Satoru Takagi

Metabolic Syndrome and Cardiac Disease in Japanese Men: Applicability of the Concept of Metabolic Syndrome Defined by the National Cholesterol Education Program–Adult Treatment Panel III to Japanese Men—The Tanno and Sobetsu Study

Results of a 6-year follow-up study were used to determine whether the concept of and the criteria for metabolic syndrome as defined by the National Cholesterol Education Program–Adult Treatment Panel III (NCEP-ATP III) can be applied to Japanese men for prediction of the occurrence of cardiac disease. The subjects were 808 men who underwent mass health check-ups in 1993 and who were not on medication for hypertension, diabetes or hyperlipidemia. Individuals who had hypertriglyceridemia, hypo-high density lipoprotein (HDL) cholesterolemia, high blood pressure, and/or high fasting plasma glucose levels were identified on the basis of the NCEP-ATP III criteria. Not in conformity with the NCEP-ATP III, however, a cut-off value of 85 cm was used for waist girth as an indicator of abdominal obesity. The subjects who had 3 or more risk factors were judged as having metabolic syndrome. The proportion of subjects having metabolic syndrome was 25.3%. In the 6-year follow-up study, cardiac disease occurred in 11.7% of the subjects in the metabolic syndrome group and in 6.7% of the subjects in the non-metabolic syndrome group. Results of regression analysis using Coxs proportional hazards model showed that subjects in the metabolic syndrome group had a 2.2-times greater risk of developing cardiac disease than did subjects in the non-metabolic syndrome group. The concept of metabolic syndrome as defined in the NCEP-ATP III was therefore considered to be useful for predicting the occurrence of cardiac disease in Japanese men.

Correlations of adiponectin level with insulin resistance and atherosclerosis in Japanese male populations

objective  Adiponectin, which is secreted specifically by adipose tissue, has been shown to have an anti‐atherosclerotic effect and to improve insulin resistance. The aim of this study was to determine the correlations of plasma adiponectin concentration with insulin resistance and atherosclerosis.

Relationship between visceral fat and cardiovascular disease risk factors: the Tanno and Sobetsu study.

We assessed the amount of visceral fat using ultrasonography (US) and studied its relationship to cardiovascular disease risk factors, particularly blood pressure. The subjects in the first study were 45 male and 61 female outpatients. We measured the visceral fat area (VFA) of each subject using abdominal CT and waist circumference (WC), and visceral fat distance (VFD) using US. The subjects in the second study were 353 male and 457 female inhabitants of a rural community, for whom VFD and WC were measured. We divided subjects into tertiles based on VFD and WC, and studied the relationship between each group and individual risk factors. In an analysis of outpatient subjects, the correlation coefficient between VFA and VFD was satisfactory: r=0.660 for men and r=0.643 for women. In the analysis of the rural subjects, the high VFD group had a significantly higher odds ratio than the low VFD group in high blood pressure (HBP) and hypertriglyceridemia (HTG) for men and in HBP, HTG and low high-density lipoprotein cholesterolemia (LHDL) for women. Moreover, adjusting VFD for body mass index revealed that, in comparison to WC, VFD was significantly related to risk factors. VFD was used as an independent variable in multiple regression analysis with blood pressure level as a dependent variable; no significant association between WC and blood pressure was obtained. Visceral fat assessment by US may be useful for epidemiological study and for clinics with no abdominal CT equipment for identifying high-risk individuals, such as those with metabolic syndrome.

Incidence of Type 2 Diabetes in Individuals With Central Obesity in a Rural Japanese Population: The Tanno and Sobetsu Study

According to the new International Diabetes Federation (IDF) definition of metabolic syndrome, for a person to be defined as having metabolic syndrome they must have central obesity defined by waist circumference (1). In the definition, there are some ethnic or country-specific differences in the cutoff points of waist circumference, and Japanese cutoff points have been separately established in the IDF definition (≥85 cm for men and ≥90 cm for women). The Japanese Society of Internal Medicine and eight related scientific societies have also jointly announced new Japanese criteria of metabolic syndrome using the same cutoff points of waist circumference (2). However, the impact of central obesity using the cutoff points as a risk of type 2 diabetes is not known. In this study, we investigated the incidence of type 2 diabetes in citizens of two rural communities in Japan to determine the relationship between type 2 diabetes and central obesity, and we also investigated the independent effects of central obesity compared with those of overall obesity. The subjects were 348 men and 523 women selected from 938 citizens who had undergone medical examinations in the towns of Tanno and Sobetsu, Hokkaido, both in 1994 and 2003 or 2004. The following participants in medical examinations in 1994 were excluded: those with missing data on blood …

GENDER DIFFERENCE IN THE RELATIONSHIPS AMONG HYPERLEPTINEMIA, HYPERINSULINEMIA, AND HYPERTENSION

Studies reveals that plasma leptin levels (LEP) in females are higher than those in males, and that LEP in hypertensive subjects are higher than those in BMI-matched normotensive subjects. To investigate the relationships among LEP, blood pressure (BP) and insulin sensitivity, we studied these relationships in 133 Japanese males and 263 females. LEP were positively correlated with BP, body mass index, body fat mass (FM) and homeostasis model assessment (HOMA). Regression analysis in which age and FM were adjusted showed LEP were associated with BP and HOMA. Even with adjustment by age, FM and HOMA, LEP were still positively correlated BP in males. LEP in insulin-resistant hypertensives was significantly higher than those in insulin-sensitive hypertensives, in insulin-sensitive normotensives and in insulin-resistant normotensives in males. However, in females, a significantly higher LEP was observed in insulin-resistant subjects than in insulin-sensitive subjects regardless of hypertension. These data suggest that it would be sexual difference in the relationships among hyperleptinemia, hyperinsulinemia and hypertension.

Incidence of insulin resistance in obese subjects in a rural Japanese population: The Tanno and Sobetsu study

Objectives:  Although it is well known that obesity is closely related to insulin resistance, the incidence of the development of insulin resistance in people with obesity is not known. In this study, we investigated the incidence of insulin resistance in citizens of two rural communities in Japan.

Relationship between insulin resistance and accumulation of coronary risk factors

We examined correlations between the frequency of insulin resistance and the accumulation of coronary risk factors in residents of rural comities in Japanese, using simple criteria for determination of insulin resistance based on evaluation by the euglycaemic‐hyperinsulinaemic glucose clamp (GC) method. The subjects were 376 men and 589 women living in two rural communities in Japan. We measured body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), triglyceride (TG), HDL cholesterol (HDL), and homeostasis model assessment (HOMA‐R). Correlations between HOMA‐R and those parameters were examined. To assess the existence of insulin resistance in these subjects, we used a practical index based on the GC method. The subjects with value of HOMA‐R ≥ 1.73 have insulin resistance. In addition, the HOMA‐R was divided into five quantiles based on the frequency distribution (0.60 or below, from 0.61 to 0.82, from 0.83 to 1.18, from 1.19 to 1.69, and 1.70 or higher), to examine the concentration of risk factors in each group. In total, 74 (19.6%) of the men and 119 (20.3%) of the women had insulin resistance (HOMA‐R ≥ 1.73). It was found that the higher the HOMA‐R, the higher was the number of coronary risk factors, such as hypertension, obesity, hypertriglyceridaemia and hypo HDL cholesterolaemia. The number of coronary risk factors was particular high in subjects with HOMA‐R ≥ 1.70. HOMA‐R in the case of no glucose loading is a useful and practical index for evaluation of insulin resistance and coronary risk factors in the epidemiological study.

Development and progression of atherosclerotic disease in relation to insulin resistance and hyperinsulinemia

It is unclear whether the role of insulin resistance in the development of atherosclerotic cardiovascular disease is similar in populations in which the incidence of atherosclerotic diseases significantly differs from that in Western countries. The aim of this study was to determine the relationship between insulin resistance and the development of cardiovascular disease in the Japanese population. We conducted 75 g-oral glucose tolerance tests (OGTTs) on 1,928 inhabitants of two towns in Hokkaido, Japan. Subjects using anti-hypertensive agents and known diabetic patients were excluded from the study. Data from the remaining 1,227 subjects (540 males and 687 females; mean age 56.0±10.8 years) were used for the analysis, and 1,051 subjects were seen in a follow-up care setting for a period of 8 years. The presence of insulin resistance was defined according to the guidelines reported our previous study: insulin levels of 64.0 mU/l or higher 2 h after the 75 g-OGTT. The insulin-resistant (IR) group had several risk factors such as hypertension, diabetes, treated or untreated hypercholesterolemia, hypertriglyceridemia, low high-density-lipoprotein (HDL) cholesterol levels, and obesity. During the follow-up period of 8 years, the incidence of coronary artery disease, which was adjusted for age, body mass index, sex, systolic blood pressure, fasting plasma glucose, total cholesterol, triglyceride, and HDL cholesterol was significantly (3.2 times) higher in the IR group than in the insulin non-resistant group. The results suggested that insulin resistance is an independent risk factor for coronary artery disease in Japanese subjects, as has also been demonstrated in the case of individuals in Europe and USA.

Relationship between insulin-resistance and remnant-like particle cholesterol

We investigated the relationship between insulin-resistance (IR) and remnant-like particle cholesterol (RLP-C) using 472 subjects (174 men and 298 women) randomly selected from inhabitants of two rural communities in Japan, Tanno and Sobetsu. The level of fasting immunoreactive insulin (FIRI), fasting blood glucose (FBS), total cholesterol (TC), triglyceride (TG), HDL cholesterol, LDL cholesterol, and RLP-C were measured in each subject. Homeostasis model assessment (HOMA-R) was used as an indicator of IR. The subjects were divided into two groups according to the value of HOMA-R: an IR group of subjects with HOMA-R > approximately equal to 1.73 and a normal (NR) group of subjects with HOMA-R <1.73. There was a significant positive correlation between HOMA-R and RLP-C. The value of RLP-C was higher in the IR group than in the NR group (7.1 vs. 3.9 mg/dl in men and 5.3 vs. 3.6 mg/dl in women). The frequency of hyper RLP cholesterolemia (RLP-C > approximately equal to 7.5 mg/dl) was higher in the IR than in the NR group (23.7 vs. 6.6% in men and 20.3 vs. 6.6% in women). The results of multiple regression analysis showed that HOMA-R was closely related to RLP-C. The results of this study suggest that RLP-C is closely associated with IR syndrome.

Effects of Angiotensin II Type 1 Receptor Gene Polymorphisms on Insulin Resistance in a Japanese General Population: The Tanno-Sobetsu Study

Although gene polymorphisms in the renin-angiotensin system (RAS) are predisposing factors for cardiovascular diseases, the precise mechanisms and interactions among confounding factors have not been clarified. We investigated whether genetic variants of RAS are involved in insulin sensitivity in a Japanese general population. During a medical checkup in 2001, participants (n=550) were recruited from among the residents of the towns of Tanno and Sobetsu, and written informed consent was obtained to participate in the genetic analysis and the epidemiological study. The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme gene (ACE), the Met235Thr polymorphism of the angiotensinogen gene (AGT), and the A1166C polymorphism of the angiotensin II type 1 receptor gene (AGTR1) were determined by gel electrophoresis or the TaqMan PCR method. We assessed insulin sensitivity using the homeostasis model assessment insulin resistance (HOMA-IR). The RAS gene polymorphisms were not associated with log-transformed values of HOMA-IR, whereas borderline association (p=0.02) was found between the A1166C polymorphism and dichotomous categorization of insulin resistance (defined as HOMA-IR ≥1.73). Our results suggested that the A1166C polymorphism of AGTR1 might affect insulin resistance by altering the responsiveness to angiotensin II signaling, though this mechanism is as yet inconclusive. Further study is required to confirm these findings in a larger, multi-ethnic population.