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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.
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Diabetes Mellitus Tipo 1 , Hipoglucemia , Anciano , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hemoglobina Glucada/análisis , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemia/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/efectos adversos , Anticuerpos Insulínicos , Sistemas de Infusión de Insulina , Masculino , Persona de Mediana EdadRESUMEN
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.
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Diabetes Mellitus , Resistencia a la Insulina , Periodoncia , Glucemia , Índice de Masa Corporal , Diabetes Mellitus Tipo 2 , Ayuno , Humanos , InsulinaRESUMEN
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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Ácidos Grasos Omega-3/administración & dosificación , Polimorfismo de Nucleótido Simple , Resistina/sangre , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Estudios Transversales , Ingestión de Alimentos , Femenino , Genotipo , Humanos , Japón , Masculino , Persona de Mediana Edad , Resistina/genética , Encuestas y Cuestionarios , Adulto JovenRESUMEN
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.
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Metilación de ADN , Epigénesis Genética/genética , ARN Mensajero/metabolismo , Resistina/genética , Anciano , Pueblo Asiatico/genética , Índice de Masa Corporal , Proteína C-Reactiva/metabolismo , Línea Celular , Islas de CpG , Diabetes Mellitus Tipo 2/genética , Femenino , Genotipo , Humanos , Japón , Masculino , Persona de Mediana Edad , Monocitos , Polimorfismo de Nucleótido Simple , Resistina/sangreRESUMEN
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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Factor de Transcripción Activador 4/metabolismo , Estrés del Retículo Endoplásmico , Monocitos/metabolismo , Resistina/metabolismo , Factor de Transcripción CHOP/metabolismo , eIF-2 Quinasa/metabolismo , Adulto , Línea Celular , Femenino , Expresión Génica , Humanos , Masculino , ARN Mensajero/metabolismo , Resistina/genética , Transducción de Señal , Tunicamicina/toxicidad , Adulto JovenRESUMEN
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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Aterosclerosis/fisiopatología , Proteína C-Reactiva/metabolismo , Ritmo Circadiano/fisiología , Encuestas Epidemiológicas , Inflamación/sangre , Adulto , Distribución por Edad , Anciano , Aterosclerosis/sangre , Aterosclerosis/epidemiología , Glucemia , Estudios Transversales , Progresión de la Enfermedad , Electrocardiografía , Femenino , Estudios de Seguimiento , Frecuencia Cardíaca , Humanos , Inflamación/complicaciones , Inflamación/fisiopatología , Resistencia a la Insulina/fisiología , Japón/epidemiología , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Morbilidad/tendencias , Estudios Retrospectivos , Factores de Riesgo , Distribución por SexoRESUMEN
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 ≥200â 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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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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Glucemia/análisis , Diabetes Mellitus Tipo 2/diagnóstico , Frecuencia Cardíaca/fisiología , Corazón/fisiopatología , Resistencia a la Insulina , Adulto , Anciano , Pueblo Asiatico/estadística & datos numéricos , Glucemia/metabolismo , Índice de Masa Corporal , Estudios Transversales , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/etnología , Femenino , Intolerancia a la Glucosa/sangre , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Japón , Estilo de Vida , Masculino , Persona de Mediana Edad , Análisis MultivarianteRESUMEN
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.
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Homeostasis/fisiología , Resistencia a la Insulina , Verduras/química , Vitamina A/sangre , beta Caroteno/sangre , Adulto , Anciano , Glucemia/análisis , Femenino , Humanos , Insulina/sangre , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Factores de RiesgoRESUMEN
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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Masticación/fisiología , Obesidad/metabolismo , Saliva/metabolismo , Adulto , Pueblo Asiatico/estadística & datos numéricos , Índice de Masa Corporal , Estudios Transversales , Femenino , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Obesidad/epidemiología , Tasa de Secreción , Circunferencia de la CinturaRESUMEN
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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Intolerancia a la Glucosa/etiología , Síndromes de la Apnea del Sueño/complicaciones , Adulto , Anciano , Diabetes Mellitus Tipo 2/etiología , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Resistencia a la Insulina , Japón/epidemiología , Masculino , Persona de Mediana Edad , OximetríaRESUMEN
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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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Antígenos de Histocompatibilidad Clase II/genética , Insulina/efectos adversos , Insulina/genética , Anciano , Anticuerpos/inmunología , Pueblo Asiatico/etnología , Pueblo Asiatico/genética , Diabetes Mellitus Tipo 1/inducido químicamente , Diabetes Mellitus Tipo 1/etnología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/etnología , Diabetes Mellitus Tipo 2/genética , Femenino , Predisposición Genética a la Enfermedad/etnología , Predisposición Genética a la Enfermedad/genética , Genotipo , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/inmunología , Insulina/inmunología , Masculino , Persona de Mediana Edad , Repeticiones de Minisatélite/genética , Factores de RiesgoRESUMEN
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 (ß=-0.074, p=0.019) and insulin resistance (ß=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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Enfermedades de las Arterias Carótidas/sangre , Circulación Cerebrovascular/fisiología , Diabetes Mellitus Tipo 2/sangre , Resistencia a la Insulina , Anciano , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/fisiopatología , Estudios de Cohortes , Estudios Transversales , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Prueba de Tolerancia a la Glucosa , Hematócrito , Hemodinámica , Humanos , Masculino , Factores de Riesgo , UltrasonografíaRESUMEN
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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Pueblo Asiatico/genética , Decorina/genética , Polimorfismo de Nucleótido Simple , Resistina/sangre , Anciano , Índice de Masa Corporal , Estudios Transversales , Decorina/sangre , Femenino , Humanos , Resistencia a la Insulina/genética , Japón , Desequilibrio de Ligamiento , Masculino , Persona de Mediana EdadRESUMEN
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 75âg of glucose, and blood samples were obtained at 0, 60, 120âmin after glucose loading. RESULTS: Mean SBP2 was found to be lower than mean brachial systolic BP (SBP) (119â±â20, 126â±â19âmmHg, Pâ<â0.001), and differences between SBP and SBP2 were significantly larger in patients with reduced insulin sensitivity (-8.2â±â5.2, -7.2â±â5.3, -7.1â±â5.1, and -6.5â±â4.9âmmHg, in the first, second, third and fourth quartiles, respectively; Pâ=â0.002) and increased insulin resistance (-6.6â±â5.1, -6.6â±â4.8, -7.3â±â4.8, -8.5â±â5.6âmmHg, Pâ<â0.001). Multiple linear regression analysis identified reduced insulin sensitivity (ßâ=â0.067, Pâ=â0.033) and increased insulin resistance (ßâ=â-0.081, Pâ=â0.009) 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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Aorta/fisiología , Presión Sanguínea/fisiología , Resistencia a la Insulina/fisiología , Adulto , Anciano , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/fisiopatología , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Hipertensión/complicaciones , Hipertensión/fisiopatología , Japón , Modelos Lineales , Masculino , Persona de Mediana Edad , Factores de Riesgo , Sístole , Rigidez Vascular/fisiologíaRESUMEN
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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Glucemia/genética , Diabetes Mellitus Tipo 2/genética , Resistencia a la Insulina/genética , Polimorfismo Genético , Proteínas Serina-Treonina Quinasas/genética , Triglicéridos/metabolismo , Anciano , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Quinasas del Centro Germinal , Humanos , Japón , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , RiesgoRESUMEN
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.
Asunto(s)
Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Resistina/sangre , Resistina/genética , Alelos , Línea Celular , Estudios Transversales , Etnicidad , Genotipo , Haplotipos , Homocigoto , Humanos , Resistencia a la Insulina , Japón , Regiones Promotoras Genéticas , Análisis de RegresiónRESUMEN
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.
Asunto(s)
Glucemia/análisis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Regiones Promotoras Genéticas/genética , Resistina/genética , Tiazolidinedionas/uso terapéutico , Adulto , Anciano , Femenino , Hemoglobina Glucada/análisis , Homeostasis/efectos de los fármacos , Homocigoto , Humanos , Hiperglucemia/prevención & control , Hipoglucemiantes/administración & dosificación , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Farmacogenética/métodos , Proyectos Piloto , Pioglitazona , Polimorfismo de Nucleótido Simple , Resistina/sangre , Estudios Retrospectivos , Tiazolidinedionas/administración & dosificación , Resultado del TratamientoRESUMEN
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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PPAR gamma/genética , Polimorfismo de Nucleótido Simple , Resistina/sangre , Resistina/genética , Anciano , Pueblo Asiatico/genética , Estudios Transversales , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación MissenseRESUMEN
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.