Insulin Resistance In Japanese Men Research Articles

Effects of testosterone ointment in Japanese men with metabolic syndrome

ABSTRACT The metabolic syndrome involves a cluster of clinical features including visceral obesity, insulin resistance, hypertension, glucose intolerance, and dyslipidemia. Recent studies have shown that low testosterone levels are significantly associated with metabolic syndrome and type 2 diabetes. We examined the change in insulin resistance after testosterone treatment in 23 Japanese men with metabolic syndrome and low free testosterone levels. Testosterone supplements were administered by testosterone ointment (Glowmin,Daito Pharmaceutrical, Tokyo, Japan) for 3 to 6 months. Glowmin contains 10mg of testosterone per 1g of matrix. A 2-cm line of Glowmin was applied to the submandibular skin and contained a dosage of 3mg of testosterone and this was given twice a day in the morning and evening. Fasting plasma glucose (FPG), fasting serum insulin (F-IRI), HbA1c, total cholesterol(TCHO), triglyceride(TG), HDL-C, LDL-C, free testosterone, LH, FSH, BMI and waist circumference were measured. We used homeostasis model assessment (HOMA-R) as an index of insulin resistance and investigated the change in insulin resistance and lipid profiles after testosterone treatment. After treatment, F-IRI, HOMA-R, TCHO and LDL-C were significantly decreased from 17.3±6.2μIU/ml to 11.9±4.0μIU/ml, 4.70±1.86 to 3.09±1.20, 252±23mg/dl to 216±19mg/dl and 175±25mg/dl to 139±22mg/dl, respectively. Free testosterone was significantly increased from 5.7±1.0pg/ml to 9.1±1.4pg/ml. Other parameters were not changed significantly. In conclusion, these results suggest that testosterone replacement therapy by testosterone ointment improves insulin resistance in Japanese men with metabolic syndrome and low free testosterone levels. Disclosure Work supported by industry: no.

ALDH2 rs671 Is Associated With Elevated FPG, Reduced Glucose Clearance and Hepatic Insulin Resistance in Japanese Men.

A recent meta-analysis of genome-wide association studies data from East Asians identified aldehyde dehydrogenase 2 (ALDH2) rs671 as a susceptibility variant for type 2 diabetes in males. To investigate the association between ALDH2 rs671 and metabolic characteristics. We studied 94 nonobese, nondiabetic, Japanese men. Using a 2-step hyperinsulinemic-euglycemic clamp, we evaluated insulin sensitivity in muscle and liver. Intrahepatic lipid and fat distribution were measured using 1H-magnetic resonance spectroscopy and magnetic resonance imaging, respectively. We divided participants into a risk-carrying group with ALDH2 rs671 G/G (n = 53) and a nonrisk-carrying group with ALDH2 rs671 G/A or A/A (n = 41). The risk-carrying group had significantly higher levels of alcohol consumption (18.4 [interquartile range, IQR, 10.4-48.9]) vs 12.1 (IQR, 1.3-29.0) g/day; P = .003), elevated fasting plasma glucose (FPG) (97.5 ± 7.9 vs 93.5 ± 6.2 mg/dL; P = .010), lower hepatic insulin sensitivity (61.7 ± 20.5% vs 73.1 ± 15.9%; P = .003), and lower fasting glucose clearance (0.84 ± 0.8 dL·m-2·min-1 vs 0.87 ± 0.09 dL·m-2·min-1; P = .047) than the nonrisk-carrying group, while insulin resistance in muscle and body fat distribution were similar. The single linear correlation analysis revealed significant correlations between alcohol consumption and hepatic insulin sensitivity (r = -0.262, P = .011), fasting glucose clearance (r = -0.370, P < .001), or FPG (r = 0.489, P < .001). The multiple regression analysis revealed that both ALDH2 rs671 G/G genotype and alcohol consumption were significant independent correlates for hepatic insulin sensitivity, whereas only alcohol consumption was a significant independent correlate for fasting glucose clearance. Our data suggest that high-alcohol intake-dependent and independent hepatic insulin resistance and reduced fasting glucose clearance due to high alcohol intake could be a relatively upstream metabolic abnormality in ALDH2 rs671 G/G carriers.

The Relationship between Serum 25-Hydroxyvitamin D Concentration, Cardiorespiratory Fitness, and Insulin Resistance in Japanese Men

Here, we aim to investigate the independent and combined associations of serum 25-hydroxyvitamin D (25(OH)D) and cardiorespiratory fitness (CRF) with glucose metabolism. Fasting blood samples of 107 men aged 40–79 years were analyzed for 25(OH)D, glucose, insulin, glycated hemoglobin, and lipid profile. Homeostasis model assessment of insulin resistance index (HOMA-IR) was calculated from the fasting concentrations of glucose and insulin. Visceral fat area (VFA) was determined by magnetic resonance imaging and CRF by measuring maximal oxygen uptake. Median 25(OH)D concentration was 36.3 nmol/L, while the prevalence of 25(OH)D deficiency was 74.8%. Participants with high CRF had significantly lower HOMA-IR, glycated hemoglobin, and insulin values than participants with low CRF (p < 0.05). Higher 25(OH)D concentration was strongly correlated with lower HOMA-IR and insulin values independent of VFA (p < 0.01) but significantly affected by CRF. In the high CRF group, participants with higher 25(OH)D concentration had lower HOMA-IR values than participants with low 25(OH)D concentration (p < 0.05). Higher 25(OH)D and CRF are crucial for reducing insulin resistance regardless of abdominal fat. In addition, higher 25(OH)D concentration may strengthen the effect of CRF on reducing insulin resistance in middle-aged and elderly Japanese men with high CRF.

Testosterone Treatment Improves Insulin Resistance in Japanese Male Metabolic Syndrome

The metabolic syndrome involves a cluster of clinical features including visceral obesity, insulin resistance, hypertension, glucose intolerance, and dyslipidemia. Recent studies have shown that low testosterone levels are significantly associated with metabolic syndrome and type 2 diabetes. We examined the change in insulin resistance after testosterone treatment in five Japanese men with metabolic syndrome and low free testosterone levels (age : 50.2 ± 8.7 yrs, BMI : 30.5 ± 5.0, waist : 97 ± 7 cm ; Mean ± SD). Testosterone supplements were administered by intramuscular injection (250 mg every 2 weeks) for 3 to 6 months. Fasting plasma glucose (FPG), fasting serum insulin (F-IRI), HbA1c, total cholesterol(TCHO), triglyceride(TG), HDL-C, LDL-C, free testosterone, LH, FSH, BMI and waist circumference were measured. We used homeostasis model assessment (HOMA-R) as an index of insulin resistance and investigated the change in insulin resistance after testosterone treatment. Average results before treatment were as follows: BMI 30.5 ± 5.0, waist 97 ± 7 cm, FPG 112 ± 6 mg/dl, F-IRI 25.1 ± 8.5 μIU/ml, HOMA-R 7.0 ± 2.7, HbA1c(NGSP) 5.8 ± 0.3%, TCHO 227 ± 31 mg/dl, TG 185 ± 64 mg/dl, HDL-C 43 ± 9 mg/dl, LDL-C 149 ± 37 mg/dl, free testosterone 5.9 ± 1.0 pg/ml, LH 1.7 ± 0.6 IU/ml, FSH 3.7 ± 0.7 IU/ml. After treatment, F-IRI, HOMA-R, TCHO and LDL-C were significantly decreased to 12.9 ± 3.6 μIU/ml, 3.3 ± 1.1 199 ± 29 mg/dl and 120 ± 31 mg/dl, respectively. Free testosterone was significantly increased to 8.5 ± 0.6 pg/ml. Other parameters were not changed significantly. In conclusion, these results suggest that testosterone treatment improves insulin resistance in Japanese men with metabolic syndrome and low free testosterone levels.

Impact of cigarette smoking on impaired insulin secretion and insulin resistance in Japanese men: The Saku Study.

To assess the impact of smoking on impaired insulin secretion and insulin resistance in Japanese men. This study included 1,199 men aged 30-79years without diabetes, impaired insulin secretion and insulin resistance at baseline who underwent a comprehensive medical check-up between April 2006 and March 2007 at Saku Central Hospital. Smoking status was categorized as current, ex-smoker and never-smoker. Insulinogenic index and homeostasis model assessment-insulin resistance were determined using a standard 75-g oral glucose tolerance test. The Japan Diabetes Society criteria were used to define impaired insulin secretion and insulin resistance. Participants were followed up until March 2011. A total of 449 and 99 men developed impaired insulin secretion and insulin resistance during 3,403 and 4,092 person-years follow up, respectively. The multivariable-adjusted hazard ratios (HRs) for impaired insulin secretion were 1.06 (95% confidence interval [CI] 0.84-1.33) in ex-smokers and 1.95 (95% CI 1.44-2.63) in current smokers compared with never-smokers after adjustment for age, familial history of diabetes, alcohol consumption, exercise, systolic blood pressure, triglyceride, γ-glutamyltransferase, waist circumference, leukocyte count, changes in smoking status and changes in waist circumference. The number of pack-years was positively associated with the risk for impaired insulin secretion in a dose-dependent manner (P-values for trend <0.001). The multivariable-adjusted HRs for insulin resistance were 0.95 (95% CI 0.56-1.61) in ex-smokers and 1.11 (95% CI 0.67-1.79) in current smokers compared with never-smokers. Cigarette smoking is a modifiable risk factor for impaired insulin secretion. The findings might also be important for other Asian populations, which have low insulin secreting ability.

Serum ferritin is associated with markers of insulin resistance in Japanese men but not in women

ObjectiveSeveral epidemiological studies have reported that high concentrations of circulating ferritin, a marker of iron stores, are related to insulin resistance (IR); however, questions remain regarding inconsistent data between Asian men and women and the inadequate consideration of potential confounding effects on the relationship between ferritin and IR. Our aim was to examine the relationship between serum ferritin concentrations and IR markers in the Japanese population. Materials/MethodsWe analyzed data (n=493) from a cross-sectional survey conducted in 2009 among a Japanese working population aged 20–68years. Fasting serum ferritin and insulin levels and fasting plasma glucose levels were determined, and the homeostatic model assessment of IR (HOMA-IR) was calculated. Multiple regression analysis was performed with adjustments for demographic and lifestyle factors, body mass index and serum C-reactive protein. ResultsFasting insulin and HOMA-IR significantly increased with increasing levels of serum ferritin after adjustment for covariates in men (P for trend=.005 and .001, respectively). Compared with men in the lowest tertile of serum ferritin, those in the highest tertile had a 24% higher HOMA-IR score. Additional data suggested a positive association between iron intake and HOMA-IR (P for trend=.07) in men. Neither serum ferritin nor iron intake was related to IR markers in women, even in postmenopausal women. ConclusionsSerum ferritin concentrations were positively associated with fasting insulin and HOMA-IR in men but not in women, suggesting an important role of iron storage in the pathogenesis of IR in Japanese men.

Serum Fetuin-A is an Independent Marker of Insulin Resistance in Japanese Men

Fetuin-A, also known as alpha2-Heremans Schmid glycoprotein, is an abundant plasma protein synthesized predominantly in the liver. Fetuin-A inhibits insulin receptor autophosphorylation, which is mediated by its intrinsic tyrosine kinase activity. In this study, we examined the association between the serum fetuin-A level and insulin resistance in Japanese men. We recruited 300 unrelated Japanese men without known chronic diseases, such as diabetes mellitus, or a history of regular drug use, and who underwent health examinations. From a 75-g oral glucose tolerance test, the study population included 194 individuals with normal glucose tolerance, 91 with impaired glucose tolerance and/or impaired fasting glucose, and 15 with diabetes mellitus. Serum fetuin-A concentrations were measured using an ELISA kit. Serum fetuin-A concentrations were positively correlated with fasting insulin levels (r = 0.269, p<0.001), HOMA-IR (r = 0.274, p<0.001) and LDL-cholesterol (r = 0.172, p<0.01), and negatively correlated with HDL-cholesterol concentrations (r = -0.191, p<0.001). Fetuin-A concentrations were also positively correlated with serum leptin (r = 0.150, p<0.01) and negatively with adiponectin concentrations (r = -0.208, p<0.001). Stepwise regression analyses confirmed that the fetuin-A concentration was independently associated with the fasting insulin level and HOMA-IR, as were body mass index, triglyceride, LDL-cholesterol, leptin and adiponectin concentrations. Our data suggest that increased serum fetuin-A levels constitute an independent marker of insulin resistance and an atherogenic lipid profile in Japanese men.

Association of Ob-R gene polymorphism and insulin resistance in Japanese men

Leptin and its receptors are known to play a role in glucose metabolism. We succeeded in cloning human Ob-R cDNA and revealed 7 single nucleotide polymorphisms (SNPs) (Lys109Arg, Arg223Gln, Ser343Ser, Ser492Thr, Lys656Asn, Ala976Asp, and Pro1019Pro) in the coding region of Ob-Rb. Although these 7 SNPs were not associated with an obese phenotype, several studies have reported that some of them were associated with impaired glucose metabolism. To clarify whether the Arg223Gln and A3057G (Pro1019Pro) polymorphisms influence glucose metabolism in Japanese, 696 Japanese men were genotyped. Individually, the Arg223Gln and the A3057G polymorphisms were not associated with the glucose metabolic parameters. No associations were found between haplotype and clinical parameters. However, in 327 subjects with normal glucose tolerance (NGT), the subjects with Arg/Gln or Gln/Gln + A/A haplotype showed significantly higher serum insulin levels and homeostasis model assessment (HOMA) index than those with Arg/Arg + A/A haplotype and Arg/Gln or Gln/Gln + A/G or G/G haplotype. The subjects with Arg/Gln or Gln/Gln + A/A haplotype showed a significantly lower fasting glucose to insulin (GI) ratio than those with Arg/Arg + A/A haplotype. These results suggest that the Ob-R gene may serve as a modifier gene for insulin resistance in Japanese men.

Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus

The aim of the present study was to investigate the association of serum adiponectin concentration with regional adiposity and insulin resistance in subjects with type 2 diabetes mellitus. A total of 73 Japanese men with type 2 diabetes (aged 59 ± 11 years and body mass index [BMI] 23.8 ± 3.0 kg/m 2, mean ± SD) were studied. Fasting serum adiponectin and leptin concentrations were determined by radioimmunoassay. Regional adiposity was measured by abdominal computed tomography (CT) at the umbilical level, and insulin resistance was estimated by homeostasis model assessment (HOMA-R). Univariate regression analysis showed that serum adiponectin levels were negatively correlated with subcutaneous and visceral fat areas. With multivariate regression analysis, visceral fat area was a predominant determinant of serum adiponectin levels. In contrast, subcutaneous fat area was strongly associated with serum leptin concentrations. Among subcutaneous and visceral fat areas, BMI, and serum leptin levels, both subcutaneous and visceral fat areas were independently associated with HOMA-R. In another model incorporating serum adiponectin levels, serum adiponectin levels were selected as an independent determinant of HOMA-R instead of visceral fat area. In conclusion, hypoadiponectinemia was associated with visceral fat accumulation rather than subcutaneous fat depot in Japanese men with type 2 diabetes mellitus. Both subcutaneous and visceral fat accumulation contribute to insulin resistance in these subjects, and the contribution of visceral fat may be mediated, in part, by hypoadiponectinemia.

Characteristics of Insulin Resistance in Japanese Men Working Abroad.

The aim of the present study was to investigate the relationship among the clinical and laboratory signs in response to insulin resistance evaluated by a homeostasis model (HOMA-IR) in Japanese non-obbbbese men working abroad. A significantly positive correlation was observed between body mass index (BMI) and HOMA-IR values in the normal weight (r=0.34; p<0.0001) and the obese group (r=0.52; p<0.0001), but not in the lean group (r=0.16; p=0.28) . There was a significantly positive correlation between fasting plasma glucose values and HOMA-IR in three groups. Plasma alanine transferase (ALT), γ-glutamyltranspeptidase (γ-GPT) and Cholinesterase (Ch-E) values were significantly lower in the lean group than those in other groups; ALT: 18.7, 24.2, 42.3 IU/l; γ-GTP: 36.0, 51.0, 74.3 IU/l; Ch-E: 268, 310, 353 IU/l, respectively. There was a significantly positive correlation between HOMA-IR and plasma ALT or Ch-E values in three groups, but other liver functions values were not correlated with HOMA-IR in three groups. These data indicated that insulin resistance was present in almost all men with fatty liver, and insulin resistance was never associated with obesity, hyperdyslipemia in the non-obese men, and the mechanism for underlying insulin resistance in the non-obese men might be different from that in the obese men.

Tumor necrosis factor-β gene Nco I polymorphism decreases insulin resistance in Japanese men

Given that the NcoI polymorphism of the tumor necrosis factor-β (TNF-β) gene has been shown to be associated with tumor necrosis factor-α (TNF-α) secretory capacity, we know that this TNF-β gene polymorphism may influence insulin resistance. In Caucasians, 2 polymorphisms of the TNF-α promoter region (positions −308 and −238) have been reported to be associated with insulin resistance. Thus, we investigated how genetic variation in the TNF-β and TNF-α genes was associated with insulin resistance in 211 Japanese men. The frequency of the TNF-β gene polymorphism was 0.41, and insulin resistance, estimated by homeostasis model assessment (HOMA), was significantly lower in variant homozygotes versus wild-type allele. The frequencies of the −308 and −238 polymorphisms were 0.01 and 0.02, respectively, and these polymorphisms were not associated with insulin resistance. Our results suggest that the TNF-β gene polymorphism decreases insulin resistance, and that the −308 and −238 polymorphisms of the TNF-α promoter region are not a major contributing factor to insulin resistance in Japanese men. Copyright © 2000 by W.B. Saunders Company

Effect of the Pro12Ala Variant of the Human Peroxisome Proliferator-Activated Receptor γ2 Gene on Adiposity, Fat Distribution, and Insulin Sensitivity in Japanese Men

To examine the role of the Pro12Ala variant of the human PPARγ2 gene on adiposity and insulin resistance, we studied the effect of the variant on fat distribution assessed by CT scan, plasma glucose, and insulin levels during a 75g oral glucose load in 215 non-diabetic Japanese men. The allele frequency of the variant was 0.03 in this population. There were no differences in body mass index (BMI), subcutaneous fat area (S), visceral fat area (V), V/S ratio, fasting plasma insulin levels, or insulin resistance index in homeostatic model assessment between 203 subjects who were homozygous for the wild-type Pro12 allele and 12 subjects with the variant Ala12 allele (11 heterozygotes and one homozygote). These data suggest that the Pro12Ala variant is not a major contributor to adiposity, fat distribution, or insulin resistance in Japanese men.

Association between Ala54Thr substitution of the fatty acid-binding protein 2 gene with insulin resistance and intra-abdominal fat thickness in Japanese men

Alanine to threonine substitution at codon 54 of the fatty acid-binding protein 2 (FABP2) gene was recently shown to be associated with insulin resistance in Pima Indians. It has been hypothesized that the mutation may result in enhanced intestinal up-take of fatty acids, and thereby an impairment of insulin action. We analysed the association of the Ala54Thr substitution with insulin sensitivity and abdominal fat thickness in 395 Japanese men aged 50.5 +/- 8.8 years (mean +/- SD) with a body mass index of 24.4 +/- 3.0 kg/m2. The frequency of the Thr54 allele was 0.34. Although the polymorphism was not significantly associated with diabetes or impaired glucose tolerance, subjects homozygous for the Thr54 allele had higher basal insulin levels. Analysis by homeostasis model assessment showed an association between the amino acid substitution and greater insulin resistance, and slightly higher beta-cell function. Oral glucose tolerance tests performed in 392 subjects without fasting hyperglycaemia showed higher 2-h insulin concentrations in individuals homozygous for the Thr54 allele when compared with heterozygotes or homozygotes for the Ala54 allele. No significant association was obtained between the polymorphism of the FABP2 gene and body mass index. However, ultrasound measurements of abdominal fat thickness revealed a greater accumulation of intra-abdominal fat in subjects homozygous for the Thr54 allele, whereas subcutaneous fat thickness was not associated with the polymorphism. These observations suggest that the Ala54Thr substitution in the FABP2 gene is associated with insulin resistance in Japanese men, and that visceral fat accumulation might be involved in the impaired insulin action associated with the substitution.