An inverse association between serum resistin levels and n-3 polyunsaturated fatty acids intake was strongest in the SNP-420 G/G genotype in the Japanese cohort: The Toon Genome Study.

OBJECTIVE: Resistin is secreted by monocytes/macrophages and is associated with insulin resistance, inflammation and cardiovascular diseases. In the Japanese cohort, serum resistin is tightly associated with a single-nucleotide polymorphism (SNP) at -420 (rs1862513) in the promoter region of the human resistin gene. However, interactions between SNP-420 and environmental factors remain to be elucidated. The aim of this study was to investigate the association between serum resistin levels and nutrient intake, and the effect of SNP-420 on this association. DESIGN, PARTICIPANTS AND MEASUREMENTS: The Toon Genome Study is a cohort study of Japanese community-dwelling subjects. A total of 1981 participants were cross-sectionally analysed. Each nutrient intake was assessed using the semiquantitative food frequency questionnaire and categorized into the quartiles (Q1-Q4). Serum resistin was measured by ELISA. RESULTS: Serum resistin tended to be inversely associated with fish intake and positively associated with meat intake after adjustment for age, sex, BMI and energy intake. Serum resistin was inversely associated with n-3 polyunsaturated fatty acids (PUFA) intake after adjustment for age, sex, BMI and energy intake (Q1 12.5, Q2 12.5, Q3 12.2, Q4 11.5 ng/mL; P for trend = .007). This inverse association was strongest in the G/G genotype of SNP-420, followed by C/G and C/C (G/G, Q1 18.9, Q2 19.5, Q3 18.4, Q4 14.5 ng/mL, P = .001; C/G, 14.4, 13.3, 13.1, 12.9, P = .015; C/C, 9.5, 9.5, 9.2, 8.8, P = .020; P for interaction = .004). CONCLUSIONS: The inverse association between serum resistin and n-3 PUFA intake was strongest in SNP-420 G/G genotype in the Japanese cohort.

Heart Rate Variability, Insulin Resistance, and Insulin Sensitivity in Japanese Adults: The Toon Health Study.

BACKGROUND: Although impaired cardiac autonomic function is associated with an increased risk of type 2 diabetes in Caucasians, evidence in Asian populations with a lower body mass index is limited. METHODS: Between 2009-2012, the Toon Health Study recruited 1899 individuals aged 30-79 years who were not taking medication for diabetes. A 75-g oral glucose tolerance test was used to diagnose type 2 diabetes, and fasting and 2-h-postload glucose and insulin concentrations were measured. We assessed the homeostasis model assessment index for insulin resistance (HOMA-IR) and Gutt's insulin sensitivity index (ISI). Pulse was recorded for 5 min, and time-domain heart rate variability (HRV) indices were calculated: the standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive difference (RMSSD). Power spectral analysis provided frequency domain measures of HRV: high frequency (HF) power, low frequency (LF) power, and the LF:HF ratio. RESULTS: Multivariate-adjusted logistic regression models showed decreased SDNN, RMSSD, and HF, and increased LF:HF ratio were associated significantly with increased HOMA-IR and decreased ISI. When stratified by overweight status, the association of RMSSD, HF, and LF:HF ratio with decreased ISI was also apparent in non-overweight individuals. The interaction between LF:HF ratio and decreased ISI in overweight individuals was significant, with the odds ratio for decreased ISI in the highest quartile of LF:HF ratio in non-overweight individuals being 2.09 (95% confidence interval, 1.41-3.10). CONCLUSIONS: Reduced HRV was associated with insulin resistance and lower insulin sensitivity. Decreased ISI was linked with parasympathetic dysfunction, primarily in non-overweight individuals.

Recurrent Hypoglycemia Due to a High Titer of Insulin Antibody in Response to Exogenous Insulin Administration in Two Cases of Type 1 Diabetes.

In the first case, a 60-year-old man who was using continuous subcutaneous insulin infusion (CSII), developed recurrent hypoglycemia due to insulin antibodies. This is the first report of such a case using CSII. In the second case, a 70-year-old man was follow-up case who developed hypoglycemia while using human insulin. In both cases, the hypoglycemia subsided after switching to multiple daily insulin injection and/or insulin preparation. The results of Scatchard analyses of the two cases were similar to those of cases of insulin autoimmune syndrome (IAS) that improved after recovery from hypoglycemia.The clinical characteristics and Scatchard analysis data were essentially the same as those for IAS, except for the presence of insulin administration.

The GCKR rs780094 polymorphism is associated with susceptibility of type 2 diabetes, reduced fasting plasma glucose levels, increased triglycerides levels and lower HOMA-IR in Japanese population.

It was recently reported that GCKR rs780094 was associated with fasting plasma glucose (FPG) and triglyceride (TG) levels in various ethnic populations (A allele for low FPG and high TG). An association between GCKR rs780094 and type 2 diabetes mellitus (T2DM) (A allele for low risk) has also been reported. We examined the association between GCKR rs780094 and T2DM in Japanese subjects by analyzing 488 cases and 398 controls. A meta-analysis was performed involving two previous association studies. We also analyzed the association between the single-nucleotide polymorphism and clinical parameters in the general Japanese population (n=1854). In the case-control study, the A allele of GCKR rs780094 was associated with a reduced risk of T2DM (odds ratio=0.711 (95% confidence interval=0.589-0.859), P=4.2 × 10(-4)). A meta-analysis confirmed the association of GCKR rs780094 with T2DM susceptibility. In the general Japanese population, subjects with the A/A genotype had lower levels of FPG, fasting plasma insulin and homeostasis model assessment of insulin resistance than those with the G/G genotype. Conversely, subjects with the A/A genotype had higher levels of TG than those with the G/G genotype. We replicated GCKR rs780094 as a marker of T2DM susceptibility in Japanese subjects. This suggests that GCKR rs780094 is a common variant for T2DM susceptibility in various ethnic groups.

PPARgamma Pro12Ala Pro/Pro and resistin SNP-420 G/G genotypes are synergistically associated with plasma resistin in the Japanese general population.

OBJECTIVE: The Ala allele of the Pro12Ala polymorphism (rs1801282) of peroxisome proliferator-activated receptor gamma (PPARgamma) is protective against type 2 diabetes (T2DM). Resistin, secreted from adipocytes, causes insulin resistance in rodents. Resistin gene expression is reduced by the PPARgamma ligand. We previously reported that subjects with the G/G genotype of a resistin gene single nucleotide polymorphism (SNP) at -420 (rs1862513) had the highest circulating resistin levels, followed by C/G and C/C. The aim of this study was to determine the relationship among PPARgamma Pro12Ala polymorphism, resistin SNP-420, and plasma resistin. DESIGN, PATIENTS AND MEASUREMENTS: We cross-sectionally analysed 2077 community-dwelling subjects attending an annual medical check-up. Genotypes were determined by TaqMan analysis. Fasting plasma resistin was measured using ELISA. RESULTS: Plasma resistin appeared to be higher in subjects with the Pro/Pro genotype of PPARgamma than those with Pro/Ala and Ala/Ala genotypes (mean +/- SE, 11.6 +/- 0.2 vs. 10.4 +/- 0.5 microg/l). Multiple regression analysis, adjusted for age, gender, BMI, and resistin SNP-420, revealed that the Pro/Pro genotype was a positive predictor of plasma resistin (PPARgamma , Pro/Pro vs. Pro/Ala + Ala/Ala, unstandardized regression coefficient (beta) = 1.03, P = 0.0384). The effects of the Pro/Pro genotype of PPARgamma (Pro/Pro vs. Pro/Ala + Ala/Ala) and the G/G genotype of resistin SNP-420 (G/G vs. C/C) on plasma resistin were synergistic (beta = 4.76, P = 0.011). CONCLUSIONS: The PPARgamma Pro12Ala Pro/Pro and resistin SNP-420 G/G genotypes were synergistically associated with plasma resistin, when adjusted for age, gender, and BMI, in the Japanese general population.

Bone morphogenetic protein-induced MSX1 and MSX2 inhibit myocardin-dependent smooth muscle gene transcription.

During the onset and progression of atherosclerosis, the vascular smooth muscle cell (VSMC) phenotype changes from differentiated to dedifferentiated, and in some cases, this change is accompanied by osteogenic transition, resulting in vascular calcification. One characteristic of dedifferentiated VSMCs is the down-regulation of smooth muscle cell (SMC) marker gene expression. Bone morphogenetic proteins (BMPs), which are involved in the induction of osteogenic gene expression, are detected in calcified vasculature. In this study, we found that the BMP2-, BMP4-, and BMP6-induced expression of Msx transcription factors (Msx1 and Msx2) preceded the down-regulation of SMC marker expression in cultured differentiated VSMCs. Either Msx1 or Msx2 markedly reduced the myocardin-dependent promoter activities of SMC marker genes (SM22alpha and caldesmon). We further investigated interactions between Msx1 and myocardin/serum response factor (SRF)/CArG-box motif (cis element for SRF) using coimmunoprecipitation, gel-shift, and chromatin immunoprecipitation assays. Our results showed that Msx1 or Msx2 formed a ternary complex with SRF and myocardin and inhibited the binding of SRF or SRF/myocardin to the CArG-box motif, resulting in inhibition of their transcription.

A pilot study suggests that the G/G genotype of resistin single nucleotide polymorphism at -420 may be an independent predictor of a reduction in fasting plasma glucose and insulin resistance by pioglitazone in type 2 diabetes.

The aim of this study was to determine the relation between the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at -420 (rs1862513) and glycemic control by pioglitazone in type 2 diabetes. In Study 1, 121 type 2 diabetic patients were treated with pioglitazone (15 or 30 mg/day) for 12 weeks, in addition to previous medication. In Study 2, 63 patients who had been treated with pioglitazone for 12 weeks were examined retrospectively. In Study 1, multiple regression analysis revealed that the G/G but not C/G genotype was correlated with a reduction in fasting plasma glucose (FPG) and homeostasis model assessment of insulin resistance (HOMA-IR) compared to C/C. When adjusted for age, gender, and BMI, the G/G genotype was an independent factor for the reduction of FPG (P=0.020) and HOMA-IR (P =0.012). When studies 1 and 2 were combined by adjusting the studies, age, gender, and BMI, the reduction of HbA1c was correlated with the G/G genotype (beta=-0.511, P=0.044). Therefore, this pilot study suggests that the G/G genotype of resistin SNP -420 may be an independent predictor of the reduction of fasting plasma glucose and HOMA-IR by pioglitazone.

Effect of non-surgical periodontal therapy on insulin resistance and insulin sensitivity among individuals with borderline diabetes: A randomized controlled trial.

OBJECTIVE: To investigate the effect of non-surgical periodontal therapy on insulin resistance and sensitivity among individuals with borderline diabetes not receiving medications. METHODS: A crossover, randomized controlled trial was conducted among participants with borderline diabetes diagnosed by a 75-g oral glucose tolerance test. Participants were randomly assigned to either an early or later intervention group. The early intervention group underwent non-surgical periodontal therapy of scaling and root planing during the first 6 months, followed by a 6-month non-intervention period. The order was reversed in the later intervention group. Primary outcomes included: fasting or post-load serum glucose and insulin, body mass index (BMI), HOMA-IR, HOMA-ß, and Matsuda Index. RESULTS: Seventy-four participants were randomized, and 71 participants completed the trial. There were no significant differences between groups in glucose and insulin concentrations during the intervention and non-intervention periods. When analyzed within groups by median-split of bleeding on probing (BOP) levels before intervention, the lower BOP group showed improved changes in BMI, HOMA-IR, HOMA-ß, and Matsuda Index (P < 0.05). Further, we observed a positive correlation between baseline BOP and change in BMI (P = 0.06). Change in BMI was positively correlated with changes in HbA1c, HOMA-IR, and HOMA-ß (P < 0.05), and inversely correlated with change in Matsuda Index (P = 0.001). CONCLUSIONS: Periodontal therapy had no significant effect on markers related to insulin and glucose metabolism among individuals with borderline diabetes. However, participants with a lower BOP (%) showed significant improvements in BMI, fasting serum insulin, HOMA-IR, HOMA-ß and Matsuda Index. CLINICAL SIGNIFICANCE: Among individuals diagnosed with borderline diabetes, those who had <37% of a lower BOP (%) showed potential improvements in BMI, fasting serum insulin, HOMA-IR, HOMA-ß and Matsuda Index following non-surgical periodontal therapy.

Serum resistin is positively correlated with the accumulation of metabolic syndrome factors in type 2 diabetes.

OBJECTIVE: Resistin, secreted from adipocytes, causes insulin resistance in rodents. We reported that the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at -420 increases type 2 diabetes (T2DM) susceptibility by enhancing promoter activity. We also showed that serum resistin was positively correlated with G at SNP-420, the duration of T2DM, and HbA1c in T2DM. The aim of this study was to determine the relation between serum resistin and factors related to the metabolic syndrome (MetS) in T2DM. DESIGN, PATIENTS AND MEASUREMENTS: We analysed 238 Japanese T2DM subjects (124 males and 114 females, age 60.2 +/- 11.3 years, body mass index (BMI) 24.1 +/- 3.9) whose overnight fasting sera were available. Serum resistin was measured using ELISA. RESULTS: Serum resistin was higher in subjects with either obesity (P = 0.041), low HDL (P = 0.004), high triglycerides (TG) (P = 0.019), hypertension (HT) (P = 0.001) or atherosclerosis (P = 0.012). Simple regression analysis revealed that serum resistin was correlated with lower HDL, TG and high-sensitivity C-reactive protein (hsCRP). Multiple regression analysis (or logistic regression analysis for HT), adjusted for age, gender, BMI and the duration of T2DM, revealed that serum resistin was correlated with lower HDL (P = 0.008), TG (P = 0.041), HT (P = 0.031) and hsCRP (P = 0.004). Serum resistin was positively correlated with the number of MetS factors, independent of age, gender and the duration of T2DM (P < 0.001). Adjustment by either thiazolidinedione (TZD) treatment or hsCRP had no effects on these findings. CONCLUSIONS: Serum resistin was positively correlated with the accumulation of MetS factors in T2DM.

The G/G genotype of a single nucleotide polymorphism at -1066 of c-Jun N-terminal kinase 1 gene (MAPK8) does not affect type 2 diabetes susceptibility despite the specific binding of AP2alpha.

OBJECTIVE: The c-Jun N-terminal kinase 1 (JNK1, mitogen-activated kinase 8; MAPK8) phosphorylates insulin receptor substrate-1 (IRS-1) at serine 307, which induces insulin resistance. MAPK8 activity is increased in obese insulin-resistant mice, whereas mapk8 (-/-) mice show decreased adiposity and improved insulin sensitivity. The aim of this study was to determine the relationship between single nucleotide polymorphisms (SNPs) of MAPK8 and type 2 diabetes (T2DM). DESIGN, PATIENTS AND MEASUREMENTS: Approximately 2 kb of 5' flanking and the coding regions were initially sequenced in 24 Japanese T2DM subjects. Identified SNPs were genotyped in 204 T2DM cases and 201 nondiabetic controls. The function of promoter SNP-1066 (g.-1066G > A, rs10857561) was analysed by electrophoretic mobility shift assay (EMSA) and luciferase assay. SNP-1066 was further genotyped in a total of 498 cases and 407 controls, and in 2075 subjects in the general population. RESULTS: In 204 cases and 201 controls, 11 identified SNPs were not associated with T2DM. These SNPs were in the same linkage disequilibrium (LD) block. The tag SNP-1066 was not associated with T2DM in a total of 498 cases and 407 controls with the power > 80% when the relative risk is > 1.31. Functionally, transcription factor AP2alpha specifically recognized G but not A at -1066. MAPK8 promoter activity was unchanged between G and A. In 2075 subjects, neither body mass index (BMI), fasting plasma glucose (FPG), homeostasis model assessment insulin resistance index (HOMA-IR), nor beta cell function index (HOMA-beta) was associated with SNP-1066. CONCLUSIONS: The G/G genotype of MAPK8 SNP-1066 did not affect T2DM susceptibility despite specific binding of AP2alpha.

Serum resistin is reduced by glucose and meal loading in healthy human subjects.

Resistin is an adipokine that induces insulin resistance in mice; serum concentrations are decreased by fasting and increased by feeding. Adiponectin, another adipokine, improves insulin sensitivity. The aims of this study were to determine the effects of glucose and meal loading on serum resistin and total and high-molecular weight (HMW) adiponectin in humans and to explore potential determinants of fasting serum resistin and of changes in resistin. Serum resistin and total and HMW adiponectin were measured by enzyme-linked immunosorbent assay in young, lean, nondiabetic subjects during 75-g oral glucose tolerance test (OGTT) and meal tolerance test (MTT). Resistin single nucleotide polymorphism (SNP) -420 was typed. Serum resistin was decreased at 60 and 120 minutes during OGTT compared with baseline (n = 36, 1-way repeated-measures analysis of variance, P < .0001; Scheffe, P = .0457 and P < .0001, respectively). Serum resistin was also reduced at 240 minutes during MTT (n = 33, 1-way repeated measures analysis of variance, P < .0001; Scheffe, P = .0002). Multiple regression analysis adjusted for age, sex, and body mass index revealed that the reductions in serum resistin were dependent on baseline resistin levels. Subjects with greater baseline concentrations of resistin experienced more pronounced declines in resistin (OGTT, unstandardized regression coefficient (beta) = -0.19, P = .0005; MTT, beta = -0.63, P < .0001). Serum total and HMW adiponectin was unchanged. Fasting serum resistin was positively correlated with the G allele number of SNP -420 (beta = 7.70, P = .01) and white blood cell count (beta = 0.007, P = .0001) adjusted for age, sex, and body mass index. Therefore, in young, lean, nondiabetic humans, serum resistin was reduced by glucose and meal loading; the reduction in resistin was greater in subjects with higher fasting resistin. Fasting resistin was correlated with SNP -420 and white blood cell count.

Dual Effects of a RETN Single Nucleotide Polymorphism (SNP) at -420 on Plasma Resistin: Genotype and DNA Methylation.

CONTEXT: We previously reported that single nucleotide polymorphism (SNP)-420 C>G (rs1862513) in the promoter region of RETN was associated with type 2 diabetes. Plasma resistin was tightly correlated with SNP-420 genotypes. SNP-420 is a CpG-SNP affecting the sequence of cytosine-phosphate-guanine dinucleotides. OBJECTIVE: To examine whether methylation at SNP-420 affects plasma resistin, we analyzed plasma resistin and methylation at RETN SNP-420. DESIGN AND METHODS: Genomic DNA was extracted from peripheral white blood cells in 2078 Japanese subjects. Quantification of the methylation was performed by pyrosequencing after DNA bisulfite conversion. RESULTS: Methylation at SNP-420 was highest in the C/C genotype (36.9 ± 5.7%), followed by C/G (21.4 ± 3.5%) and G/G (2.9 ± 1.4%; P < 0.001). When assessed in each genotype, methylation at SNP-420 was inversely associated with plasma resistin in the C/C (ß = -0.134, P < 0.001) or C/G (ß = -0.227, P < 0.001) genotype. In THP-1 human monocytes intrinsically having the C/C genotype, a demethylating reagent, 5-aza-dC, decreased the methylation at SNP-420 and increased RETN messenger RNA. SNP+1263 (rs3745369), located in the 3' untranslated region of RETN, was also associated with methylation at SNP-420. In addition, highly sensitive C-reactive protein was inversely associated with methylation at SNP-420 in the C/C genotype, whereas body mass index was positively associated. CONCLUSIONS: Plasma resistin was inversely associated with the extent of methylation at SNP-420 mainly dependent on the SNP-420 genotype. The association can also be explained partially independent of SNP-420 genotypes. SNP-420 could have dual, genetic and epigenetic effects on plasma resistin.

Impact of heart rate variability on C-reactive protein concentrations in Japanese adult nonsmokers: The Toon Health Study.

OBJECTIVE: Lower heart rate variability (HRV) is associated with the inflammation that is linked with the progression of atherosclerosis. We examined this association, taking insulin sensitivity into consideration, as it is related to both HRV and inflammation. METHODS: Subjects were 1728 individuals ages 30-79 years who did not smoke between 2009 and 2012. C-reactive protein (CRP) concentrations and white blood cell (WBC) counts were assessed as markers of inflammation. The homeostasis model assessment index for insulin resistance (HOMA-IR) and Gutt's insulin sensitivity index (ISI) were calculated based on fasting and 2h-post-load glucose and insulin concentrations in a 75-g oral glucose tolerance test. Pulse was recorded for 5 min, and time-domain HRV indices of standard deviation of NN intervals (SDNN) and root mean square of successive differences (RMSSD) were calculated. Power spectral analysis provided frequency domain measures of HRV: high frequency (HF) power, low frequency (LF) power and LF/HF. RESULTS: Sex and age-adjusted logistic models presented quartiles of SDNN, RMSSD, LF, and HF significantly associated with the highest quartile of CRP or WBC. After adjustment for body mass index and ISI, the associations were attenuated for WBC; however, even after further adjustment for several variables, SDNN, RMSSD, LF, and HF remained significantly associated with elevated CRP concentrations. When results were stratified by weight, the associations appeared more evident among non-overweight individuals. CONCLUSION: Lowered HRV, primarily due to parasympathetic dysfunction, was associated with elevated inflammation, independent of weight, insulin sensitivity, and other related factors.

Endoplasmic reticulum stress induced by tunicamycin increases resistin messenger ribonucleic acid through the pancreatic endoplasmic reticulum eukaryotic initiation factor 2α kinase-activating transcription factor 4-CAAT/enhancer binding protein-α homologous protein pathway in THP-1 human monocytes.

AIMS/INTRODUCTION: Resistin, secreted from adipocytes, causes insulin resistance in mice. In humans, the resistin gene is mainly expressed in monocytes and macrophages. Tunicamycin is known to induce endoplasmic reticulum (ER) stress, and reduce resistin gene expression in 3T3-L1 mouse adipocytes. The aim of the present study was to examine whether ER stress affects resistin gene expression in human monocytes. MATERIALS AND METHODS: The relationship between resistin messenger ribonucleic acid (mRNA) and ER stress markers mRNA was analyzed by reverse transcription polymerase chain reaction in isolated monocytes of 30 healthy volunteers. The effect of endotoxin/lipopolysaccharides or tunicamycin on resistin gene expression was analyzed in THP-1 human monocytes. Signaling pathways leading to resistin mRNA were assessed by the knockdown using small interfering RNA or overexpression of key molecules involved in unfolded protein response. RESULTS: Resistin mRNA was positively associated with immunoglobulin heavy chain-binding protein (BiP) or CAAT/enhancer binding protein-α homologous protein (CHOP) mRNA in human isolated monocytes. In THP-1 cells, lipopolysaccharides increased mRNA of BiP, pancreatic endoplasmic reticulum eukaryotic initiation factor 2α kinase (PERK) and CHOP, as well as resistin. Tunicamycin also increased resistin mRNA. This induction appeared to be dose- and time-dependent. Tunicamycin-induced resistin mRNA was inhibited by chemical chaperone, 4-phenylbutyric acid. The knockdown of either PERK, activating transcription factor 4 (ATF4) or CHOP reduced tunicamycin-induced resistin mRNA. Conversely, overexpression of ATF4 or CHOP increased resistin mRNA. CONCLUSIONS: Endoplasmic reticulum stress induced by tunicamycin increased resistin mRNA through the PERK-ATF4-CHOP pathway in THP-1 human monocytes. ER stress could lead to insulin resistance through enhanced resistin gene expression in human monocytes.

Vascular remodeling induced by naturally occurring unsaturated lysophosphatidic acid in vivo.

BACKGROUND: We previously identified unsaturated (16:1, 18:1, and 18:2) but not saturated (12:0, 14:0, 16:0, and 18:0) lysophosphatidic acids (LPAs) as potent factors for vascular smooth muscle cell (VSMC) dedifferentiation. Unsaturated LPAs strongly induce VSMC dedifferentiation via the coordinated activation of the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK), resulting in the proliferation and migration of dedifferentiated VSMCs. Here, we investigated the effects of 18:1 and 18:0 LPAs (as representative unsaturated and saturated LPAs, respectively) on the vasculature in vivo. METHODS AND RESULTS: Rat common carotid arteries (CCAs) were treated transiently with 18:1 or 18:0 LPA and then examined by histological and biochemical analyses. The 18:1 but not 18:0 LPA potently induced vascular remodeling that was composed primarily of neointima. The incorporation of [3H]18:1 LPA into the CCAs revealed that a sufficient amount of unmetabolized [3H]18:1 LPA to induce VSMC dedifferentiation was present in the vascular wall. The 18:1 LPA-induced neointimal formation in vivo was also dependent on the coordinated activation of ERK and p38MAPK. Unlike balloon-injured CCAs, the 18:1 LPA-treated CCAs showed a histological similarity to human atherosclerotic arteries. CONCLUSIONS: This is the first report demonstrating a role for a naturally occurring unsaturated LPA in inducing vascular remodeling in vivo and provides a novel animal model for neointimal formation.

Epiregulin as a major autocrine/paracrine factor released from ERK- and p38MAPK-activated vascular smooth muscle cells.

BACKGROUND: The coordinated activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) is critical for the induction of vascular and visceral smooth muscle cell (SMC) dedifferentiation. We previously reported that on the forced activation of both MAPKs, visceral SMCs secrete a non-heparin-binding protein factor(s) that is involved in the dedifferentiation of neighboring SMCs. In this study, we sought to identify the dedifferentiation factor(s) derived from vascular SMCs (VSMCs). METHODS AND RESULTS: We fractionated the VSMC dedifferentiation factor(s) in the conditioned medium obtained from differentiated VSMCs in which both ERK and p38MAPK were forcedly activated and identified epiregulin as a major autocrine/paracrine factor for VSMC dedifferentiation. The epiregulin-induced VSMC dedifferentiation was mediated through the coordinated activation of ERK and p38MAPK. Unsaturated lysophosphatidic acid and platelet-derived growth factor-BB, which are potent VSMC dedifferentiation factors, rapidly upregulated epiregulin mRNA expression in an ERK- and p38MAPK-dependent manner. Reverse transcriptase-polymerase chain reaction and/or immunohistological analyses revealed the restricted expression of epiregulin in human atherosclerotic and balloon-injured rat arteries, in which the phenotypic modulation of medial VSMCs occurred in vivo. CONCLUSIONS: Epiregulin is released from VSMCs primed by atherogenic factors and acts as a major autocrine/paracrine factor for VSMC dedifferentiation. It may be involved in the progression of vascular remodeling such as atherosclerosis.

Associations of serum ß-carotene and retinol concentrations with insulin resistance: the Toon Health Study.

OBJECTIVE: Although green and yellow vegetables have beneficial effects against type 2 diabetes, the relationship of their nutritive content with insulin resistance is poorly understood. The aim of this study was to examine the associations of serum ß-carotene and retinol concentrations with glucose and insulin concentrations. METHODS: We recruited 951 Japanese men and women ages 30 to 79 y who were not undergoing treatment for diabetes and measured their serum ß-carotene and retinol concentrations. A 75-g oral glucose tolerance test was performed and the homeostasis model assessment for insulin resistance (HOMA-IR) and the Matsuda Index were calculated as measures of insulin resistance. Several confounding factors were adjusted for with multivariable logistic models. RESULTS: Multivariable-adjusted odds ratios of the highest quartile of serum ß-carotene compared with the lowest quartile for HOMA-IR >1.6 and Matsuda Index <4.9 were 0.56 (95% confidence interval, 0.34-0.94) and 0.62 (0.37-1.02), respectively. When stratified by sex and overweight status, these associations were observed for women and non-overweight individuals. Serum retinol concentration was not associated with either index. Furthermore, according to the nutritional survey, serum ß-carotene concentration was associated with green and yellow vegetable intake (P = 0.01). CONCLUSION: Our findings suggest that higher serum ß-carotene levels, associated with higher intake of green and yellow vegetables, confer beneficial effects against insulin resistance.

The impact of masticatory ability as evaluated by salivary flow rates on obesity in Japanese: The Toon health study.

OBJECTIVE: This study examined the associations of masticatory ability evaluated by chewing-gum-stimulated salivary flow rate with anthropometric indices among a general Japanese population. METHODS: In total, 921 Japanese men and women aged 30-79 years participated in this cross-sectional study. Saliva production was stimulated by 5 min of gum chewing, then collected; salivary flow rate was calculated as g/min. Overweight, abdominal obesity in terms of waist circumference (WC), and waist-hip ratio (WHR), and elevated skinfold thickness statuses were determined. RESULTS: The multivariable odds ratio and 95% confidence intervals of overweight, abdominal obesity (WC, WHR), and elevated skinfold thickness status for highest vs. lowest quartile of salivary flow rate were 0.59 (0.37-0.95, P for trend = 0.02), 0.65 (0.43-0.98, P = 0.03), 0.54 (0.35-0.83, P < 0.01), and 0.61 (0.39-0.96, P < 0.01), respectively. The linear trends of multivariable-adjusted means of BMI, WC, WHR, and skinfold thickness according to quartiles of salivary flow rate did not vary after stratification by overweight status. CONCLUSIONS: Higher stimulated salivary flow rate, a surrogate marker for mastication ability, was associated with lower prevalence of overweight, abdominal obesity (whether WC- or WHR-defined), and elevated skinfold thickness among the general Japanese population.

Clinical implication of blood glucose monitoring in general dental offices: the Ehime Dental Diabetes Study.

OBJECTIVE: We examined whether general dentists can contribute to the detection of patients with undiagnosed diabetes and prediabetes by monitoring blood glucose in dental clinics. RESEARCH DESIGN AND METHODS: A total of 716 patients who visited clinics for dental treatment were enrolled and classified into 3 groups (mild, moderate, and severe) according to Kornman's criteria for periodontitis. The correlations between the casual blood glucose level, presence or absence of the history of diabetes, and/or severity of periodontitis were evaluated. RESULTS: 68 patients (9.5%) had hyperglycemia (blood glucose ≥200 mg/dL). Of these patients, 20 (29.4%) did not have a history of diabetes. Blood glucose tended to be higher with greater periodontitis severity. Of the 3 groups, the severe periodontitis group had the highest proportion of patients with hyperglycemia (p<0.0001). CONCLUSIONS: Patients with dental problems could be screened for diabetes, especially undiagnosed diabetes. General dentists could function as practitioners to screen for diabetes. TRIAL REGISTRATION NUMBER: UMIN-CTR 000014877.

Sleep-related intermittent hypoxemia and glucose intolerance: a community-based study.

BACKGROUND: Intermittent hypoxemia is a fundamental pathophysiological consequence of sleep-disordered breathing and may alter glucose metabolism. To characterize the association between sleep-related intermittent hypoxemia and glucose metabolism, overnight pulse-oximetry and an oral glucose tolerance test were completed in a cohort of middle-aged and older Japanese adults. METHODS: The study sample consisted of 1836 community-dwelling Japanese (age, 30-79 years; women, 65.5%; mean body mass index, 23.1 kg/m(2)). The oxygen desaturation index (ODI) was quantified during sleep using a ≥3% oxygen desaturation threshold and categorized as normal (<5.0 events/h), mild (5.0-15.0 events/h), and moderate to severe (≥15.0 events/h). The independent associations between the ODI and the prevalence of impaired fasting glucose, impaired glucose tolerance, diabetes, and two metrics of insulin resistance [homeostasis model assessment index for insulin resistance (HOMA-IR) and Matsuda index] were examined. RESULTS: Compared with subjects with an ODI < 5 events/h, the adjusted odds ratio for prevalent impaired fasting glucose, glucose intolerance, and diabetes for subjects with an ODI ≥15.0 events/h were 1.27 (95% confidence interval, 0.72-2.23), 1.69 (1.03-2.76), and 1.28 (0.59-2.79), respectively. Both HOMA-IR and Matsuda index were significantly associated with the severity of sleep-related intermittent hypoxemia as assessed by the ODI (P for trend = 0.03 and 0.007, respectively). CONCLUSION: Among middle-aged and older Japanese adults, sleep-related intermittent hypoxemia is associated with glucose intolerance and insulin resistance, and may contribute to the development of type 2 diabetes mellitus.