapy needs multiple insulin injections per a day. In this regard, a biphasic insulin analogue needs only twice-daily injections, and is able to correct postprandial hyperglycemia. Therefore it may achieve the blood glucose control as same as that of BB therapy and prevent the diabetic complications including macroangiopathy.MethodsIn PROBE (Prospective, Randomized, Open, Blinded-Endpoint) design, forty-two type 2 diabetic patients (male: 73.8%, median(inter quartile range) age: 64.5(56.8~71.0)years) with secondary failure of sulfonylurea (SU) were randomly assigned to BB therapy with a thrice-daily insulin aspart and once-daily basal insulin (BB group) or to conventional therapy with a twice-daily biphasic insulin analogue (30 Mix group), and were followed up for 6 months to compare changes in HbA1c, daily glycemic profile, intima-media thickness (IMT) of carotid artery, adiponectin levels, amounts of insulin used, and QOL between the two groups.ResultsAfter 6 months, HbA1c was significantly reduced in both groups compared to baseline (30 Mix; 9.3(8.1~11.3) → 7.4(6.9~8.7)%, p < 0.01, vs BB;8.9(7.7~10.0) → 6.9(6.2~7.3)%, p < 0.01), with no significant difference between the groups in percentage change in HbA1c (30 Mix; -14.7(-32.5~-7.5)% vs BB -17.8(-30.1~-11.1)%, p = 0.32). There was a significant decrease in daily glycemic profile at all points except dinner time in both groups compared to baseline. There was a significant increase in the amount of insulin used in the 30 Mix group after treatment compared to baseline (30 Mix;0.30(0.17~0.44) → 0.39(0.31~0.42) IU/kg, p = 0.01). There was no significant difference in IMT, BMI, QOL or adiponectin levels in either group compared to baseline.ConclusionBoth BB and 30 mix group produced comparable reductions in HbA1c in type 2 diabetic patients with secondary failure. There was no significant change in IMT as an indicator of early atherosclerotic changes between the two groups. The basal-bolus insulin therapy may not be necessarily needed if the type 2 diabetic patients have become secondary failure.Trial registrationCurrent Controlled Trials number, NCT00348231

Changes in body mass index, leptin and adiponectin in Japanese children during a three-year follow-up period: a population-based cohort study

ObjectiveThe study examined changes in and relationship between body mass index (BMI), leptin and adiponectin levels over a 3-year period in a pediatric population-based cohort.Study designA 3-year prospective cohort study of 268 boys and 251 girls aged 9–10 in Ina, Saitama, Japan.ResultsMedian body mass index (BMI) significantly increased from baseline (age 9–10) to follow up (age 12–13) in boys from 17.1 to 18.3 kg/m2 (P < 0.001) and in girls from 16.5 to 18.5 kg/m2 (P < 0.001), respectively. Adiponectin values significantly decreased from baseline to follow up in boys (13.5 to 8.9 μg/ml, respectively) (P < 0.001) and in girls (12.4 to 9.5 μg/ml, respectively) (P < 0.001). Leptin values at follow up significantly decreased from baseline in boys (4.9 to 2.3 ng/dl, respectively) (P < 0.001) and also in girls (5.3 to 5.1 ng/dl, respectively) (P = 0.049).A relatively strong correlation was seen in BMI (Spearmans correlation coefficient, r = 0.864, P < 0.001 in boys; r = 0.873, P < 0.001 in girls), adiponectin (r = 0.705, P < 0.001 in boys; r = 0.695, P < 0.001 in girls), and leptin (r = 0.449, P < 0.001 in boys; r = 0.610, P < 0.001 in girls) before and after the three-year period.The ratio of follow up to baseline BMI was negatively correlated with that for adiponectin (r = -0.224, P < 0.001 in boys; r = -0.165, P = 0.001 in girls) and positively correlated with that for leptin (r = 0.518, P < 0.001 in boys; r = 0.609, P < 0.001 in girls).ConclusionThis study demonstrated that baseline adiponectin, leptin and BMI values measured at ages 9–10 correlated with those measured three years later. However, adiponectin values decreased and leptin values increased in those subjects whose BMI increased during over this period.

Relationship of body mass index to percent body fat and waist circumference among schoolchildren in Japan--the influence of gender and obesity: a population-based cross-sectional study.

BackgroundAlthough the correlation coefficient between body mass index (BMI) and percent body fat (%BF) or waist circumference (WC) has been reported, studies conducted among population-based schoolchildren to date have been limited in Japan, where %BF and WC are not usually measured in annual health examinations at elementary schools or junior high schools. The aim of the present study was to investigate the relationship of BMI to %BF and WC and to examine the influence of gender and obesity on these relationships among Japanese schoolchildren.MethodsSubjects included 3,750 schoolchildren from the fourth and seventh grade in Ina-town, Saitama Prefecture, Japan between 2004 and 2008. Information about subjects age, sex, height, weight, %BF, and WC was collected from annual physical examinations. %BF was measured with a bipedal biometrical impedance analysis device. Obesity was defined by the following two criteria: the obese definition of the Centers for Disease Control and Prevention, and the definition of obesity for Japanese children. Pearsons correlation coefficients between BMI and %BF or WC were calculated separately for sex.ResultsAmong fourth graders, the correlation coefficients between BMI and %BF were 0.74 for boys and 0.97 for girls, whereas those between BMI and WC were 0.94 for boys and 0.90 for girls. Similar results were observed in the analysis of seventh graders. The correlation coefficient between BMI and %BF varied by physique (obese or non-obese), with weaker correlations among the obese regardless of the definition of obesity; most correlation coefficients among obese boys were less than 0.5, whereas most correlations among obese girls were more than 0.7. On the other hand, the correlation coefficients between BMI and WC were more than 0.8 among boys and almost all coefficients were more than 0.7 among girls, regardless of physique.ConclusionsBMI was positively correlated with %BF and WC among Japanese schoolchildren. The correlations could be influenced by obesity as well as by gender. Accordingly, it is essential to consider gender and obesity when using BMI as a surrogate for %BF and WC for epidemiological use.

Comparing the Efficacy of α-Glucosidase Inhibitors in Suppressing Postprandial Hyperglycemia Using Continuous Glucose Monitoring: A Pilot Study—The MAJOR Study

BACKGROUND This study aimed to compare glucose variability in patients given the α-glucosidase inhibitors miglitol and acarbose using continuous glucose monitoring (CGM). METHODS Ten type 2 diabetes patients were hospitalized for 4 days, and their glucose levels were measured using CGM. Patients were given miglitol (50 mg) or acarbose (100 mg) before each meal on Day 2, and vice versa on Day 3, in a randomized crossover design. The patients had three identical test meals on Days 2 and 3. The CGM data were used to compare each parameter for glycemic variability after each of the three meals. RESULTS No significant differences were observed between miglitol treatment or acarbose treatment in regard to the range of increase in glucose levels from baseline to peak, time to peak postprandial glucose levels from the preprandial period, and area under the curve for glycemic variability from the preprandial period to 3 h after each meal. However, the range of increase in glucose levels at 30 min (0.4 vs. 30.7 mg/dL, P < 0.0001) and 60 min (32.8 vs. 67.5 mg/dL, P <0.0001) after lunch and 30, 60, and 90 min after dinner (3.3 vs. 22.2 mg/dL, P = 0.0249; 36.6 vs. 67.5 mg/dL, P < 0.0001; and 60.5 vs. 81.6 mg/dL, P = 0.0073, respectively) was significantly smaller in miglitol treatment compared with acarbose treatment. CONCLUSIONS In a pilot study with a crossover design in 10 type 2 diabetes patients, it was shown that although there was no significant difference in glucose variability with miglitol or acarbose after a fat-rich diet, glucose increases was significantly reduced with miglitol after a meal comprising typical Japanese diet 60-90 min postprandially.

High Blood Pressure in Obese and Nonobese Japanese Children: Blood Pressure Measurement is Necessary Even in Nonobese Japanese Children

Background Although the prevalences of obesity and hypertension (HT) are increasing in children, there have been few epidemiological studies of HT in Japanese children. We evaluated the prevalences of HT and high-normal blood pressure (HNBP), and examined the relationship between blood pressure (BP) and body mass index (BMI), in Japanese children. Methods The subjects of this study were 2420 children living in the town of Ina, Saitama Prefecture, Japan during the period from 2006 through 2008. Body height, weight, and BP were measured. HT and HNBP were defined according to the HT criteria for Japanese children. Children with HNBP or HT were defined as having high blood pressure (HBP). Results The prevalences of HBP were 15.9% and 15.8% in fourth-grade boys and girls, respectively, and 11.1% and 10.8% in seventh-grade boys and girls, respectively. Irrespective of sex or grade level, a higher BMI was associated with a higher prevalence of HBP (P < 0.001). When compared with the <50th percentile BMI category, the crude odds ratios (ORs) were statistically significant for the 75th to 84th percentile category in fourth-grade boys (OR: 4.54, 95% CI: 2.36–8.76), the ≥95th percentile in fourth-grade girls (13.29, 5.93–29.77), the 85th to 94th percentile (3.16, 1.46–6.84) in seventh-grade boys, and the ≥95th percentile (7.96, 3.18–19.93) in seventh-grade girls. Conclusions BMI was associated with HBP in Japanese school children. In addition, some children in the lower BMI categories also had HBP.

Effects of luseogliflozin, a sodium–glucose co-transporter 2 inhibitor, on 24-h glucose variability assessed by continuous glucose monitoring in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, crossover study

The aim of the present study was to determine the effects of luseogliflozin on 24‐h glucose levels, assessed by continuous glucose monitoring, and on pharmacodynamic variables measured throughout the day. In this double‐blind, placebo‐controlled, crossover study, 37 patients with type 2 diabetes mellitus inadequately controlled with diet and exercise were randomized into two groups. Patients in each group first received luseogliflozin then placebo for 7 days each, or vice versa. After 7 days of treatment, the mean 24‐h glucose level was significantly lower with luseogliflozin than with placebo [mean (95% confidence interval) 145.9 (134.4–157.5) mg/dl vs 168.5 (156.9–180.0) mg/dl; p < 0.001]. The proportion of time spent with glucose levels ≥70 to ≤180 mg/dl was significantly greater with luseogliflozin than with placebo [median (interquartile range) 83.2 (67.7–96.5)% vs 71.9 (46.9–83.3)%; p < 0.001] without inducing hypoglycaemia. The decrease in glucose levels was accompanied by reductions in serum insulin levels throughout the day.

Relationship between hemoglobin A1c and cardiovascular disease in mild-to-moderate hypercholesterolemic Japanese individuals: subanalysis of a large-scale randomized controlled trial

BackgroundAlthough the ADA/EASD/IDF International Expert Committee recommends using hemoglobin A1c (HbA1c) to define diabetes, the relation between HbA1c and cardiovascular disease (CVD) has not been thoroughly investigated. We analyzed this relation using clinical data on Japanese individuals with hypercholesterolemia.MethodsIn the large-scale MEGA Study 7832 patients aged 40 to 70 years old with mild-to-moderate hypercholesterolemia without CVD were randomized to diet alone or diet plus pravastatin and followed for >5 years. In the present subanalysis of that study a total of 4002 patients with baseline and follow-up HbA1c data were stratified according to having an average HbA1c during the first year of follow-up <6.0%, 6.0%-<6.5%, or ≥6.5% and their subsequent 5-year incidence rates of CVD compared according to sex, low-density lipoprotein cholesterol (LDL-C), and treatment arm.ResultsOverall, risk of CVD was significantly 2.4 times higher in individuals with HbA1c ≥6.5% versus <6.0%. A similar relation was noted in men and women (hazard ratio [HR], 2.1; p <0.01 and HR, 3.0; p <0.01, respectively) and was regardless of treatment arm (diet alone group: HR, 2.2; p <0.001; diet plus pravastatin group: HR, 1.8; p = 0.02). Spline curves showed a continuous risk increase according to HbA1c level in all subpopulations studied.ConclusionsIn hypercholesterolemic individuals the risk of CVD increases linearly with HbA1c level. This significant contribution by elevated HbA1c to increased CVD is independent of pravastatin therapy, and thus requires appropriate HbA1c management in addition to lipids reduction.