[Show abstract][Hide abstract] ABSTRACT: Aim:
Diabetes is accompanied by abdominal obesity, which produces various metabolic abnormalities. While metabolic factors have been considered to promote the development of coronary atherosclerosis in the early-stage of diabetes, it remains unknown whether the presence of obesity in early-stage diabetics affects the natural history of coronary atherosclerosis. We herein investigated the characteristics of the disease substrate in obese early-stage diabetics.
The DIANA (DIAbetes and diffuse coronary NArrowing) study was a serial evaluation of angiographic disease progression in early-stage diabetics with coronary artery disease. A total of 252 study subjects were stratified into non-obese (n=168) and obese groups (n=84). Obesity in Japanese subjects was defined as a body mass index ≥25 kg/m(2) according to the statement about Japanese obesity from the Japan Society for the Study of Obesity. Coronary atherosclerotic changes were evaluated by a quantitative computed analysis. The total lesion length (TLL=total length of all atherosclerotic lesions) was compared between the groups.
The obese patients were younger (p=0.0002) and had higher levels of fasting (p=0.002) and postprandial insulin (p=0.01), and higher triglyceride levels (p=0.02). On serial angiographic evaluations, obese patients had greater disease progression, reflected by a larger percent change in the TLL (24.7±13.7 vs. 7.4±10.0%, p=0.04). However, the improvement of abnormal glucose tolerance was associated with a slowing of disease progression in both non-obese (-0.9±10.7 vs. ＋15.0±11.2%, p=0.04) and obese (＋4.2±22.8 vs. ＋55.5±26.5%, p=0.005) patients.
Obese patients with early-stage diabetes exhibit profound disease progression. Glycemic control attenuated the progression of their coronary atherosclerosis. Our findings indicate progressive but modifiable disease in obese early-stage diabetics under optimal glycemic management.
Full-text · Article · Dec 2014 · Journal of atherosclerosis and thrombosis
[Show abstract][Hide abstract] ABSTRACT: Aim:
In the DIANA(DIAbetes and diffuse coronary NArrowing) study, which evaluated the impact of glucose-lowering therapy in early-stage diabetics with coronary artery disease(CAD), optimal glycemic control resulted in reduced disease progression on angiography. However, despite having a favorable glycemic status, some patients continued to exhibit disease progression. Factors associated with disease progression despite optimal glucose control remain to be elucidated. We sought to investigate clinical characteristics associated with substantial atheroma progression in early-stage diabetic patients with CAD who achieve favorable glycemic control.
The DIANA study is a prospective randomized trial comparing the effects of lifestyle intervention and treatment with voglibose or nateglinide on disease progression on angiography in 302 CAD patients with impaired glucose tolerance/newly diagnosed diabetes. Of these patients, 137 CAD subjects who achieved optimal glycemic control were stratified according to the presence of disease progression on angiography: progressors(n=64) and non-progressors(n=73). Serial coronary angiography studies and quantitative coronary angiography analyses were conducted to evaluate disease progression. A multivariate analysis was performed to elucidate factors associated with disease progression.
Despite the achievement of optimal glycemic control, atheroma progression was observed in 46% of the study subjects. The progressors exhibited lower decreases in systolic blood pressure(SBP: p=0.007) and reduced baseline total lesion lengths(TLL: p=0.01). The multivariate analysis demonstrated that a greater increase in SBP(p=0.006), treatment without statins(p=0.03) and the baseline TLL(p=0.007) were independently associated with disease progression.
Residual risk factors contribute to the progression of coronary atherosclerosis in early-stage diabetics who exhibit improvements in their glycemic status. The present findings underscore the need to intensively modify multiple risk factors during the early diabetic phase in order to prevent atheroma progression.
No preview · Article · Jan 2014 · Journal of atherosclerosis and thrombosis
[Show abstract][Hide abstract] ABSTRACT: Postprandial hyperglycemia and hyperinsulinemia have been considered as important determinants for the development of atherosclerosis. However, it remains to be elucidated whether correction of the postprandial glycemic status prevents atherosclerotic changes.
The DIANA (DIAbetes and diffuse coronary NArrowing) study is a prospective randomized open-label multicenter trial. The 302 patients with coronary artery disease (CAD), impaired glucose tolerance/diabetes mellitus (DM) pattern according to 75-g oral glucose tolerance test and HbA(1c) <6.9% were randomly assigned to life-style intervention (n=101), voglibose (0.9 mg/day, n=100) or nateglinide treatment (180 mg/day, n=101). We compared 1-year coronary atherosclerotic changes evaluated by quantitative coronary arteriography. Although voglibose significantly increased the number of patients with normal glucose tolerance at 1 year, there were no significant differences in coronary atherosclerotic changes at 1 year. However, overall, less atheroma progression was observed in patients in whom glycemic status was improved at 1 year (%change in total lesion length: 3.5% vs. 26.2%, P<0.01, %change in averaged lesion length: 0.7% vs. 18.6%, P=0.02).
Although coronary atherosclerotic changes were similar for voglibose and nateglinide, an improvement in glycemic status at 1 year was associated with less atheroma progression regardless of the treatment. Our findings underscore the management of glycemic abnormality to prevent coronary atherosclerotic changes in Japanese early-stage DM patients with CAD.
No preview · Article · Feb 2012 · Circulation Journal
[Show abstract][Hide abstract] ABSTRACT: Few prospective studies have examined the combined impact of blood pressure (BP) categories and glucose abnormalities on the incidence of cardiovascular disease (CVD) in the general Asian population. This study aimed to examine the effect of the combined risks of these factors on the incidence of CVD in a general Japanese population. We studied 5321 Japanese individuals (aged 30-79 years), without CVD at baseline, who received follow-up for an average of 11.7 years. Serum fasting glucose categories were defined according to the 2003 American Diabetes Association recommendations. BP categories were defined by the 2009 Japanese Society of Hypertension Guidelines for the Management of Hypertension. The Cox proportional hazard ratios (HRs) for CVD according to the serum glucose and BP categories were calculated. In 62,036 person-years of follow-up, we documented 364 CVD events (198 stroke and 166 coronary heart disease (CHD)). Compared with normoglycemic subjects, the multivariable HRs (95% confidence intervals (CIs)) for CVD, CHD and stroke were 1.25 (1.00-1.58), 1.46 (1.04-2.04) and 1.11 (0.81-1.52), respectively, in individuals with impaired fasting glucose (IFG), whereas these values were 2.13 (1.50-3.03), 2.28 (1.34-3.88) and 2.08 (1.29-3.35), respectively, in individuals with diabetes mellitus (DM). Compared with normoglycemic and optimal blood pressure (BP) subjects, increased risks of CVD were observed in the normoglycemic subjects with high-normal BP or hypertension, the IFG subjects with normal or higher BP, and the DM subjects regardless of BP category (P-value for interaction=0.046). In conclusion, the high-normal BP subjects in all glucose categories and the normal BP subjects with IFG showed increased risk of CVD in this Japanese population. Further investigation of larger cohorts of DM subjects should be conducted to better understand this phenomenon.
Full-text · Article · Oct 2010 · Hypertension Research
[Show abstract][Hide abstract] ABSTRACT: The inverse association between plasma B-type natriuretic peptide (BNP) levels and body mass index (BMI) has been reported in Western populations. Here we analyzed the relationship between plasma BNP and obesity in a general urban Japanese population. We recruited 1,759 subjects without atrial fibrillation or history of ischemic heart disease aged 38-95 years (mean age +/- standard deviation 64.5 +/- 10.9 years, 56.1% women, mean BMI 22.8 +/- 3.1 kg/m(2)) from the participants in the Suita Study between August 2002 and December 2003. In multivariable regression analyses adjusted for age, systolic blood pressure, pulse rate, serum creatinine, left ventricular hypertrophy in ECG, the inverse relationships between BNP levels and BMI (kg/m(2)) was found in both sexes (both p<0.001). Multivariable-adjusted mean plasma BNP levels in the group of BMI<18.5, 18.5< or =BMI< 22, 22< or =BMI<25, and 25< or =BMI were 23.4, 17.9, 14.0 and 13.0 pg/mL, respectively (trend p<0.001). The negative association of body fat (percentage and mass), skin fold thickness, or waist circumference with BNP levels was observed the negative associations in both sexes (p<0.01). Among the obesity indices, body fat mass is most tightly associated with BNP. In conclusion, plasma BNP was inversely associated with obesity related markers such as body fat mass, skinfold thickness and waist circumferences after adjusted for relevant covariates in a Japanese population.
No preview · Article · Aug 2010 · Endocrine Journal
[Show abstract][Hide abstract] ABSTRACT: Familial hypercholesterolemia (FH) patients are at particular risk for premature coronary artery disease (CAD) caused by high levels of low density lipoprotein (LDL). Administration of statins enabled us to reduce LDL-C levels in heterozygous FH patients. To evaluate the impact of statins on the clinical fate of heterozygous FH, a retrospective study was performed.
We analyzed the clinical influence of statins on age at the first clinical onset of CAD in 329 consecutive FH patients referred to the lipid clinic of the National Cardiovascular Center. Among 329 heterozygous FH patients, the onset of CAD was identified in 101.
The age at onset of CAD was 58.8+/-12.5 years in the 25 patients on statins at onset, significantly higher than that in the 76 patients not on statins (47.6+/-10.5 years) (p <0.001). The average age at CAD onset was significantly higher after widespread use of statins (54.2+/-13.2 years in 48 patients, Group 1) compared to before October 1989 when statins were approved in Japan (46.9+/-9.6 years in 53 patients; Group 2, p=0.002). A significant difference was seen between Groups 1 and 2 in the variables, including sex, prevalence of smoking habit, LDL-C, and the use of statins, aspirin and probucol. After adjusting for these variables, only statin use was independently associated with the difference in age at CAD onset by multivariable analysis.
Statins have improved the clinical course of patients with heterozygous FH.
No preview · Article · Jul 2010 · Journal of atherosclerosis and thrombosis
[Show abstract][Hide abstract] ABSTRACT: The effects of exercise intervention and to assess its long-term efficacy in preventing subsequent cardiovascular events in patients with type 2 diabetes were little known on randomized controlled trial.
Thirty-eight type 2 diabetic patients (21 men and 17 women) were assigned to either the exercise group (n=21) or the control group without exercise training (n=17) by simple randomization. The exercise training group was scheduled for aerobic and resistance exercise programs for 3 months. After the 3-month, we investigated endothelial function, insulin resistance, adipocytokines and inflammatory markers. The endothelial function was evaluated by examining a flow-mediated endothelium-dependent vasodilatation (FMD). Furthermore, we followed the incidence of cardiovascular events for 24 months.
After 3-month, HbA1C was decreased significantly in both groups. FMD was increased from 7.3+/-4.7% to 10.9+/-6.2% only in the exercise group (p<0.05). Long-term follow-up data showed that the control group developed cardiovascular events more frequently than did the exercise group (p<0.05).
Exercise improves endothelial dysfunction independently of glycemic control and insulin sensitivity in patients with type 2 diabetes. The beneficial effects of 3-month exercise to reduce cardiovascular events persist for 24 months.
No preview · Article · May 2010 · Journal of atherosclerosis and thrombosis
[Show abstract][Hide abstract] ABSTRACT: The association between BMI and low levels of B-type natriuretic peptide (BNP), a marker of heart failure, has been demonstrated in a large population-based cohort. We examined the effects of obesity on BNP levels in patients with diabetes that are often associated with obesity and a higher risk for heart failure.
Plasma BNP levels, BMI, and cardiac function parameters were measured in 608 patients with type 2 diabetes. A computed tomography scan was performed to measure abdominal fat.
In multivariable regression analyses adjusted for age, sex, systolic blood pressure, pulse rate, serum creatinine, asynergy, left atrial dimension, percent fractional shortening, and left ventricular mass, there was an inverse relationship between BMI and BNP (p<0.001). Obese individuals with 25</=BMI<30 and 30</=BMI individuals were more likely to have lower BNP levels compared with BMI<22 individuals (multivariable-adjusted odds ratios (95% CIs): 1.61 (1.16-2.26) and 2.07 (1.35-3.22), respectively). Inverse associations were noted between BNP and visceral fat area (VFA) in both sexes (p=0.029 for men, p=0.024 for women).
In patients with type 2 diabetes, BNP levels are significantly lower in obese subjects after multivariable adjustments. Among various obesity parameters, visceral fat was most closely associated with BNP levels.
No preview · Article · Apr 2010 · Diabetes research and clinical practice
[Show abstract][Hide abstract] ABSTRACT: The autosomal recessive hypercholesterolemia (ARH) gene is located on chromosome 1p35 and encodes a 308-amino acid protein containing a phosphotyrosine-binding domain. Several researchers have identified mutations of ARH that cause autosomal recessive hypercholesterolemia; however, it remains unknown whether this gene is involved in common hypercholesterolemia.
We searched for polymorphisms of the ARH gene by denaturing high-performance liquid chromatography and direct sequencing. We identified 18 single nucleotide polymorphisms of the gene, including 9 novel polymorphisms, and determined 2 haplotype blocks. No association was observed between common hypercholesterolemia and any polymorphisms or haplotypes of the ARH gene; however, we newly identified a rare Thr56Met missense mutation located in the phosphotyrosine-binding domain, which is the functional domain responsible for cholesterol metabolism. Among 1,800 Japanese individuals enrolled in the Suita study, only 4 were heterozygous for Thr56Met and all had hypercholesterolemia. The total cholesterol level and low-density lipoprotein cholesterol level of diabetic patients with the Thr56Met missense mutation was 276.3+/-13.8 mg/dL and 185.3+/-7.37 mg/dL, respectively.
Because the Thr56Met missense mutation occurs in an orthologously conserved functional domain and all subjects with the mutation had hypercholesterolemia resembling familiar hypercholesterolemia, it may be a cause of familial hypercholesterolemia.
No preview · Article · Feb 2010 · Journal of atherosclerosis and thrombosis
[Show abstract][Hide abstract] ABSTRACT: The impact of elevated triglycerides (TG) and non-high density lipoprotein cholesterol (non-HDLC) on the incidence of stroke and myocardial infarction (MI) has not been well evaluated in Asian populations such as in Japan, which have a lower incidence of myocardial infarction, but a higher risk of stroke than Western populations.
The authors conducted an 11.7-year prospective study ending in 2005 of 5098 Japanese aged 30-79 living in an urban population, initially free of stroke or MI. The relationship between serum lipids and the risk for stroke and MI was determined by dividing the participants into four groups stratified by the combination of serum levels of TG and non-HDLC. The cut-off value was 1.7mmol/L for TG and 4.9mmol/L for non-HDLC.
The total person-years were 59,774 (27,461 for men and 32,313 for women). During the follow-up period, there were 113 cases of MI and 180 of stoke (with 116 cerebral infarctions). Compared with the low TG/low non-HDLC group, the hazard ratio (95% confidence interval) for MI in the high TG/high non-HDLC group was 2.55 (1.53-4.24) after adjustment for other cardiovascular risk factors. The hazard ratio for cerebral infarction in the high TG alone group was 1.63 (1.03-2.56); however, the risk of cerebral infarction was not significantly increased in the other groups. High serum levels of TG and non-HDLC are both important targets for the prevention of cardiovascular disease in Japan.
[Show abstract][Hide abstract] ABSTRACT: Epidemiologic studies have shown that in utero malnutrition is a risk factor for adult cardiovascular disease (CVD). Recently, we reported a mouse animal model of 30% maternal caloric reduction, in which offspring showed a significant increase in systolic blood pressure (SBP) as well as in cardiac remodeling-associated morphological parameters such as cardiac enlargement and coronary perivascular fibrosis in adulthood. Using a similar animal model, we here demonstrated that an increased level of protein consumption during an undernourished pregnancy (high-protein diet; HPD) corrected for the development of CVD risk factors found in fetal undernourishment with less protein consumption (standard-protein diet; SPD). In contrast, maternal ad libitum feeding with HPD resulted in significantly elevated SBP and cardiac enlargement in offspring at 16 wks. Appropriate maternal protein ingestion might partly protect against the development of CVD risk factors in offspring.
No preview · Article · Jun 2009 · Endocrine Journal
[Show abstract][Hide abstract] ABSTRACT: 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), one of the isoforms of the 11beta-hydroxysteroid dehydrogenase enzymes, acts as an oxo-reductase to reactivate cortisone to cortisol, plays a critical role in tissue-specific corticosteroid reactions, and is therefore a key molecule associated with the development of metabolic syndrome. We investigated whether variations in the 11beta-HSD1 gene correlated with metabolic syndrome. We performed case-control study using a population-based urban Japanese cohort. Among 3005 urban residents, we examined 431 subjects diagnosed with metabolic syndrome according to the Japanese definition and 777 subjects with none of metabolic syndrome criteria as control. We genotyped three single nucleotide polymorphisms (SNPs) (+9410T>A, +17925C>T, +27447G>C) across the 11beta-HSD1 gene in them and analyzed the associations of SNPs and haplotypes with metabolic syndrome. The +9410A allele showed a tendency to metabolic syndrome (OR=1.5, 95%C.I., 1.0-2.2; P=0.041 and Bonferroni corrected P=0.123) without statistical significance. However, we could not find any significant association between metabolic syndrome and SNPs in the 11beta-HSD1 gene. Our findings indicate that polymorphisms and haplotypes in the 11beta-HSD1 gene are not significantly associated with metabolic syndrome in the Japanese population.
No preview · Article · Jun 2009 · Diabetes research and clinical practice
[Show abstract][Hide abstract] ABSTRACT: Objectives
Metabolic syndrome is defined as a cluster of risk factors for cardiovascular disease and is intimately related to insulin resistance. Resistin, a hormone secreted by adipocytes, may play an important role in communication between adiposity and insulin resistance. We investigated whether variations in the resistin gene associated with metabolic syndrome in a Japanese population.
We analyzed five SNPs, two of which were located in the promoter region (−420C > G, −358G > A), two in intron 2 (+157C > T, +299G > A), and one in the 3′-untranslated region (3′UTR) (+1263G > C) across the resistin gene in 2968 residents from an urban Japanese cohort. The associations of SNPs and haplotypes with metabolic syndrome were analyzed.
The GAC and CGC haplotypes (comprising −420C > G, −358G > A, and +157C > T) had opposite influences on metabolic syndrome susceptibility in men; the former was associated with an increased risk and the latter with a decreased risk. We also found that the −420G allele was significantly associated with an increased risk of metabolic syndrome and significantly correlated with high diastolic blood pressure, high HOMA-IR values, high serum triglyceride levels, low HDL-cholesterol levels and high serum levels of adiponectin.
We identified a risk-conferring SNP and haplotype of the resistin gene for metabolic syndrome in a Japanese population. Our data suggested that resistin gene is a susceptibility gene for metabolic syndrome in Japanese men.
No preview · Article · May 2009 · Obesity Research & Clinical Practice
[Show abstract][Hide abstract] ABSTRACT: Chronic kidney disease (CKD) is increasingly recognized as an independent risk factor for stroke and myocardial infarction (MI). Few studies, however, have examined the relationship between blood pressure (BP) category and these diseases in subjects with and without CKD.
We studied 5494 Japanese individuals (ages 30 to 79, without stroke or MI at baseline) who completed a baseline survey and received follow-up through December 2005. The glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease study equation modified by the Japanese coefficient. CKD was defined as an estimated GFR <60 mL/min/1.73 m2. BP categories were defined by the European Society of Hypertension and European Society of Cardiology 2007 criteria.
In 64 395 person-years of follow-up, we documented 346 incidences of cardiovascular diseases (CVD; 213 strokes and 133 MI events). Compared with the GFR (> or =90 mL/min/1.73 m2) group, the hazard ratios (95% confidential intervals) for stroke were 1.9 (1.3 to 3.0) in the GFR 50 to 59 mL/min/1.73 m2 group and 2.2 (1.2 to 4.1) in the GFR <50 mL/min/1.73 m2 group. Results for cerebral infarction were similar. Compared with the optimal BP subjects without CKD, the normal BP, high-normal BP, and hypertensive subjects without CKD showed increased risks of CVD and stroke; however the impact of each BP category on CVD (P for interaction: 0.04 in men, 0.49 in women) and stroke (0.03 in men, 0.90 in women) was more evident in men with CKD.
CKD may increase the association of BP and CVD in a Japanese urban population.