Nondiabetic Japanese Subjects Research Articles

1647-P: High Serum YKL-40 Concentration Is Associated with One-Hour Post-Load Hyperglycemia

Objective: Postprandial hyperglycemia is associated with oxidative stress and low-grade inflammation, which is involved in the pathogenesis of cardiovascular disease. The aim of this study was to examine whether post-load plasma glucose during oral glucose tolerance tests (OGTT) affect inflammatory biomarkers in nondiabetic subjects. Methods: We recruited 322 nondiabetic Japanese subjects including 252 with a normal glucose tolerance (NGT) and 70 with an impaired glucose tolerance (IGT). All subjects underwent OGTT and measurement of several inflammatory biomarkers. Results: No significant differences were observed in white blood cell counts, high-sensitive CRP, high-mobility group box 1 protein (HMGB1) or S100A8/A9 levels between NGT subjects with 1-h post-load plasma glucose (1h-PG) < 155 mg/dL and subjects with 1h-PG ≥ 155 mg/dL. Conversely, NGT subjects with 1h-PG ≥ 155 mg/dL exhibited higher YKL-40 levels than subjects with 1h-PG < 155mg/dL (101.6 ± 85.8 vs. 61.6 ± 53.9 ng/mL, P < 0.0001). No significant difference was observed in YKL-40 levels between NGT subjects with 1h-PG ≥ 155 mg/dL and subjects with IGT. YKL-40 levels, but not white blood cell counts, high-sensitivity CRP, HMGB1 or S100A8/A9, showed significantly positive correlations with 1h-PG (r = 0.251, P < 0.0001). Multiple regression analysis showed that YKL-40 levels were independently associated with 1h-PG, as were age, gender, alanine transaminase and systolic blood pressure. Conclusions: In nondiabetic subjects, serum YKL-40 levels correlated positively with post-load plasma glucose levels. YKL-40 is produced by several cell types such as activated macrophages, vascular smooth muscle and endothelial cells, and plays an important role in the innate immune response, angiogenesis and remodeling of extracellular matrix. Elevated YKL-40 levels related to postprandial hyperglycemia may contribute to the progression of atherosclerosis and cardiovascular events. Disclosure Y. Ikeda: None. N. Hisakawa: None. H. Takata: None. T. Ohguro: None. J. Nishiuchi: None. Y. Kumon: None.

The ratio of glycated albumin to glycated hemoglobin is associated with insulin resistance-related features in non-diabetic Japanese subjects

Aim: Hemoglobin A1c (HbA1c) and glycated albumin (GA) are used as markers of glycemic control in clinical practice. These glycated proteins are affected by various factors other than chronic glycemic control. GA levels are negatively associated with obesity in non-diabetic subjects and diabetic patients, and the GA/HbA1c ratio is significantly affected by postprandial glucose excursions. This study aimed to investigate whether GA/HbA1c is associated with insulin resistance-related features in non-diabetic subjects.

Association of Low Urine pH with Insulin Resistance in Non-Diabetic Japanese Subjects.

Epidemiology studies have revealed that patients with obesity, hyperglycemia, or hypertension are associated with a decreased urine pH. These metabolic disorders are related to insulin resistance; however, the association between urine pH and insulin resistance remains unclear. To evaluate this association while controlling for covariates, the present study was conducted in 1084 non-diabetic Japanese subjects undergoing health examination. Fasting urine pH was analyzed using an automated urine dipstick analyzer. The subjects were divided into five groups according to urine pH: those with pH <5.5, 5.5, 6.0, 6.5, and >6.5. Insulin resistance was determined using the homeostatic model assessment of insulin resistance (HOMA-IR) and divided into three categories: lower, middle, and higher tertiles of HOMA-IR. Analysis of covariance and multivariate logistic regression analysis were used to control confounding factors including serum uric acid. Analysis of covariance showed an increase in the mean HOMA-IR from 1.26, 1.46, 1.69, and 1.75 to 1.89 with a decrease in urine pH (p<0.001). Subjects with urine pH ≤5.5 had a significantly higher HOMA-IR than those with urine pH>6.5. Furthermore, multivariate logistic regression analysis showed that urine pH had an inverse and independent association with HOMA-IR. In subjects with urine pH 5.5 and <5.5, adjusted odds ratio (95% confidence interval) for the incidence of higher tertile of HOMA-IR was 1.34 (1.04-1.73) and 1.52 (1.09-2.13), respectively (reference, subjects with a urine pH>6.5). Insulin resistance is independently associated with a lower urine pH, possibly via lower formation of ammonium in the kidneys.

Effects of a Low Advanced Glycation End Products Diet on Insulin Levels: The Feasibility of a Crossover Comparison Test

BackgroundAdvanced glycation end products (AGEs) are associated with diabetes mellitus. Digested food-derived AGEs have been implicated in the pathogenesis of AGE-related disorders, and restricting diet-derived AGEs improves insulin resistance in animal models. The AGE content in foods changes according to cooking method, and it is higher in baked or oven-fried foods than in those prepared by steaming or simmering. Here, we examined the feasibility of crossover comparison tests for determining how different cooking methods (normal diet vs. low-AGE diet) affect insulin levels in non-diabetic Japanese subjects.MethodsFive adult men and women (age, 41 ± 7 years; body mass index (BMI), 21.7 ± 2.6 kg/m2) were enrolled. The following dietary regimen was used: days 1 - 3, control meal; day 4, test meal (normal diet vs. low-AGE diet); day 5, washout day; and day 6, test meal. On days 4 and 6, blood samples were collected before and at 2, 4, and 6 h after meals.ResultsBlood levels of N-(carboxymethyl) lysine (CML) increased with dietary intake, but the increase was similar for the normal diet and low-AGE diet groups. Mean plasma glucose, insulin, triglycerides (TG), and CML did not differ significantly between the two groups. The area under the curve (AUC) for insulin levels was lower in the low-AGE diet group (d = 0.8). The sample size calculated from the effect size of the insulin AUC change was 22.ConclusionsTwenty-two subjects may be needed to investigate the changes in clinical parameters attributable to cooking method in non-diabetic Japanese subjects.

Effects of combination of change in visceral fat and thigh muscle mass on the development of type 2 diabetes.

We investigated the association between combined changes of visceral fat and thigh muscle over 5 years and incident type 2 diabetes in a prospective study of Japanese Americans. We followed 420 nondiabetic Japanese American subjects for 5 years and assessed visceral fat and thigh muscle by computed tomography (CT) at baseline and at 5 years. We categorized study subjects into 4 body composition change groups: visceral fat loss/thigh muscle gain (VF-loss/TM-gain), visceral fat loss/thigh muscle loss (VF-loss/TM-loss), visceral fat gain/thigh muscle gain (VF-gain/TM-gain), and visceral fat gain/thigh muscle loss (VF-gain/TM-loss) by combining changes from baseline in CT measured visceral fat and estimated thigh muscle areas. We fit a logistic regression model to examine the association between body composition categories and the development of incident type 2 diabetes at 5 years. Cumulative incidence of type 2 diabetes was 9.8% at 5 years. VF-gain/TM-gain and VF-loss/TM-loss groups had higher risk for incident type 2 diabetes in a model adjusted for age, sex, family history of diabetes, and body mass index compared to VF-loss/TM-gain group as the reference category (OR=6.83 (1.85-25.17), 4.55 (1.06-19.48), respectively). However, the VF-gain/TM-loss group did not show a significant association with the odds of incident diabetes (3.24; 95% CI. 0.78-13.47). Concordant gain or loss in visceral fat and thigh muscle was related to higher risk of incident type 2 diabetes compared to the reference combination of loss of visceral fat and gain of thigh muscle in Japanese Americans.

Careful readings for a flash glucose monitoring system in nondiabetic Japanese subjects: individual differences and discrepancy in glucose concentrarion after glucose loading [Rapid Communication

The FreeStyle Libre Flash Glucose Monitoring System (FGM), which can continuously measure glucose concentration in the interstitial fluid glucose (FGM-ISFG), has been in clinical use worldwide. However, it is not clear how accurately FGM-ISFG reflects plasma glucose concentration (PG). In the present study, we examined the clinical utility of FGM by oral glucose tolerance test (OGTT). In eight healthy volunteers (3 males; mean age, 41.8 y) wearing FGM sensors for 14 days, OGTT was performed during days 1-7 and days 8-14, and then both FGM-ISFG and PG were compared. Parkes error grid analysis indicated that all of 65 FGM-ISFG values were within Zone A (no effect on clinical action) and Zone B (little or no effect on clinical outcome). However, in OGTT, the mean FGM-ISFG was higher than the mean actual PG at 30, 60, and 90 minutes after loading (155.5 vs. 139.2 mg/dL, 166.2 vs. 139.2 mg/dL, 149.5 vs. 138.2 mg/dL, respectively; p<0.05). Moreover, the area under the curve of FGM-ISFG was also significantly larger than that of PG (17,626.2 vs. 15,195.0 min·mg/dL; p<0.05). In four of eight subjects, FGM-ISFG tended to be higher than PG in both OGTTs, and the greatest difference between the two values was 58 mg/dL. FGM is useful for glycemic control, whereas it is not appropriate to change therapeutic regimens based on the judgment of nocturnal hypoglycemia and postprandial hyperglycemia by FGM-ISFG. Careful attention is required for proper application of FGM.

Investigation of the relationship between hemoglobin and serum iron levels and early-phase insulin secretion in non-diabetic subjects.

Recent biological and epidemiological studies have found that insulin resistance is linked to iron overload. However, little is known about the association between hemoglobin and/or serum iron levels and pancreatic β-cell function. In this gender-separated cross-sectional study, we aimed to investigate the association of hemoglobin and serum iron levels with early-phase insulin secretion in non-diabetic subjects. A total of 804 non-diabetic Japanese subjects (482 males and 322 females) aged over 30years old were enrolled in the study. Early-phase insulin secretion was estimated using the insulinogenic index (IGI [ΔInsulin(30-0min)/ΔGlucose(30-0min)]) during a 75-g oral glucose tolerance test. Simple linear regression analysis showed that IGI negatively correlated with hemoglobin levels in male but not in female subjects. However, IGI did not correlate with serum iron levels in either gender. Multivariate linear regression analysis in male subjects revealed that hemoglobin levels were predictors of IGI, responsible for 3.0% of IGI variation (P=0.008). The association was independent of age, BMI, fasting glucose and insulin levels, and lipid profiles. In non-diabetic Japanese males, hemoglobin levels significantly and negatively correlated with early-phase insulin secretion. Our finding suggests that elevated hemoglobin levels may have a gender-specific impact on β-cell function and could be an independent predictor of β-cell dysfunction.

Etiology of Insulin Resistance in Asian Non-Obese Subjects -Juntendo Sportology Center Core Study-

Obesity and its associated metabolic disorders are rapidly disseminating all over the world. While they became serious health problem, such diseases in Asians shows different features from those in other races such as Caucasian and African. One of the important features is a susceptibility to develop to type 2 diabetes even without excess body mass index. To search for the mechanism underlying this feature is important to find the suitable therapeutic strategy for Asian obesity. Thus, as a core study of the Sportology Center of Juntendo University Graduate School of Medicine, we assessed tissue-specific insulin resistance in Japanese non-obese subjects. In this study, we recruited non-obese and non-diabetic Japanese subjects and measured insulin sensitivity in muscle and liver by a 2-step hyperinsulinemiceuglycemic clamp with glucose tracer and ectopic fat content in muscle and liver by proton magnetic resonance spectroscopy. So far, our data suggests that muscle insulin resistance may play a central role in future onset of the diseases that could make the healthy people to disable people.

Association between insulin resistance and plasma amino acid profile in non-diabetic Japanese subjects.

Aims/IntroductionElevation of the branched-chain amino acids (BCAAs), valine, leucine and isoleucine; and the aromatic amino acids, tyrosine and phenylalanine, has been observed in obesity-related insulin resistance. However, there have been few studies on Asians, who are generally less obese and less insulin-resistant than Caucasian or African-Americans. In the present study, we investigated the relationship between homeostasis model assessment of insulin resistance (HOMA-IR) and plasma amino acid concentration in non-diabetic Japanese participants.Materials and MethodsA total of 94 healthy men and women were enrolled, and plasma amino acid concentration was measured by liquid chromatography/mass spectrometry after overnight fasting. The associations between HOMA-IR and 20 amino acid concentrations, and anthropometric and clinical parameters of lifestyle-related diseases were evaluated.ResultsThe mean age and body mass index were 40.1 ± 9.6 years and 22.7 ± 3.9, respectively. Significantly positive correlations were observed between HOMA-IR and valine, isoleucine, leucine, tyrosine, phenylalanine and total BCAA concentration. Compared with the HOMA-IR ≤ 1.6 group, the HOMA-IR > 1.6 group showed significantly exacerbated anthropometric and clinical parameters, and significantly elevated levels of valine, isoleucine, leucine, tyrosine, phenylalanine and BCAA.ConclusionsThe present study shows that the insulin resistance-related change in amino acid profile is also observed in non-diabetic Japanese subjects. These amino acids include BCAAs (valine, isoleucine and leucine) and aromatic amino acids (tyrosine and phenylalanine), in agreement with previous studies carried out using different ethnic groups with different degrees of obesity and insulin resistance.

Circulating TNF Receptor 2 is Closely Associated with the Kidney Function in Non-Diabetic Japanese Subjects

Chronic kidney disease (CKD) is associated with cardiovascular events. Tumor necrosis factor (TNF) and/or its receptors have been postulated to be involved in renal pathophysiology. It is unclear whether an increased TNF system activity is present before the development of apparent CKD. Four hundred and twenty non-diabetic Japanese subjects with an estimated GFR (eGFR) greater than 60 ml/min/1.73 m(2) were recruited for measurement of the HbA1c, insulin, TNF system activity (TNF-α, soluble TNF receptor 1 (sTNF-R1) and sTNF-R2) levels and various parameters, including the lipid, high-sensitivity C-reactive protein (hsCRP), high-molecular-weight (HMW) adiponectin and leptin levels. The subjects were stratified according to the eGFR: the G1 level (eGFR ≧90 ml/min/1.73 m(2)) and the G2 level (90 ＞eGFR ≧60 ml/min/1.73 m(2)). Whereas no significant differences were observed in gender, body mass index (BMI), blood pressure, insulin, TNF-α, hsCRP, HMW adiponectin or leptin between the two groups, the values for age, HbA1c, triglycerides, sTNF-R1 and sTNF-R2 were significantly higher in the subjects with a G2 level of eGFR than in those with a G1 level. In contrast, the HDL cholesterol levels were significantly lower in the subjects with a G2 level than in those with a G1 level. Linear negative correlations were also observed between eGFR and age, BMI, HbA1c, triglycerides, sTNF-R1 and sTNFR2, respectively. A multiple logistic regression analysis revealed that only sTNF-R2 was associated with the presence of a G2 level of eGFR (Odds ratio 1.092, 95% CI 1.013-1.177, P=0.021). The circulating sTNF-R2 level is closely associated with the kidney function in non-diabetic Japanese subjects.

Incretin secretion stimulated by ursodeoxycholic acid in healthy subjects

Bile acids play an important role in post-prandial glucose metabolism by stimulating release of glucagon-like peptide-1 (GLP-1) via the G-protein-coupled receptor TGR5, which is expressed in intestinal L cells. Thus, bile acid sequestrants are expected to stimulate secretion of endogenous GLP-1 through TGR5. We investigated incretin and insulin secretion after a meal with and without ursodeoxycholic acid (UDCA), a widely used therapeutic agent in liver diseases, in 7 non-diabetic Japanese subjects. We found that UDCA intake resulted in higher GLP-1 secretion (area under the curve [AUC] of 0–60 min after meal without UDCA, 450 ± 162 mmol·min/l; with UDCA, 649 ± 232 mmol·min/l, P = 0.046) and lower blood glucose (AUC of 0–60 min without UDCA, 7191 ± 250 mg·min/dl; with UDCA, 6716 ± 189 mg·min/dl, P = 0.001) , although we did not find statistically significant insulin increase by UDCA intake (AUC of 0–60 min without UDCA, 1551 ± 418 μU·min/ml; with UDCA, 1941 ± 246 μU·min/ml, P = 0.065). These results suggest that UDCA increases bile-induced GLP-1 secretion. Ours is the first report showing increased GLP-1 secretion and decreased blood glucose in response to UDCA.

Optimal cut-off point for homeostasis model assessment of insulin resistance to discriminate metabolic syndrome in non-diabetic Japanese subjects.

We have recently established a 'health-associated' reference interval of homeostasis model assessment of insulin resistance (HOMA-IR) between 0.4 and 2.4. In the present study, the aim was to establish a 'decision-based' limit of HOMA-IR for the discrimination of metabolic syndrome (MetS) in non-diabetic Japanese subjects. The receiver-operating characteristic curve of HOMA-IR for detecting MetS was developed using data from 6868 non-diabetic subjects (3727 men, 3141 women). The optimal cut-off point was determined based on the point that yielded the minimum value of the square root of [(1 - sensitivity)(2) + (1 - specificity)(2)]. HOMA-IR = 1.7 was determined as the optimal cut-off value, with a sensitivity and specificity of 73.4% and 70.5% for men, and 81.5% and 77.0% for women, respectively. In conclusion, the optimal cut-off value for HOMA-IR to discriminate MetS in non-diabetic Japanese subjects appears to be 1.7. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00194.x, 2012).

Serum Levels of Advanced Glycation End Products (AGEs) are Independent Correlates of Insulin Resistance in Nondiabetic Subjects

Advanced glycation end products (AGEs) evoke oxidative stress generation and inflammatory reactions, thus being involved in vascular complications in diabetes. Since oxidative stress and inflammation impair insulin actions as well, it is conceivable that AGEs may play some role in insulin resistance. However, there is no clinical study to examine the relationship between serum levels of AGEs and insulin resistance. This study investigated whether serum AGE levels were independent correlates of insulin resistance in humans. Three hundred twenty-two nondiabetic Japanese subjects (216 male and 106 female; mean age 61.5 ± 9.1 years) underwent a complete history and physical examination, determinations of blood chemistries, anthropometric and metabolic variables, including AGEs. Serum AGE levels were examined with an enzyme-linked immunosorbent assay. Mean serum AGE levels were 8.96 ± 2.57 U/mL. In univariate analysis, waist circumference, diastolic blood pressure (BP), mean BP, AGEs, low-density lipoprotein (LDL) cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol (inversely), hemoglobin A1c (GHb), creatinine clearance, uric acid, and high sensitivity C-reactive protein were significantly associated with insulin resistance evaluated by homeostasis model assessment of insulin resistance (HOMA-IR) index. After performing multiple regression analysis, waist circumference (P < 0.001), GHb (P < 0.001), triglycerides (P < 0.001), and AGEs (P < 0.01) still remained significant independently. When age-adjusted HOMA-IR levels stratified by AGE tertiles were compared using ANCOVA, a significant trend was demonstrated in both males and females. The present study demonstrated for the first time that serum AGE levels were one of the independent correlates of HOMA-IR index, thus suggesting that AGEs may play some pathological role in insulin resistance in humans.

ADRB2 and LEPR Gene Polymorphisms: Synergistic Effects on the Risk of Obesity in Japanese

The objective of the present study was to validate a recently reported synergistic effect between variants located in the leptin receptor (LEPR) gene and in the β-2 adrenergic receptor (ADRB2) gene on the risk of overweight/obesity. We studied a middle-aged/elderly sample of 4,193 nondiabetic Japanese subjects stratified according gender (1,911 women and 2,282 men). The LEPR Gln223Arg (rs1137101) variant as well as both ADRB2 Arg16Gly (rs1042713) and Gln27Glu (rs1042714) polymorphisms were analyzed. The primary outcome was the risk of overweight/obesity defined as BMI ≥25 kg/m(2), whereas secondary outcomes included the risk of a BMI ≥27 kg/m(2) and BMI as a continuous variable. None of the studied polymorphisms showed statistically significant individual effects, regardless of the group or phenotype studied. Haplotype analysis also did not disclose any associations of ADRB2 polymorphisms with BMI. However, dimensionality reduction-based models confirmed significant interactions among the investigated variants for BMI as a continuous variable as well as for the risk of obesity defined as BMI ≥27 kg/m(2). All disclosed interactions were found in men only. Our results provide external validation for a male specific ADRB2-LEPR interaction effect on the risk of overweight/obesity, but indicate that effect sizes associated with these interactions may be smaller in the population studied.

Low‐Density Lipoprotein Levels are One of the Independent Determinants of Circulating Levels of Advanced Glycation End Products in Nondiabetic Subjects

Nonenzymatic modification of proteins by reducing sugars leads to the formation of advanced glycation end products (AGEs), whose process has been reported to progress under diabetes. Recently, diet has been found to be a major environmental source of proinflammatory AGEs in humans. Further, fats or meat-derived products processed by high heat such as broiling have been shown to contain more AGEs than carbohydrates boiled for longer periods. Since circulating levels of low-density lipoprotein cholesterol (LDL-C) are also regulated by dietary cholesterol, it is conceivable that intake of cholesterol-rich foods could regulate serum levels of AGEs in humans. In this study, we investigated whether LDL-C levels are one of the independent determinants of circulating AGEs levels in a nondiabetic general population. A total of 170 nondiabetic Japanese subjects underwent a complete history, physical examination, determination of blood chemistries, and serum AGEs. Univariate analysis showed that AGEs levels were associated with LDL-C (P < 0.05) and fasting plasma glucose levels (P < 0.05). By the use of multiple stepwise regression analyses, LDL-C (P < 0.01) and fasting plasma glucose levels (P < 0.05) remained significant and were independently related to AGEs levels (R2 = 0.069). The present study is the first demonstration that LDL-C levels are one of the independent determinants of serum levels of AGEs in a nondiabetic general population. Intake of cholesterol-rich foods may regulate serum levels of AGEs in nondiabetic subjects.

Association of Metabolic Syndrome with Urinary Albumin Excretion, Low-grade Inflammation, and Low Glomerular Filtration Rate among Non-diabetic Japanese Subjects

Several studies have reported a significant association of metabolic syndrome with urinary albumin excretion, high-sensitivity C-reactive protein, or chronic kidney disease; however, no study has investigated the association of metabolic syndrome with these 3 factors together in the same individual. Therefore, we conducted the present study to obtain more information on this association. We enrolled 712 Japanese subjects without diabetes, macroalbuminuria, or medications, who entered our hospitalized health check-up program (180 women and 532 men; mean age, 53.2 years; mean body mass index, 24.1 kg/m(2)). Metabolic syndrome was diagnosed by 4 major definitions. Low glomerular filtration rate was defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m(2). Both urinary albumin excretion and high-sensitivity C-reactive protein were significantly higher in those with metabolic syndrome than without, and metabolic syndrome was an independent determinant of both. In contrast, estimated glomerular filtration rate and the prevalence of low glomerular filtration rate did not differ significantly between those with and without metabolic syndrome. Among the 5 components of metabolic syndrome and other clinical variables, systolic blood pressure was an independent determinant of urinary albumin excretion; the 5 components and low-density lipoprotein cholesterol were all independent determinants of high-sensitivity C-reactive protein; systolic blood pressure was an independent determinant of low glomerular filtration rate. Metabolic syndrome is associated with vascular dysfunction and low-grade inflammation and the latter association is strong, whereas the association of metabolic syndrome with low glomerular filtration rate may be less apparent among those without diabetes, macroalbuminuria, and medications.

Underweight as a Predictor of Diabetes in Older Adults

A total of 39,201 men and 88,012 women aged 40–79 years who underwent health checkups in 1993 and who were free of diabetes were followed until the end of 2004 to examine an association between underweight and risk of diabetes. Incident diabetes was defined by a fasting blood glucose concentration ≥7.0 mmol/l or nonfasting glucose ≥11.1 mmol/l and/or diabetes treatment. The multivariable hazard ratio of diabetes adjusted for age, baseline blood glucose level, fasting status, and other confounding variables among subjects who had a BMI <18.5 kg/m2 compared with those with a BMI 18.5–24.9 kg/m2 was 1.32 (95% CI 1.12–1.56) in men aged 60–79 years and 1.31 (1.07–1.60) in women aged 60–79 years. Underweight may be associated with risk of diabetes among older adults. In the present study, we enrolled 181,863 nondiabetic Japanese subjects (58,402 men and 123,461 women) from community residents aged 40–79 years who underwent health checkups in 1993 conducted by the local governments under the Japan Health Laws. We excluded 19,201 men and 35,449 women who did not participate in the 1994 survey, thereby ensuring that the subjects were followed up for at least 1 year. A total of 39,201 men and …

Serum Level of Advanced Glycation End-Products (AGEs) is an Independent Determinant of Plasminogen Activator Inhibitor-1 (PAI-1) in Nondiabetic General Population

Glucose can react nonenzymatically with amino groups of proteins to form senescent macroprotein derivatives termed advanced glycation end-products (AGEs). Recently, AGEs have been shown to play an important role in atherosclerosis even in nondiabetic subjects. However, the molecular mechanism underlying this is not fully understood. We have now investigated whether serum AGE level was an independent determinant of plasminogen activator inhibitor-1 (PAI-1), a major physiological inhibitor of fibrinolysis, in nondiabetic general population. One-hundred and eighty-six nondiabetic Japanese subjects underwent a complete history and physical examination, determination of blood chemistries, PAI-1, and AGEs. Uni- and multivariate analyses were applied for the determinants of PAI-1 levels. The average PAI-1 levels were 29.7+/-23.8 ng/ml in males and 21.8+/-17.1 ng/ml in females, respectively. Univariate regression analysis showed that PAI-1 levels were associated with age (inversely, p=0.003), male (p=0.003), body mass index (BMI) (p<0.001), HDL-cholesterol (inversely, p<0.001), triglycerides (p<0.001), fasting plasma glucose (p<0.001), insulin (p<0.001), uric acids (p<0.001), AGEs (p=0.037), and alcohol intake (p<0.001). By the use of multiple regression analyses, BMI (p<0.001), male (p=0.003), fasting plasma glucose (p=0.005), age (inversely, p=0.017), and AGEs (p=0.034) remained significant. The present study is the first demonstration that serum AGE level was one of the independent determinants of PAI-1 in nondiabetic general population. The AGE-associated thrombogenic abnormality may be involved in atherogenesis in nondiabetic subjects.

Monocyte chemoattractant protein-1 promoter −2518 polymorphism is associated with post-challenge insulin and glucose levels in non-diabetic Japanese subjects

We investigated that the association of MCP-1 polymorphism at position −2518 with insulin sensitivity and insulin secretion by measuring the fasting and post-challenge glucose and insulin levels during 75 g OGTT in 409 non-diabetic Japanese subjects. The blood sampling was performed before glucose loading and after 30 and 120 min. Polymorphism was evaluated by PCR-RFLP method by genomic DNA isolated from peripheral blood leukocytes. The genotype distribution was 44.8% for G/G, 46.0% for G/A and 9.2% for A/A. The plasma glucose levels were significantly increased in A/A as compared to G/G ( p < 0.05), but it was not compared with G/A at 120 min. The serum insulin levels were significantly increased in A/A as compared to G/A ( p < 0.05) or G/G ( p < 0.05) at 30 min. Moreover, the serum insulin levels in A/A were significantly increased compared with G/A ( p < 0.02) or G/G ( p < 0.005) at 120 min. Elevation in post-challenge glucose (120 min) and insulin levels (30 and 120 min) suggests that reduced insulin sensitivity during glucose loading occurs in subjects with A/A polymorphism. The present study demonstrates that the A/A polymorphism of the MCP-1 gene at position −2518 is associated with insulin resistance during glucose loading in non-diabetic Japanese subjects.

Promoter polymorphism in the macrophage migration inhibitory factor gene is associated with obesity

To explore the association of promoter polymorphisms of macrophage migration inhibitory factor (MIF) gene with obesity. In total, 213 nondiabetic Japanese subjects. They were divided into three groups according to World Health Organization definitions: lean (body mass index (BMI) <25 kg/m2), overweight (25 < or = BMI < 30 kg/m2) and obese (BMI> or = 30 kg/m2). We examined two polymorphic loci in the MIF gene in the subjects: a single-nucleotide polymorphism at position -173 (G/C) and a CATT-tetranucleotide repeat polymorphism at position -794, which both can affect promoter activity in different cells. We detected four alleles: 5-, 6-, 7- and 8-CATT at position -794. Genotypes without the 5-CATT allele (X/X, X refers to 6-, 7- or 8-CATT alleles) were more common in obese subjects than in lean or overweight groups (P = 0.013). The X-CATT allele was more frequent in obese subjects than in lean or overweight subjects (P = 0.030). In contrast, -173G/C was not associated with obesity. Among the haplotypes of the two promoter polymorphisms, G/5-CATT ((-173G/C)/(-794[CATT](5-8))) was associated with a decreased risk of obesity (P = 0.025) and G/6-CATT with an increased risk of overweight (P=0.028). Promoter polymorphism in the MIF gene is linked with obesity.