Publications by authors named "Wataru Nishida"

33 Publications

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

J Dent 2019 06 12;85:18-24. Epub 2019 Apr 12.

Department of Public Health and Epidemiology, Faculty of Medicine, Oita University 1-1 Idaigaoka, Hasama-machi, Yufu-shi Oita, 879-5593, Japan. Electronic address:

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-β, 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-β, 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 HbA, HOMA-IR, and HOMA-β (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-β 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-β and Matsuda Index following non-surgical periodontal therapy.
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http://dx.doi.org/10.1016/j.jdent.2019.04.005DOI Listing
June 2019

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.

Clin Endocrinol (Oxf) 2018 Jan 8;88(1):51-57. Epub 2017 Nov 8.

Department of Diabetes and Molecular Genetics, Ehime University Graduate School of Medicine, Ehime, Japan.

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.
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http://dx.doi.org/10.1111/cen.13500DOI Listing
January 2018

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

J Clin Endocrinol Metab 2017 Mar;102(3):884-892

Departments of Diabetes and Molecular Genetics.

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 (β = -0.134, P < 0.001) or C/G (β = -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.
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http://dx.doi.org/10.1210/jc.2016-2417DOI Listing
March 2017

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.

J Diabetes Investig 2016 May 18;7(3):312-23. Epub 2015 Nov 18.

Department of Diabetes and Molecular Genetics Ehime University Graduate School of Medicine Ehime Japan.

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.
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http://dx.doi.org/10.1111/jdi.12434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847884PMC
May 2016

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

BMJ Open Diabetes Res Care 2015 13;3(1):e000151. Epub 2015 Nov 13.

Ehime Dental Diabetes Study Group , Ehime , Japan ; Department of Diabetes and Molecular Genetics , Ehime University Graduate School of Medicine , Ehime , Japan.

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.
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http://dx.doi.org/10.1136/bmjdrc-2015-000151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653862PMC
December 2015

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

Atherosclerosis 2016 Jan 4;244:79-85. Epub 2015 Nov 4.

Department of Public Health, Juntendo University Graduate School of Medicine, Tokyo, Japan.

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.
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http://dx.doi.org/10.1016/j.atherosclerosis.2015.10.112DOI Listing
January 2016

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

J Epidemiol 2015 15;25(9):583-91. Epub 2015 Aug 15.

Department of Community Health Systems Nursing, Ehime University Graduate School of Medicine.

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.
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http://dx.doi.org/10.2188/jea.JE20140254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549610PMC
January 2016

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

Nutrition 2015 Jul-Aug;31(7-8):975-80. Epub 2015 Mar 24.

Department of Public Health, Juntendo University Graduate School of Medicine, Bunkyo, Japan.

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 β-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 β-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 β-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 β-carotene concentration was associated with green and yellow vegetable intake (P = 0.01).

Conclusion: Our findings suggest that higher serum β-carotene levels, associated with higher intake of green and yellow vegetables, confer beneficial effects against insulin resistance.
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http://dx.doi.org/10.1016/j.nut.2015.02.015DOI Listing
May 2016

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

Obesity (Silver Spring) 2015 Jun 9;23(6):1296-302. Epub 2015 May 9.

Department of Public Health, Juntendo University Graduate School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, Japan.

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.
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http://dx.doi.org/10.1002/oby.21071DOI Listing
June 2015

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

Sleep Med 2014 Oct 27;15(10):1212-8. Epub 2014 Jun 27.

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.

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.
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http://dx.doi.org/10.1016/j.sleep.2014.05.027DOI Listing
October 2014

Insulin administration may trigger type 1 diabetes in Japanese type 2 diabetes patients with type 1 diabetes high-risk HLA class II and the insulin gene VNTR genotype.

J Clin Endocrinol Metab 2014 Sep 27;99(9):E1793-7. Epub 2014 Jun 27.

Department of Diabetes and Molecular Genetics (W.N., R.K., H.On., H.Os., H.M.), Ehime University Graduate School of Medicine, To-on, Ehime 791-0295, Japan; Department of Internal Medicine (M.N.), Kokogawa W City Hospital, Hyogo 675-8611, Japan; Department of Metabolic Medicine (A.I.), Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Department of Internal Medicine (I) (T.H.), Osaka Medical College, Osaka 569-8686, Japan; University of Tsukuba (J.O.), Ibaraki, Japan; 6) Division of Diabetes (K.T.), Department of Internal Medicine, Kurashiki Central Hospital, Kurashiki 710-8602, Japan; Department of Diabetes (T.S.), Kochi Takasu Hospital, Kochi 781-5103, Japan; Sumitomo Hospital (Y.Y.), Osaka 530-0005, Japan; Diabetes Research Center (D.C.), National Center for Global Health and Medicine, Tokyo 162-8655, Japan; Department of Metabolism/Diabetes and Clinical Nutrition (E.K.), Nagasaki University Hospital, Nagasaki 852-8501, Japan; and Shiraishi Hospital Diabetes Center (H.M.), Imabari, Ehime 794-0041, Japan.

Context: Insulin administration causes various types of immune responses to insulin. We previously reported three cases of type 1 diabetes mellitus (T1DM) triggered by insulin administration in Japanese type 2 diabetes mellitus patients.

Objective: The objective of this study was to collect information and characterize insulin-triggered T1DM immunologically and genetically.

Methods: Data for six patients (four men and two women) with insulin-triggered T1DM aged 59.5 ± 12.8 years were collected. Serum or urinary C-peptides, islet-related autoantibodies, insulin antibody, human leukocyte antigen, or the insulin gene variable number of tandem repeat genotype were analyzed. Th1- or Th2-associated responses were evaluated using an Enzyme-Linked ImmunoSpot assay.

Results: None of the subjects had received insulin therapy or had an autoantibody to the 65-kDa isoform of glutamic acid decarboxylase before insulin administration. After insulin administration blood glucose control deteriorated acutely without any apparent cause, whereas C-peptide levels rapidly decreased to insulin-deficient levels. The mean duration of insulin administration to the development of T1DM was 7.7 ± 6.1 months. Islet-related autoantibodies became positive, whereas insulin allergy or a high titer of insulin antibody was observed in several cases. All had T1DM high-risk human leukocyte antigen class II (IDDM1) and the insulin gene variable number of tandem repeats genotype (IDDM2). GAD-reactive and insulin peptide-reactive Th1 cells, but not Th2 cells, were identified in two of four cases.

Conclusions: The findings suggest that insulin administration may have triggered TIDM in patients with type 2 diabetes mellitus. IDDM1 and IDDM 2 as well as autoreactive T cells may contribute to the development of T1DM. Developing insulin-triggered T1DM if a patient's blood glucose control acutely deteriorates after insulin administration should be carefully considered.
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http://dx.doi.org/10.1210/jc.2014-1759DOI Listing
September 2014

Plasma resistin is associated with single nucleotide polymorphisms of a possible resistin receptor, the decorin gene, in the general Japanese population.

Diabetes 2013 Feb 27;62(2):649-52. Epub 2012 Nov 27.

Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Ehime, Japan.

Resistin is an adipokine secreted from adipocytes in mice. We previously reported that a single nucleotide polymorphism (SNP) -420 (rs1862513) in the human resistin gene (RETN), is correlated with plasma resistin. Decorin is a multifunctional proteoglycan, and its isoform, lacking 14 amino acids from the N terminal region of mature core decorin, recently was identified as a resistin receptor in mice. To examine whether SNPs in the vicinity of the human decorin gene (DCN) are associated with plasma resistin, we cross-sectionally analyzed six tag SNPs selected around DCN in the same linkage disequilibrium block in 2,078 community-dwelling Japanese subjects. Plasma resistin was associated with the rs7139228, rs7956537, rs516115, and rs3138167 genotypes in DCN. A multiple regression analysis revealed that the genotype of rs7308752 (G/G) or rs516115 (C/C) was associated with decreased plasma resistin after adjusted for age, sex, BMI, and the RETN SNP rs1862513. The effect of rs7139228 and rs1862513 seemed to be additive without synergistic interaction. Therefore, plasma resistin was associated with some tag SNPs around DCN in the general Japanese population. The possibility that human decorin is a human resistin receptor should be pursued.
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http://dx.doi.org/10.2337/db12-0058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3554371PMC
February 2013

Association of hematological parameters with insulin resistance, insulin sensitivity, and asymptomatic cerebrovascular damage: the J-SHIP and Toon Health Study.

Clin Hemorheol Microcirc 2013 ;55(3):297-311

Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon City, Japan Division of Anti-aging and Genetics, Ehime University Proteo-Medicine Research Center, Toon City, Japan.

Background: Elevated hematocrit levels have been suggested to be an independent determinant of insulin resistance and type 2 diabetes. To clarify the diagnostic significance of hematocrit level, we investigated the association with hemodynamic profiles, insulin resistance and insulin sensitivity, arterial properties, and asymptomatic cerebrovascular damage in a general Japanese population.

Methods: This study included 1,978 participants from two independent cohorts. Insulin sensitivity was assessed by the oral 75 g glucose tolerance test. Carotid ultrasonography was performed to evaluate atherosclerosis and wall shear stress. Periventricular hyperintensity and lacunar infarction were assessed by brain magnetic resonance imaging.

Results: Hematocrit quartile showed a stepwise association with insulin sensitivity (Q1: 2.2±0.7, Q2: 2.0±0.7, Q3: 1.9±0.7, Q4: 1.8±0.6, p<0.001) and insulin resistance (1.0±0.6, 1.2±0.7, 1.3±0.8, 1.5±1.0, p<0.001). Multiple linear regression analysis adjusted for possible covariates identified hematocrit as an independent determinant of insulin sensitivity (β=-0.074, p=0.019) and insulin resistance (β=0.115, p<0.001). However, this association was lost after further adjustment for visceral fat area and plasma alanine aminotransferase level. Further, no significant association was observed between hematocrit and carotid intima-media thickness (p=0.306) where as wall shear stress was inversely associated with the carotid atherosclerosis (r=-0.250, p<0.001). In contrast, a low hematocrit level was independently associated with periventricular hyperintensity (odds ratio 0.87 (95% CI 0.80-0.95), p=0.001).

Conclusion: Hematocrit was positively associated with insulin resistance and insulin sensitivity. This association was epiphenomenon of visceral and hepatic adiposity. Conversely, low hematocrit was a significant risk factor for periventricular hyperintensity independent of insulin resistance.
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http://dx.doi.org/10.3233/CH-2012-1634DOI Listing
October 2014

Relatively lower central aortic pressure in patients with impaired insulin sensitivity and resistance: the Toon Health Study.

J Hypertens 2011 Oct;29(10):1948-54

Department of Basic Medical Research and Education, Ehime University Proteo-Medicine Research Center, Ehime, Japan.

Objective: Central aortic blood pressure (BP) has been postulated to correlate more closely with cardiovascular disease risk than brachial cuff BP. However, the effect of insulin sensitivity and resistance on central BP is not fully understood. Here, we evaluated the associations between insulin sensitivity/resistance and central BP using the oral glucose tolerance test.

Methods: A total of 1034 Japanese participants were enrolled in this study. The absolute pressure of the late systolic peak (SBP2) of the brachial BP obtained by the radial waveform was considered to be the central systolic BP. Oral glucose tolerance test was performed by administering 75 g of glucose, and blood samples were obtained at 0, 60, 120 min after glucose loading.

Results: Mean SBP2 was found to be lower than mean brachial systolic BP (SBP) (119 ± 20, 126 ± 19 mmHg, P < 0.001), and differences between SBP and SBP2 were significantly larger in patients with reduced insulin sensitivity (-8.2 ± 5.2, -7.2 ± 5.3, -7.1 ± 5.1, and -6.5 ± 4.9 mmHg, in the first, second, third and fourth quartiles, respectively; P = 0.002) and increased insulin resistance (-6.6 ± 5.1, -6.6 ± 4.8, -7.3 ± 4.8, -8.5 ± 5.6 mmHg, P < 0.001). Multiple linear regression analysis identified reduced insulin sensitivity (β = 0.067, P = 0.033) and increased insulin resistance (β = -0.081, P = 0.009) as independent determinants of the difference between SBP and SBP2.

Conclusion: Given that both insulin sensitivity and insulin resistance were found to be significant determinants of the difference between SBP and SBP2 in a healthy general population, we suggest measuring the SBP2 in individuals with impaired insulin action in order to accurately assess their risk of developing cardiovascular disease.
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http://dx.doi.org/10.1097/HJH.0b013e32834abd06DOI Listing
October 2011

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.

J Hum Genet 2010 Sep 24;55(9):600-4. Epub 2010 Jun 24.

Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Ehime, Japan.

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.
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http://dx.doi.org/10.1038/jhg.2010.75DOI Listing
September 2010

A at single nucleotide polymorphism-358 is required for G at -420 to confer the highest plasma resistin in the general Japanese population.

PLoS One 2010 Mar 16;5(3):e9718. Epub 2010 Mar 16.

Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Ehime, Japan.

Insulin resistance is a feature of type 2 diabetes. Resistin, secreted from adipocytes, causes insulin resistance in mice. We previously reported that the G/G genotype of single nucleotide polymorphism (SNP) at -420 (rs1862513) in the human resistin gene (RETN) increased susceptibility to type 2 diabetes by enhancing its promoter activity. Plasma resistin was highest in Japanese subjects with G/G genotype, followed by C/G, and C/C. In this study, we cross-sectionally analyzed plasma resistin and SNPs in the RETN region in 2,019 community-dwelling Japanese subjects. Plasma resistin was associated with SNP-638 (rs34861192), SNP-537 (rs34124816), SNP-420, SNP-358 (rs3219175), SNP+299 (rs3745367), and SNP+1263 (rs3745369) (P<10(-13) in all cases). SNP-638, SNP -420, SNP-358, and SNP+157 were in the same linkage disequilibrium (LD) block. SNP-358 and SNP-638 were nearly in complete LD (r(2) = 0.98), and were tightly correlated with SNP-420 (r(2) = 0.50, and 0.51, respectively). The correlation between either SNP-358 (or SNP-638) or SNP-420 and plasma resistin appeared to be strong (risk alleles for high plasma resistin; A at SNP-358, r(2) = 0.5224, P = 4.94x10(-324); G at SNP-420, r(2) = 0.2616, P = 1.71x10(-133)). In haplotypes determined by SNP-420 and SNP-358, the estimated frequencies for C-G, G-A, and G-G were 0.6700, 0.2005, and 0.1284, respectively, and C-A was rare (0.0011), suggesting that subjects with A at -358, generally had G at -420. This G-A haplotype conferred the highest plasma resistin (8.24 ng/ml difference/allele compared to C-G, P<0.0001). In THP-1 cells, the RETN promoter with the G-A haplotype showed the highest activity. Nuclear proteins specifically recognized one base difference at SNP-358, but not at SNP-638. Therefore, A at -358 is required for G at -420 to confer the highest plasma resistin in the general Japanese population. In Caucasians, the association between SNP-420 and plasma resistin is not strong, and A at -358 may not exist, suggesting that SNP-358 could explain this ethnic difference.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0009718PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2838794PMC
March 2010

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.

Endocr J 2009 9;56(9):1049-58. Epub 2009 Sep 9.

Institute of Diabetes Research Center, Takanoko Hospital, Ehime, Japan.

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.
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http://dx.doi.org/10.1507/endocrj.k08e-320DOI Listing
March 2010

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

Clin Endocrinol (Oxf) 2009 Sep 30;71(3):341-5. Epub 2008 Oct 30.

Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

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.
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http://dx.doi.org/10.1111/j.1365-2265.2008.03465.xDOI Listing
September 2009

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

Metabolism 2008 Feb;57(2):149-56

Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan.

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.
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http://dx.doi.org/10.1016/j.metabol.2007.08.018DOI Listing
February 2008

Hyperresistinemia is associated with coexistence of hypertension and type 2 diabetes.

Hypertension 2008 Feb 7;51(2):534-9. Epub 2008 Jan 7.

Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan.

Numerous studies have demonstrated that high blood pressure substantially increases the risk of microvascular and macrovascular complications in patients with type 2 diabetes mellitus (T2DM). Currently, we found that serum resistin, an adipocyte- and monocyte-derived cytokine, was positively correlated with several components of the metabolic syndrome, including hypertension in T2DM. To investigate the association of resistin with an etiologic difference among subjects with hypertension with T2DM, hypertension without T2DM, and normotensive T2DM, we analyzed 210 subjects, including 91 with hypertension with T2DM, 55 with hypertension without T2DM, and 64 with normotensive T2DM. Serum resistin level was higher in subjects with hypertension with T2DM, followed by subjects with normotensive T2DM and hypertension without T2DM, irrespective of antihypertensive treatment status (20.9+/-17.6 and 14.0+/-8.9 versus 11.2+/-7.6 ng/mL, respectively; P<0.01). Simple regression analysis revealed that resistin positively correlated with blood pressure (systolic blood pressure: r=0.29, P<0.01; diastolic blood pressure: r=0.21, P<0.05) and intima-media thickness (r=0.27; P<0.05) in patients with T2DM but not in subjects with hypertension without T2DM. Multiple regression analysis, adjusted for age, gender, body mass index, fasting glucose, high-density lipoprotein cholesterol, white blood cell counts, and glomerular filtration rate, further revealed that resistin was an independent factor for high blood pressure in patients with T2DM (P<0.05). In vitro gene expression analysis in human coronary endothelial cells revealed that resistin induced fatty acid binding protein, a key molecule of insulin resistance, diabetes, and atherosclerosis. These results suggest that hyperresistinemia would contribute to the pathogenesis of hypertension in patients with T2DM, significantly linked to vascular complications and cardiovascular events.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.107.103077DOI Listing
February 2008

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

Clin Endocrinol (Oxf) 2008 Jul 1;69(1):74-80. Epub 2008 Jul 1.

Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Ehime Prefectural Hospital, Ehime, Japan.

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.
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http://dx.doi.org/10.1111/j.1365-2265.2007.03154.xDOI Listing
July 2008

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.

Clin Endocrinol (Oxf) 2008 Jul 1;69(1):36-44. Epub 2008 Jul 1.

Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Ehime Japan.

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.
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http://dx.doi.org/10.1111/j.1365-2265.2007.03143.xDOI Listing
July 2008

Insulin administration may trigger pancreatic beta-cell destruction in patients with type 2 diabetes.

Diabetes Res Clin Pract 2008 Feb 24;79(2):220-9. Epub 2007 Oct 24.

Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Toon-shi, Ehime 791-0295, Japan.

Insulin administration causes various types of immune response to insulin. However, there have been no reports that insulin administration triggers pancreatic beta-cell destruction in diabetic patients. We evaluated three patients who had suffered from type 2 diabetes or impaired glucose tolerance for 5-30 years. After an episode of diabetic mononeuropathy or poor glycemic control, they started human insulin therapy. All the patients' serum or urinary C-peptide levels were preserved before insulin therapy, whereas within a few months they rapidly declined to below detection limits. A high titer of insulin antibody was detected at or after the development of insulin deficiency. Shortly after the initiation of insulin therapy, two of the patients developed an insulin allergy. Autoantibodies to GAD65 or IA-2 were negative throughout the clinical course in two cases, but transiently positive in one case. In a histological examination of pancreas tissue obtained by a pancreatic biopsy in one case, mononuclear cell infiltration into the islets was observed. They all had a type 1 diabetes high-risk HLA class II haplotype in Japanese, and class I alleles of the insulin gene VNTR. The above findings suggest that insulin administration may have triggered pancreatic beta-cell destruction in these patients.
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http://dx.doi.org/10.1016/j.diabres.2007.08.031DOI Listing
February 2008

Plasma resistin, associated with single nucleotide polymorphism -420, is correlated with insulin resistance, lower HDL cholesterol, and high-sensitivity C-reactive protein in the Japanese general population.

Diabetes Care 2007 Jun 23;30(6):1501-6. Epub 2007 Mar 23.

Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan.

Objective: Resistin, secreted from adipocytes, causes insulin resistance in rodents. We previously reported that the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at -420 increases type 2 diabetes susceptibility by enhancing promoter activity. We report here on the relation between plasma resistin and either SNP -420 genotype or factors related to insulin resistance.

Research Design And Methods: We cross-sectionally analyzed 2,078 community-dwelling Japanese subjects attending a yearly medical checkup. The SNP -420 genotype was determined by TaqMan analysis. Fasting plasma resistin was measured using an enzyme-linked immunosorbent assay kit.

Results: Plasma resistin was associated with the SNP -420 genotype (P < 0.0001), which was highest in G/G followed by C/G and C/C. Plasma resistin was higher in elderly individuals, female subjects, nondrinkers, and subjects with high blood pressure (P < 0.001, 0.003, <0.001, and 0.001, respectively). Simple regression analysis revealed that age, female sex, homeostasis model assessment of insulin resistance (HOMA-IR) index, systolic blood pressure, low HDL cholesterol, and high-sensitivity C-reactive protein (hs-CRP) were positively correlated with plasma resistin (P < 0.001, 0.003, <0.001, 0.004, <0.001, and 0.003, respectively). Multiple regression analysis adjusted for age, sex, and BMI revealed that plasma resistin was an independent factor for HOMA-IR, low HDL cholesterol, and hs-CRP (P = 0.001, <0.001, and 0.006, respectively).

Conclusions: Plasma resistin was associated with SNP -420 and was correlated with insulin resistance, low serum HDL cholesterol, and high hs-CRP in the Japanese general population.
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http://dx.doi.org/10.2337/dc06-1936DOI Listing
June 2007

Serum resistin is associated with the severity of microangiopathies in type 2 diabetes.

Biochem Biophys Res Commun 2007 Apr 5;355(2):342-6. Epub 2007 Feb 5.

Department of Molecular and Genetic Medicine, Ehime, University Graduate School of Medicine, Toon, Ehime 791-0295, Japan.

Resistin, secreted from adipocytes, causes insulin resistance and diabetes in rodents. To determine the relation between serum resistin and diabetic microangiopathies in humans, we analyzed 238 Japanese T2DM subjects. Mean serum resistin was higher in subjects with either advanced retinopathy (preproliferative or proliferative) (P=0.0130), advanced nephropathy (stage III or IV) (P=0.0151), or neuropathy (P=0.0013). Simple regression analysis showed that serum resistin was positively correlated with retinopathy stage (P=0.0212), nephropathy stage (P=0.0052), and neuropathy (P=0.0013). Multiple regression analysis adjusted for age, gender, and BMI, revealed that serum resistin was correlated with retinopathy stage (P=0.0144), nephropathy stage (P=0.0111), and neuropathy (P=0.0053). Serum resistin was positively correlated with the number of advanced microangiopathies, independent of age, gender, BMI, and either the duration of T2DM (P=0.0318) or serum creatinine (P=0.0092). Therefore, serum resistin was positively correlated with the severity of microangiopathies in T2DM.
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http://dx.doi.org/10.1016/j.bbrc.2007.01.144DOI Listing
April 2007

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

Mol Cell Biol 2006 Dec 9;26(24):9456-70. Epub 2006 Oct 9.

Department of Neuroscience (D13), Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan.

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.
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http://dx.doi.org/10.1128/MCB.00759-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1698541PMC
December 2006

A newly identified 50 kDa protein, which is associated with phosphodiesterase 3B, is phosphorylated by insulin in rat adipocytes.

Biochem Biophys Res Commun 2005 Nov 3;337(3):976-82. Epub 2005 Oct 3.

Department of Laboratory Medicine, Ehime University School of Medicine, Toon-shi, Ehime 791-0295, Japan.

Phosphodiesterase 3B (PDE3B), a major PDE isoform in adipocytes, plays a pivotal role in the anti-lipolytic action of insulin. Insulin phosphorylates and activates PDE3B in a phosphatidylinositol 3-kinase-dependent manner. We identified a new 50 kDa protein that is phosphorylated by insulin and is co-immunoprecipitated with PDE3B by anti-PDE3B antibodies in rat adipocytes. The insulin-induced phosphorylation of the 50 kDa protein was also detected in a cell free system against the N-terminal and the catalytic regions, which are more than 700 amino acids apart recognize the 50 kDa protein, suggesting that it is not a proteolytic product, but an associated protein with PDE3B. Phosphoamino acid analysis indicated that both serine and threonine residues in the 50 kDa protein were phosphorylated, but only serine residues in PDE3B were phosphorylated. Therefore, it appears likely that this is a new protein which is associated with PDE3B.
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http://dx.doi.org/10.1016/j.bbrc.2005.09.144DOI Listing
November 2005

A nonsense mutation in the Arg345 of the insulin receptor gene in a Japanese type A insulin-resistant patient.

Endocr J 2005 Aug;52(4):499-504

Department of Diabetology and Clinical Laboratory Medicine, National University Corporation, Ehime University School of Medicine, Ehime.

Defects in insulin receptor function have been associated with insulin resistant states such as obesity and type 2 diabetes mellitus. Several types of mutations in the insulin receptor gene have been identified in patients with genetic syndromes of extreme insulin resistance. We have studied a 10-year-old Japanese girl with type A insulin resistance with hirsutism and hyperinsulinemia but without the dysmorphic features characteristic of leprechaunism or Rabson-Mendenhall syndrome. Despite the presence of severe insulin resistance, the patient did not develop overt diabetes mellitus at the time of investigation. Using direct sequencing, we identified a nonsense mutation causing premature termination after amino acid 345 in the alpha subunit of the insulin receptor.
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http://dx.doi.org/10.1507/endocrj.52.499DOI Listing
August 2005

Resistin SNP-420 determines its monocyte mRNA and serum levels inducing type 2 diabetes.

Biochem Biophys Res Commun 2005 Sep;335(2):596-602

Department of Laboratory Medicine, Ehime University School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.

Resistin, secreted from adipocytes, causes insulin resistance in rodents. Its roles and main source in humans remain unknown. The G/G genotype of resistin single nucleotide polymorphism, SNP-420, induces type 2 diabetes mellitus (T2DM) by increasing promoter activity. We elucidated factors correlated with serum resistin and effects of SNP-420 on monocyte resistin mRNA. In 198 T2DM and 157 controls, fasting serum resistin was higher in T2DM. Multiple regression analysis revealed that SNP-420 genotype was the strongest determinant of serum resistin. In T2DM, 1-year duration of T2DM and 1% HbA1c was also correlated with 0.19 and 0.54 ng/ml serum resistin, respectively. Logistic regression analysis revealed that serum resistin was an independent factor for T2DM. In 23 healthy volunteers, monocyte resistin mRNA was positively correlated with its simultaneous serum levels and was higher in G/G genotype. Thus, SNP-420 determines monocyte mRNA and serum levels of resistin, which could induce T2DM.
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http://dx.doi.org/10.1016/j.bbrc.2005.07.122DOI Listing
September 2005

The G/G genotype of a resistin single-nucleotide polymorphism at -420 increases type 2 diabetes mellitus susceptibility by inducing promoter activity through specific binding of Sp1/3.

Am J Hum Genet 2004 Oct 26;75(4):678-86. Epub 2004 Aug 26.

Department of Laboratory Medicine, Ehime University School of Medicine, Ehime, Japan.

Insulin resistance is a major cause of type 2 diabetes mellitus (T2DM). Resistin, an adipocyte-secreted hormone, antagonizes insulin. Transgenic mice that overexpress the resistin gene (Retn) in adipose tissue are insulin-resistant, whereas Retn (-/-) mice show lower fasting blood glucose, suggesting that the altered Retn promoter function could cause diabetes. To determine the role of RETN in human T2DM, we analyzed polymorphisms in its 5' flanking region. We found that the -420G/G genotype was associated with T2DM (397 cases and 406 controls) (P=.008; adjusted odds ratio = 1.97 [by logistic regression analysis]) and could accelerate the onset of disease by 4.9 years (P=.006 [by multiple regression analysis]). Meta-analysis of 1,888 cases and 1,648 controls confirmed this association (P=.013). Linkage disequilibrium analysis revealed that the -420G/G genotype itself was a primary variant determining T2DM susceptibility. Functionally, Sp1 and Sp3 transcription factors bound specifically to the susceptible DNA element that included -420G. Overexpression of Sp1 or Sp3 enhanced RETN promoter activity with -420G in Drosophila Schneider line 2 cells that lacked endogenous Sp family members. Consistent with these findings, fasting serum resistin levels were higher in subjects with T2DM who carried the -420G/G genotype. Therefore, the specific recognition of -420G by Sp1/3 increases RETN promoter activity, leading to enhanced serum resistin levels, thereby inducing human T2DM.
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http://dx.doi.org/10.1086/424761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1182055PMC
October 2004