[Metabolic syndrome].

Considerable attention has focused on the prevention of dementia in terms of non-genetic risk factors, including midlife obesity, especially visceral obesity associated with hyperglycemia, hypertension, and hypercholesterolemia. Accumulating evidence has indicated that the increased insulin resistance in relation to visceral fat accumulation is potential risk of Alzheimer's disease (AD) and vascular dementia. Reducing the accumulating visceral fat may contribute to reduce the risk of on set and progression of AD and vascular dementia. Treatment with renin-angiotensin system blockers in hypertension might slow the rate of cognitive decline in patients with AD by modulating insulin resistance.

Renin-angiotensin system blockers affect cognitive decline and serum adipocytokines in Alzheimer's disease.

BACKGROUND: Accumulating evidence indicates an association of Alzheimer's disease (AD) with the metabolic syndrome (MetS), characterized by visceral fat accumulation with insulin resistance and altered secretion of adipocytokines such as adiponectin and leptin. The renin-angiotensin system (RAS) regulates blood pressure and insulin resistance. Recent studies suggest that the RAS plays crucial roles in cognitive functions and that adipocytokines exert neuroprotective activity in the brain. We investigated whether RAS blockers (RASB) affect adipocytokines and cognitive function in patients with AD. METHODS: We studied 78 patients with a diagnosis of probable AD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition and 106 nondemented control subjects who visited our clinic with a main complaint of headache or dizziness. We examined retrospectively the effects of RASB on adipocytokines and cognitive decline in patients with AD who were divided into three groups: hypertension treated with RASB (HT-RASB; n = 17), hypertension treated with other antihypertensive drugs (HT-other; n = 34), and no hypertension (non-HT; n = 27). RESULTS: The HT-RASB group had a significantly higher serum leptin level and a relatively larger visceral fat area than the other groups, because of the bias toward patients with MetS in this group. The HT-RASB group also had a significantly lower immunoreactive insulin level, a relatively low homeostasis model assessment as an index of insulin resistance, and a relatively high serum adiponectin level among the three groups. Cognitive decline, estimated on the basis of the mean annual decline using the Hasegawa Dementia Scale score was significantly low in the HT-RASB group. CONCLUSION: Treatment with RASB might modulate serum adipocytokines and glucose homeostasis, potentially slowing cognitive decline in patients with AD.

Visceral obesity and hypoadiponectinemia are significant determinants of hepatic dysfunction: An epidemiologic study of 3827 Japanese subjects.

BACKGROUND AND AIM: Adiponectin is an anti-inflammatory and insulin-sensitizing adipocytokine, and its serum concentrations are reduced in obesity with visceral fat accumulation. Visceral fat accumulation is an independent determinant of elevated serum liver enzymes. Hypoadiponectinemia plays important roles in the clinical progression of nonalcoholic steatohepatitis. The aim of this study was to evaluate the relation between visceral fat area (VFA), serum adiponectin concentration, and biochemical liver tests, such as aspartate aminotransferase, alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT) in normal subjects. METHODS: The study group comprised 3827 Japanese subjects [mean age+/-SD; 47.6+/-10.7 y: 2854 males (48.4+/-10.7 y), 973 females (45.3+/-10.1 y)], who underwent annual health checkup in 2004. In addition to parameters measured in the annual health checkup, VFA and serum adiponectin concentration were measured by the bioelectrical impedance analysis method and a latex particle-enhanced turbidimetric assay system, respectively. RESULTS: Pearson's correlation analysis showed a significant correlation between VFA and the levels of the above 3 liver enzymes in both sexes, and a significant negative correlation between adiponectin and all biochemical liver tests in men and with ALT and GGT in women. Stepwise multiple regression analysis showed that VFA was a significant determinant of serum liver tests in both sexes. Moreover, serum adiponectin concentration significantly and negatively influenced male ALT and GGT and female GGT. CONCLUSIONS: Both visceral obesity and hypoadiponectinemia are significant determinants of subtle and asymptomatic hepatic dysfunction in normal Japanese subjects.

Short-term intervention reduces bioelectrical impedance analysis-measured visceral fat in type 2 diabetes mellitus.

In 25 patients with Type 2 diabetes mellitus, the short-term in-hospital calorie restriction combined with moderate exercise reduced visceral fat. The reduction of visceral fat can improve metabolic cardiovascular risk factors, while the reductions in body weight and waist circumference were small and reduction in subcutaneous fat was not significant.

Fat accumulation and obesity-related cardiovascular risk factors in middle-aged Japanese men and women.

OBJECTIVE: A cluster of multiple risk factors has been noted to constitute the background of cardiovascular disease. The purpose of this study was to evaluate the relationship between the visceral fat area (VFA) or subcutaneous fat area (SFA) and a cluster of obesity-related cardiovascular risk factors, including hyperglycemia, dyslipidemia and elevated blood pressure, in middle-aged Japanese men and women. METHODS: A total of 571 subjects (m=434; f=137; age: 53 ± 9 years) who underwent health examinations with evaluations of body fat distribution using computed tomography scans and assessments of 75-g oral glucose tolerance tests were enrolled in this study. RESULTS: The VFA and SFA were linearly correlated with the number of risk factors in both men and women. The area under the receiver-operating characteristic curve of VFA (m=0.741, f=0.763) was significantly higher than that of SFA (m=0.636, f=0.689) with respect to the clustering of risk factors (one or more). The men exhibited larger VFA values and smaller SFA values than the women in similar body mass index (BMI) categories. Men with a VFA of ≥100 cm(2) irrespective of BMI and women with a VFA of ≥100 cm(2) and a BMI of ≥25 kg/m(2) demonstrated a high prevalence of diabetes mellitus and impaired glucose tolerance. Men and women with a VFA of ≥100 cm(2) irrespective of BMI demonstrated a high prevalence of type IIb dyslipidemia. CONCLUSION: These results suggest that the absolute value of VFA rather than SFA is more closely associated with a cluster of risk factors irrespective of sex and is a good marker for selecting subjects to whom weight reduction should be recommended in order to prevent cardiovascular disease in the general population.

Clinical significance of visceral adiposity assessed by computed tomography: A Japanese perspective.

Abdominal obesity, rather than total amount of fat, is linked to obesity-related disorders. Visceral adiposity is an important component of obesity-related disorders in Japanese individuals with a mild degree of adiposity compared with Western subjects. In 1983, our group reported techniques for body fat analysis using computed tomography (CT) and established the concept of visceral fat obesity in which intra-abdominal fat accumulation is an important factor in the development of obesity-related complications, such as diabetes, lipid disorders, hypertension and atherosclerosis. Our group also established ideal imaging conditions for determining abdominal fat area at the umbilical level CT scan. Visceral fat area (VFA) measured in a single slice at L4 level correlated significantly with the total abdominal visceral fat volume measured on multislice CT scan. In a large-scale study of a Japanese population, the mean number of obesity-related cardiovascular risk factors (hypertension, low high-density lipoprotein cholesterolemia and/or hypertriglyceridemia, and hyperglycemia) was greater than 1.0 at 100 cm(2) of VFA, irrespective of gender, age and body mass index. Our group also demonstrated that reduction of visceral fat accumulation subsequent to voluntary lifestyle modification, "Hokenshido", correlated with a decrease in the number of obesity-related cardiovascular risk factors. It is important to select the most appropriate subjects from the general population (e.g., non-obese subjects with a cluster of risk factors for the metabolic syndrome) that are most suitable for body weight reduction, with the goal of preventing atherosclerotic cardiovascular diseases.

Insulin-secretion capacity in normal glucose tolerance, impaired glucose tolerance, and diabetes in obese and non-obese Japanese patients.

UNLABELLED: Aims/Introduction: Pronounced reduction of insulin secretion in response to a rise in glucose level has been reported in Japanese patients compared with Caucasian patients, but the mean body mass index (BMI) is also lower in Japanese patients. As BMI is a determinant of insulin secretion, we examined insulin-secretion capacity in obese and non-obese Japanese patients. MATERIALS AND METHODS: Using the oral glucose tolerance test (OGTT), we estimated the insulin-secreting capacity in obese (BMI ≥ 25) and non-obese (BMI < 25) Japanese patients, including 1848 patients with normal glucose tolerance (NGT), 321 patients with impaired glucose tolerance (IGT) and 69 diabetes (DM) patients. RESULTS: The insulinogenic index (I.I.), calculated by dividing the increment in serum insulin by the increment in plasma glucose from 0 to 30 min during OGTT, decreased from NGT to IGT and to DM in patients with and without obesity. In patients with NGT, IGT and DM, the I.I. values of obese patients were higher than those of the non-obese patients. The peak of insulin concentration in OGTT appeared at 60 min in NGT and at 120 min in IGT in both obese and non-obese patients, but in DM it was observed at 120 min in obese patients and at 60 min in non-obese patients. CONCLUSIONS: These results show that early-phase insulin secretion in obese Japanese patients is higher than in non-obese patients in all stages of glucose tolerance, and delayed insulin-secretion capacity is also conserved in obese Japanese patients, even in IGT and DM, which is similar to Caucasian patients. (J Diabetes Invest, doi:10.1111/j.2040-1124.2011.00180.x, 2011).

Predictors of deterioration of glucose tolerance and effects of lifestyle intervention aimed at reducing visceral fat in normal glucose tolerance subjects with abdominal obesity.

UNLABELLED: Aims/Introduction: The aim of the present study was to determine the predictors of deterioration of glucose tolerance in individuals with normal glucose tolerance (NGT) and abdominal obesity, and whether a lifestyle intervention to reduce visceral fat is effective in these individuals. MATERIALS AND METHODS: The study subjects were 251 individuals who had abdominal obesity with certain risk factors (hypertension, high fasting plasma glucose (FPG), elevated hemoglobin A1c (HbA1c), dyslipidemia and hyperuricemia) and underwent oral glucose tolerance test (OGTT) in 2004 and 2005. RESULTS: Using the area under the receiver operating characteristic curve, we found that PG at 0 min, 60 min, and area under the curve (AUC) of glucose from 0 to 120 min (AUC [glucose0-120]) in OGTT were significant predictors of deterioration of glucose tolerance, with optimal cut-off values of 95 mg/dL, 158 mg/dL and 271 mg h/dL, respectively. Although the rate of deterioration of glucose tolerance didn't decrease with reductions in visceral fat area (VFA) over the 1-year period in subjects with NGT, the rate tended to decrease with reductions in VFA in high-risk NGT subjects (PG at 0 min > 95 or at 60 min > 158, or AUC [glucose0-120] > 271). CONCLUSIONS: These results suggest that reduction of visceral fat over 1 year might not be beneficial in all subjects with NGT, but is beneficial in high-risk NGT. We propose that individuals with values of the aforementioned predictors higher than the cut-off levels, even those with NGT, should receive a lifestyle intervention program aimed at reducing visceral fat to prevent deterioration of glucose tolerance. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00080.x, 2011).

Health education "Hokenshido" program reduced metabolic syndrome in the Amagasaki visceral fat study. Three-year follow-up study of 3,174 Japanese employees.

OBJECTIVE: The aim of this study was to evaluate the effects of health checkup and the health education "Hokenshido" program based on the concept that visceral fat accumulation causes metabolic syndrome (MetS), leading to cardiovascular disease (CVD). METHODS AND SUBJECTS: Based on the Japanese definition of metabolic syndrome, in the annual health checkup for general subjects, the measurement of waist circumference and use of "Where am I?" chart on the way to develop atherosclerosis were introduced. The study group comprised 3,174 Japanese employees [2,440 males (46±11 years, mean ± SD), 734 females (43±10 years)], who underwent annual health checkup in 2003, 2004, and 2005. The medical staff provided "Hokenshido" for subjects assessed as having MetS and/or at high risk for CVD. RESULTS: The prevalence of the MetS in 2003, 2004 and 2005 decreased in males (20.8%, 17.2%, 14.4%, p<0.001) and females (3.0%, 2.2%, 1.9%, p=0.359), respectively. Among subjects with MetS at baseline, the number of subjects with MetS significantly decreased in males (508, 287, 247, p<0.0001) and females (22, 8, 6, p<0.0001), respectively. Mean waist loss was 1.6 cm in males (<0.0001) and 1.5 cm in females (<0.001). Among subjects with metabolic syndrome at baseline, the mean waist loss was 2.5 cm in males (<0.0001) and 3.9 cm in females (<0.05). Fatal atherosclerotic vascular events were not recorded in this study period. CONCLUSION: Health check-up and the "Hokenshido" program reduced the prevalence of the MetS, which might lead to prevention of CVD.

Absolute value of bioelectrical impedance analysis-measured visceral fat area with obesity-related cardiovascular risk factors in Japanese workers.

AIM: The accumulation of Visceral fat is known to precede metabolic disorders and atherosclerosis. This study aimed to determine the relationships between body mass index (BMI), waist circumference (WC), estimated visceral fat area (eVFA) measured by bioelectrical impedance analysis (BIA), and obesity-related cardiovascular risk factors. METHODS: The study population was 2,870 middle-aged Japanese employees (males/females=2,322/ 548), who had undergone a health check-up. RESULTS: In the receiver operating characteristic (ROC) curve, the cutoff levels yielding maximal sensitivity plus specificity for predicting the prevalence of ≥ 2 risks were, 24.5 kg/m(2) for BMI, 84.6 cm for WC, and 111 cm(2) for eVFA in males, and 23.6 kg/m(2), 81.5 cm, and 67 cm(2) in females. The average number of risk factors was over 1.0 in those with a BMI ≥ 25 kg/m(2) and with a WC ≥ 85 cm for males, ≥ 28 kg/m(2) and ≥ 95 cm respectively for females, and those with an eVFA ≥ 100 cm(2) for both males and females. In males, it was around 1.0 with cutoff levels of BMI, WC, and eVFA from the ROC curve. However, in females, it was around 0.6, because the prevalence of subjects with obesity and multiple risks was very low. CONCLUSIONS: These results suggested that the cutoff level for visceral fat reduction should be set based on an absolute value of risk factors, rather than a calculated value. In regular health check-up, it may be useful to set an absolute cutoff value for eVFA at 100 cm(2) as criteria to screen for multiple obesity-related cardiovascular risk factors.

Impaired early insulin secretion in Japanese type 2 diabetes with metabolic syndrome.

Although it is widely believed that type 2 diabetics with metabolic syndrome (MS) have insulin resistance, the beta-cell function of these patients is largely unknown. We evaluated the characteristics of insulin secretion in Japanese type 2 diabetics with MS after minimizing the influence of glucotoxity. A 75-g OGTT was performed in 192 diabetic subjects and 275 subjects with normal glucose tolerance (NGT). Although there was no significant difference of the AUC (insulin(0-120)) between the MS group and the NGT group, the insulinogenic index (I.I.) was significantly lower in MS patients compared with NGT subjects. The BMI, maximum BMI, waist circumference, and VFA were all positively correlated with I.I. in the MS group (r=0.298-0.376). By stepwise multiple regression analysis, the BMI was shown to be an independent determinant of I.I. in the MS group (standardized regression coefficient: 0.376, p=0.0004), and it accounted for 13% of the variance in I.I. The impaired I.I. was also found in the MS group with untreated type 2 diabetes. These results indicate that early insulin secretion is impaired in type 2 diabetics with MS. The positive association between BMI and I.I. in diabetics with MS may be explained by beta-cell compensation for reduced insulin sensitivity.

Relationship between the serum uric acid level, visceral fat accumulation and serum adiponectin concentration in Japanese men.

OBJECTIVE: Visceral fat accumulation is an underlying component of the metabolic syndrome (MetS). Hypoadiponectinemia is one of the key molecules of the MetS. In the present study, we investigated the relationship between the serum uric acid level, visceral fat accumulation and serum adiponectin concentration in Japanese men. PATIENTS AND METHODS: The study group comprised 1,520 Japanese employed men (mean age: 45.6+/-10.4 years, +/- SD), who had undergone an annual health check-up both in 2004 and 2005. In addition to parameters measured in the annual health check-up, visceral fat area (VFA) and serum adiponectin concentration were measured by the bioelectrical impedance analysis method and a sandwich enzyme-linked immunosorbent assay (ELISA) system, respectively. RESULTS: Visceral fat accumulation was identified in 56.1% of the subjects with hyperuricemia. There was significant positive correlation between visceral fat area and serum uric acid levels (r=0.223, p<0.0001), and negative correlation between serum adiponectin concentration and serum uric acid levels (r=-0.198, p<0.0001). The one-year change in VFA was associated with the one-year change in serum uric acid levels. Stepwise multiple regression analysis showed that VFA and the serum adiponectin concentration were significant explanatory variables for serum uric acid levels. CONCLUSION: Hyperuricemia is significantly associated with visceral fat accumulation and hypoadiponectinemia in Japanese men.

Adiponectin replenishment ameliorates obesity-related hypertension.

Patients with obesity are susceptible to hypertension. We have reported that the plasma adiponectin levels are decreased in obesity and that adiponectin has many defensive properties against obesity-related diseases, such as type 2 diabetes and coronary artery disease. The aim of this study was to determine the relationship between adiponectin and hypertension in mice. We measured blood pressure and heart rate directly by a catheter in the carotid artery and indirectly by automatic sphygmomanometer at the tail artery. Obese KKAy mice had significantly lower plasma adiponectin levels and higher systolic blood pressure than control C57BL/6J mice at 21 weeks of age. Adenovirus-delivered adiponectin significantly decreased blood pressure in KKAy mice. The direct role of adiponectin on blood pressure regulation under insulin resistance-free state was investigated in adiponectin-knockout (KO) mice. Adiponectin KO mice developed hypertension when maintained on a high-salt diet (8% NaCl) without insulin resistance. The hypertension of salt-fed adiponectin KO mice was associated with reduced mRNA levels of endothelial NO synthase (eNOS) and prostaglandin I(2) synthase in aorta and low metabolite levels of endothelial NO synthase and prostaglandin I(2) synthase in plasma. Adiponectin therapy lowered the elevated blood pressure and corrected the above mRNA levels to those of the wild type. Our results suggest that hypoadiponectinemia contributes to the development of obesity-related hypertension, at least in part, directly, in addition to its effect via insulin resistance, and that adiponectin therapy can be potentially useful for hypertension in patients with the metabolic syndrome.

Adiponectin as a biomarker of the metabolic syndrome.

BACKGROUND: The metabolic syndrome, a cluster of abdominal obesity, dyslipidemia, hypertension and hyperglycemia, is a common basis for atherosclerotic vascular diseases in industrial countries exposed to overnutrition. Adiponectin is an adipose-derived plasma protein with anti-atherogenic and insulin-sensitizing activities. METHODS AND RESULTS: A total of 661 Japanese adults (479 men, 53+/-10 years; 182 women 56+/-10 years) were enrolled. Plasma adiponectin concentrations correlated negatively with waist circumference, visceral fat area, serum triglyceride concentration, fasting plasma glucose, fasting plasma insulin, and systolic and diastolic blood pressure in both sexes. A positive correlation was found between plasma adiponectin and high-density lipoprotein cholesterol concentrations in both sexes. The mean number of components of the metabolic syndrome increased as the plasma adiponectin concentration decreased: 2.57+/-1.34 for men and 2.00+/-1.51 for women with adiponectin concentrations <4.0 microg/ml. In all, 52.3% of men and 37.5% of women with adiponectin concentrations <4.0 microg/ml fulfilled the criteria for metabolic syndrome. CONCLUSION: Hypoadiponectinemia is closely associated with the clinical phenotype of the metabolic syndrome and measuring the plasma concentration of adiponectin may be useful for management of the metabolic syndrome.