RESUMEN
AIM: To investigate the appropriate fasting plasma glucose threshold by which to define prediabetes in children and adolescents, based on its ability to predict incident paediatric diabetes. METHODS: In a nationwide survey of diabetes and renal disease conducted between 1992 and 2000 in all school-aged children in Taiwan, those with abnormal results in repeated urine tests received further physical examination and blood tests. Students who had blood tests for at least two time points were selected for the present study (N = 12 119). The incidence of paediatric diabetes, adjusted hazard ratio and predictive power of fasting plasma glucose were analysed. RESULTS: The incidence of paediatric diabetes increased with increasing fasting plasma glucose levels. Groups with fasting plasma glucose >5.6 mmol/l had a higher adjusted hazard ratio. The adjusted hazard ratio of incident diabetes for participants with higher fasting plasma glucose rose continuously when using a higher threshold for fasting plasma glucose. The area under the receiver-operating characteristic curve for fasting plasma glucose was 0.628 for predicting paediatric diabetes. The association between fasting plasma glucose and incident paediatric diabetes and the area under the receiver-operating characteristic curve were similar in boys and girls and were higher in the age group 12-18 years. According to receiver-operating characteristic curve analysis, the optimal thresholds, sensitivity and specificity were 4.75 mmol/l, 65% and 51%, respectively, for those aged 6-11 years and 5.19 mmol/l, 60% and 73%, respectively, for those aged 12-18 years. CONCLUSION: Fasting plasma glucose is associated with the incidence of paediatric diabetes. The results of the present study can be used as reference data to suggest a cut-off value to define paediatric prediabetes.
Asunto(s)
Glucemia/análisis , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Ayuno/sangre , Adolescente , Niño , Diabetes Mellitus Tipo 2/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Estado Prediabético/sangre , Estado Prediabético/epidemiología , Factores de Riesgo , Sensibilidad y Especificidad , Taiwán/epidemiologíaRESUMEN
AIMS: To compare the incidence of hyperglycaemia among participants with low, elevated and normal serum thyroid-stimulating hormone concentration, as well as the incidence of abnormal thyroid function test results among participants with normal blood glucose and those with hyperglycaemia. METHODS: In a prospective study, a cohort of 72 003 participants with normal, low and elevated serum thyroid-stimulating hormone concentration were followed from the study beginning to the first report of diabetes and prediabetes. A proportional hazards regression model was used to calculate the hazard ratios and 95% CIs for each outcome, adjusting for age, sex, education level, smoking, alcohol consumption and obesity. Analyses for the association between dysglycaemia and incident abnormal thyroid function test were also conducted. RESULTS: During a median 2.6 year follow-up, the incident rates for dysglycaemia, particularly prediabetes, were substantially higher in participants with elevated thyroid-stimulating hormone concentrations at baseline, while the rates for participants with normal and low thyroid-stimulating hormone were similar. After controlling for risk factors, participants with elevated thyroid-stimulating hormone retained a 15% increase in risk of prediabetes (adjusted hazard ratio 1.15, 95% CI 1.04-1.26), but were not at greater risk of diabetes (adjusted hazard ratio 0.96, 95% CI 0.64-1.44). By contrast, participants with normal and low thyroid-stimulating hormone concentrations had similar dysglycaemia risks. Participants with diabetes and prediabetes were not at greater risks of developing abnormal thyroid function test results when compared with participants with euglycaemia. CONCLUSIONS: People with elevated serum thyroid-stimulating hormone concentration are at greater risk of developing prediabetes. Whether this includes a greater risk of developing frank diabetes may require an extended period of follow-up to clarify.
Asunto(s)
Trastornos del Metabolismo de la Glucosa/epidemiología , Enfermedades de la Tiroides/epidemiología , Adulto , Anciano , Estudios Transversales , Femenino , Estudios de Seguimiento , Trastornos del Metabolismo de la Glucosa/sangre , Trastornos del Metabolismo de la Glucosa/complicaciones , Trastornos del Metabolismo de la Glucosa/fisiopatología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estado Prediabético/sangre , Estado Prediabético/complicaciones , Estado Prediabético/epidemiología , Estado Prediabético/fisiopatología , Enfermedades de la Tiroides/sangre , Enfermedades de la Tiroides/complicaciones , Enfermedades de la Tiroides/diagnóstico , Pruebas de Función de la Tiroides , Glándula Tiroides/fisiopatología , Tirotropina/sangreRESUMEN
OBJECTIVES: The aim of this study was to examine the characteristics of patients, physicians, and medical facilities, and their association with prescriptions that do not include metformin as the initial oral antidiabetic agent. STUDY DESIGN: Observational, cross-sectional study. METHODS: Patients with incident type 2 diabetes between January 1, 2006, and December 31, 2010, were identified from the Taiwan National Insurance Research Database. We describe trends in the initial prescription of antidiabetic medications that do not contain metformin during the study period. A multivariable logistic model and a multilevel linear model were used in the analysis of factors at a range of levels (patient, physician, and medical facility), which may be associated with the selection of oral antidiabetic drugs. RESULTS: During the study period, the proportion of prescriptions that did not include metformin declined from 43.8% to 26.2%. Male patients were more likely to obtain non-metformin prescriptions (adjusted odds ratio [OR]: 1.15; 95% confidence interval [CI]: 1.08-1.23), and the likelihood that a patient would be prescribed a non-metformin prescription increased with age. Physicians aged ≥35 years and those with specialties other than endocrinology tended to prescribe non-metformin prescriptions. Metformin was less commonly prescribed in for-profit hospitals (adjusted OR: 1.34, 95% CI: 1.11-1.61) and hospitals in smaller cities (adjusted OR: 1.28, 95% CI: 1.05-1.57) and rural areas (adjusted OR: 1.83, 95% CI: 1.32-2.54). CONCLUSIONS: Disparities continue to exist in clinical practice with regard to the treatment of diabetes. These inequalities appear to be linked to a variety of factors related to patients, physicians, and medical facilities. Further study will be required to understand the effects of continuing medical education in enhancing adherence to clinical guidelines.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Prescripciones de Medicamentos/estadística & datos numéricos , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Administración Oral , Adulto , Anciano , Estudios Transversales , Diabetes Mellitus Tipo 2/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , TaiwánRESUMEN
AIM: To compare the cardiovascular risks associated with second-line oral antidiabetic agents added to initial metformin therapy in a large nationwide observational study. METHODS: We conducted a nationwide retrospective cohort study using the Taiwan National Health Insurance database. A total of 36 118 users of different add-on oral antidiabetic agents (sulphonylureas, glinides, pioglitazone, α-glucosidase inhibitors and dipeptidyl peptidase-4 inhibitors) after initial metformin therapy were included in the analysis. The reference group was sulphonylureas added to metformin, the most commonly used combination regimen. The main outcomes of interest were hospitalizations for any cardiovascular event including acute myocardial infarction, congestive heart failure and ischaemic stroke. In the main analysis, all patients were followed within their initiation groups until the study end, disregarding any changes in treatment status over time. RESULTS: In intention-to-treat analyses, there was no difference in the risk of any cardiovascular event among the add-on combination treatment groups, but significantly lower risks of acute myocardial infarction were found for the glinides plus metformin treatment group (crude hazard ratio 0.52, adjusted hazard ratio 0.39; 95% CI 0.20-0.75) and for the α-glucosidase inhibitors plus metformin treatment group (crude hazard ratio 0.63, adjusted hazard ratio 0.54; 95% CI 0.31-0.95). No difference in risk of congestive heart failure or ischaemic stroke risk was found among the combination treatment groups. In secondary as-treated analyses, similar but less significant associations were found as compared with the primary intention-to-treat analyses for all treatment groups. CONCLUSION: There were no differences in overall cardiovascular risks among several add-on second-line oral antidiabetic agents; however, glinide plus metformin and α-glucosidase inhibitors plus metformin combination therapies might be associated with lower risks of acute myocardial infarction.
Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/prevención & control , Cardiomiopatías Diabéticas/prevención & control , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Administración Oral , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/epidemiología , Estudios de Cohortes , Diabetes Mellitus Tipo 2/complicaciones , Angiopatías Diabéticas/epidemiología , Cardiomiopatías Diabéticas/epidemiología , Quimioterapia Combinada , Registros Electrónicos de Salud , Femenino , Estudios de Seguimiento , Inhibidores de Glicósido Hidrolasas/administración & dosificación , Inhibidores de Glicósido Hidrolasas/uso terapéutico , Humanos , Hipoglucemiantes/administración & dosificación , Masculino , Metformina/administración & dosificación , Persona de Mediana Edad , Infarto del Miocardio/complicaciones , Infarto del Miocardio/epidemiología , Infarto del Miocardio/prevención & control , Programas Nacionales de Salud , Estudios Retrospectivos , Riesgo , Taiwán/epidemiologíaRESUMEN
AIMS: To evaluate whether homeostasis model assessment and high-sensitivity C-reactive protein improve the prediction of isolated post-load hyperglycaemia. METHODS: The subjects were 1458 adults without self-reported diabetes recruited between 2006 and 2010. Isolated post-load hyperglycaemia was defined as fasting plasma glucose < 7 mmol/l and 2-h post-load plasma glucose ≥ 11.1 mmol/l. Risk scores of isolated post-load hyperglycaemia were constructed by multivariate logistic regression. An independent group (n = 154) was enrolled from 2010 to 2011 to validate the models' performance. RESULTS: One hundred and twenty-three subjects (8.28%) were newly diagnosed as having diabetes mellitus. Among those with undiagnosed diabetes, 64 subjects (52%) had isolated post-load hyperglycaemia. Subjects with isolated post-load hyperglycaemia were older, more centrally obese and had higher blood pressure, HbA(1c), fasting plasma glucose, triglycerides, LDL cholesterol, high-sensitivity C-reactive protein and homeostasis model assessment of insulin resistance and lower homeostasis model assessment of ß-cell function than those without diabetes. The risk scores included age, gender, BMI, homeostasis model assessment, high-sensitivity C-reactive protein and HbA(1c). The full model had high sensitivity (84%) and specificity (87%) and area under the receiver operating characteristic curve (0.91), with a cut-off point of 23.81; validation in an independent data set showed 88% sensitivity, 77% specificity and an area under curve of 0.89. CONCLUSIONS: Over half of those with undiagnosed diabetes had isolated post-load hyperglycaemia. Homeostasis model assessment and high-sensitivity C-reactive protein are useful to identify subjects with isolated post-load hyperglycaemia, with improved performance over fasting plasma glucose or HbA(1c) alone.
Asunto(s)
Glucemia/metabolismo , Proteína C-Reactiva/metabolismo , Homeostasis/fisiología , Hiperglucemia/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Diabetes Mellitus Tipo 2/diagnóstico , Ayuno/sangre , Femenino , Prueba de Tolerancia a la Glucosa/métodos , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Medición de Riesgo , Adulto JovenRESUMEN
To dissect the genetic architecture of sexual dimorphism in obesity-related traits, we evaluated the sex-genotype interaction, sex-specific heritability and genome-wide linkages for seven measurements related to obesity. A total of 1,365 non-diabetic Chinese subjects from the family study of the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance were used to search for quantitative trait loci (QTLs) responsible for the obesity-related traits. Pleiotropy and co-incidence effects from the QTLs were also examined using the bivariate linkage approach. We found that sex-specific differences in heritability and the genotype-sex interaction effects were substantially significant for most of these traits. Several QTLs with strong linkage evidence were identified after incorporating genotype by sex (G × S) interactions into the linkage mapping, including one QTL for hip circumference [maximum LOD score (MLS) = 4.22, empirical p = 0.000033] and two QTLs: for BMI on chromosome 12q with MLS 3.37 (empirical p = 0.0043) and 3.10 (empirical p = 0.0054). Sex-specific analyses demonstrated that these linkage signals all resulted from females rather than males. Most of these QTLs for obesity-related traits replicated the findings in other ethnic groups. Bivariate linkage analyses showed several obesity traits were influenced by a common set of QTLs. All regions with linkage signals were observed in one gender, but not in the whole sample, suggesting the genetic architecture of obesity-related traits does differ by gender. These findings are useful for further identification of the liability genes for these phenotypes through candidate genes or genome-wide association analysis.
Asunto(s)
Pueblo Asiatico/genética , Obesidad/genética , Caracteres Sexuales , Adulto , Índice de Masa Corporal , Mapeo Cromosómico , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Hawaii/epidemiología , Humanos , Escala de Lod , Masculino , Persona de Mediana Edad , Obesidad/epidemiología , Oportunidad Relativa , Fenotipo , San Francisco/epidemiología , Factores Sexuales , Taiwán/epidemiologíaRESUMEN
AIM: To evaluate annual prevalence and incidence of Type 2 diabetes and to examine possible trends among adults in Taiwan. METHODS: A retrospective nationwide longitudinal study using the Taiwan National Health Insurance Research Database collected during 1999-2004. Adult patients aged > or = 20 years old with prevalent and incident Type 2 diabetes were identified using ICD-9-CM diagnostic codes. Age-specific and age-direct-standardized annual incidence and prevalence were calculated to describe their trends in different gender and age group and compared using Poisson regression. RESULTS: During the study years, the age-standardized prevalence of Type 2 diabetes increased from 4.7 to 6.5% for men and from 5.3 to 6.6% for women. The increasing trends in prevalence were significant and higher among people aged < 40 and > or = 80 years. The age-standardized incidence rates of Type 2 diabetes per 1000 person-years were approximately 7.6 and remain stable for men, but decreasing from 7.7 to 6.9 for women. However, the incidence increased significantly in younger adults aged < 40 years whose relative incidence (RI with 95% confidence interval) was 1.31 (1.20-1.42) for men and 1.04 (1.01-1.08) for women. The incidence trends for people aged > or = 40 years were decreased for men and women. The differences in incidence trends between age groups and between genders were all statistically significant (all P < 0.001). CONCLUSIONS: This study demonstrated a substantial increasing trend in Type 2 diabetes prevalence during 1999-2004 among adults in Taiwan. Despite the incidence decreased in older people, young men aged 20-40 years were most susceptible to higher incidence of Type 2 diabetes.
Asunto(s)
Bases de Datos Factuales , Diabetes Mellitus Tipo 2/epidemiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Programas Nacionales de Salud , Prevalencia , Estudios Retrospectivos , Estadística como Asunto , Taiwán/epidemiología , Adulto JovenRESUMEN
AIMS/HYPOTHESIS: We investigated whether children who are heavier at birth have an increased risk of type 1 diabetes. METHODS: Relevant studies published before February 2009 were identified from literature searches using MEDLINE, Web of Science and EMBASE. Authors of all studies containing relevant data were contacted and asked to provide individual patient data or conduct pre-specified analyses. Risk estimates of type 1 diabetes by category of birthweight were calculated for each study, before and after adjustment for potential confounders.Meta-analysis techniques were then used to derive combined ORs and investigate heterogeneity between studies. RESULTS: Data were available for 29 predominantly European studies (five cohort, 24 case-control studies), including 12,807 cases of type 1 diabetes. Overall, studies consistently demonstrated that children with birthweight from 3.5 to 4 kg had an increased risk of diabetes of 6% (OR 1.06 [95% CI 1.01-1.11]; p=0.02) and children with birthweight over 4 kg had an increased risk of 10% (OR 1.10 [95% CI 1.04-1.19]; p=0.003), compared with children weighing 3.0 to 3.5 kg at birth. This corresponded to a linear increase in diabetes risk of 3% per 500 g increase in birthweight (OR 1.03 [95% CI 1.00-1.06]; p=0.03). Adjustments for potential confounders such as gestational age, maternal age, birth order, Caesarean section, breastfeeding and maternal diabetes had little effect on these findings. CONCLUSIONS/INTERPRETATION: Children who are heavier at birth have a significant and consistent, but relatively small increase in risk of type 1 diabetes.
Asunto(s)
Peso al Nacer , Diabetes Mellitus Tipo 1/epidemiología , Adolescente , Edad de Inicio , Orden de Nacimiento , Niño , Preescolar , Femenino , Edad Gestacional , Humanos , Lactante , Recién Nacido , Edad Materna , Embarazo , Factores de RiesgoRESUMEN
BACKGROUND AND AIMS: This study aimed to investigate the association of intraocular pressure (IOP) with the metabolic syndrome and other emerging cardiometabolic risk factors. METHODS: A total of 1112 participants undergoing a health check-up in a community hospital were recruited. All participants underwent ophthalmological examination including IOP measurement. RESULTS: Participants with metabolic syndrome had significantly higher IOP than those without metabolic syndrome (mean IOP+/-SD: 15.07+/-2.74 vs 14.29+/-2.72 mm Hg, P=2x10(-4)). Each additional component of the metabolic syndrome was associated with a mean increase in IOP of 0.33 mm Hg (95% confidence interval: 0.18-0.48, trend P<0.0001). Other insulin resistance-related features, including hepatic steatosis, increased left ventricular mass, and proteinuria, were also associated with IOP (P<0.0001, 0.002, and 0.01, respectively). However, we did not find significant association of plasma apolipoprotein A, apolipoprotein B1, homocysteine, or highly sensitive C-reactive protein levels with IOP. IOP was also not associated with measures of subclinical atherosclerosis including brachial-ankle pulse wave velocity, ankle-brachial index, and vertebral artery flow. CONCLUSION: Metabolic syndrome and other insulin resistance-related features, including hepatic steatosis, increased left ventricular mass, and proteinuria, are strongly associated with IOP.
Asunto(s)
Enfermedades Cardiovasculares/fisiopatología , Presión Intraocular/fisiología , Síndrome Metabólico/fisiopatología , Adulto , Anciano , Aterosclerosis/fisiopatología , Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/epidemiología , Hígado Graso/epidemiología , Femenino , Ventrículos Cardíacos/patología , Humanos , Resistencia a la Insulina/fisiología , Masculino , Persona de Mediana Edad , Proteinuria/epidemiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
AIMS/HYPOTHESIS: Rosiglitazone, an insulin sensitiser, not only improves insulin sensitivity but also enhances insulin secretory capacity by ameliorating gluco- and lipotoxicity in beta cells. Rosiglitazone can stimulate insulin secretion at basal and high glucose levels via a phosphatidylinositol 3-kinase (PI3K)-dependent pathway. We hypothesised that regulation of phosphorylation of the ATP-sensitive potassium (K(ATP)) channel might serve as a key step in the regulation of insulin secretion. METHODS: Insulin secretory responses were studied in an isolated pancreas perfusion system, cultured rat islets and MIN6 and RINm5F beta cells. Signal transduction pathways downstream of PI3K were explored to link rosiglitazone to K(ATP) channel conductance with patch clamp techniques and insulin secretion measured by ELISA. RESULTS: Rosiglitazone stimulated AMP-activated protein kinase (AMPK) activity and induced inhibition of the K(ATP) channel conductance in islet beta cells; both effects were blocked by the PI3K inhibitor LY294002. Following stimulation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a pharmacological activator, both AICAR-stimulated insulin secretion and inhibition of K(ATP) channel conductance were unaffected by LY294002, indicating that AMPK activation occurs at a site downstream of PI3K activity. The serine residue at amino acid position 385 of Kir6.2 was found to be the substrate phosphorylation site of AMPK when activated by rosiglitazone or AICAR. CONCLUSIONS/INTERPRETATION: Our data indicate that PI3K-dependent activation of AMPK is required for rosiglitazone-stimulated insulin secretion in pancreatic beta cells. Phosphorylation of the Ser(385) residue of the Kir6.2 subunit of the K(ATP) channel by AMPK may play a role in insulin secretion.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Hipoglucemiantes/farmacología , Insulina/metabolismo , Canales KATP/efectos de los fármacos , Canales de Potasio de Rectificación Interna/metabolismo , Serina/metabolismo , Tiazolidinedionas/farmacología , Proteínas Quinasas Activadas por AMP/química , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacología , Animales , Western Blotting , Línea Celular , Cromonas/farmacología , Inhibidores Enzimáticos/farmacología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Inmunoprecipitación , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Masculino , Morfolinas/farmacología , Fosforilación/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Ribonucleótidos/farmacología , Rosiglitazona , Serina/químicaRESUMEN
AIMS/HYPOTHESIS: This multinational study was conducted to investigate the association between a mitochondrial DNA (mtDNA) T16189C polymorphism and type 2 diabetes in Asians. The mtDNA 16189C variant has been reported to be associated with insulin resistance and type 2 diabetes. However, a recent meta-analysis concluded that it is negatively associated with type 2 diabetes in Europids. Since the phenotype of an mtDNA mutant may be influenced by environmental factors and ethnic differences in the nuclear and mitochondrial genomes, we investigated the association between the 16189C variant and type 2 diabetes in Asians. METHODS: The presence of the mtDNA 16189C variant was determined in 2,469 patients with type 2 diabetes and 1,205 non-diabetic individuals from Korea, Japan, Taiwan, Hong Kong and China. An additional meta-analysis including previously published Asian studies was performed. Since mtDNA nucleotide position 16189 is very close to the mtDNA origin of replication, we performed DNA-linked affinity chromatography and reverse-phase liquid chromatography/tandem mass spectrometry and chromatin immunoprecipitation to identify protein bound to the 16189 region. RESULTS: Analysis of participants from five Asian countries confirmed the association between the 16189C variant and type 2 diabetes [odds ratio (OR) 1.256, 95% CI 1.08-1.46, p=0.003]. Inclusion of data from three previously published Asian studies (type 2 diabetes n=3,283, controls n=2,176) in a meta-analysis showed similar results (OR 1.335, 95% CI 1.18-1.51, p=0.000003). Mitochondrial single-stranded DNA-binding protein (mtSSB) was identified as a candidate protein bound to the 16189 region. Chromatin immunoprecipitation in cybrid cells showed that mtSSB has a lower binding affinity for the 16189C variant than the wild-type sequence. CONCLUSIONS/INTERPRETATION: The mtDNA 16189C variant is associated with an increased risk of type 2 diabetes in Asians.
Asunto(s)
ADN Mitocondrial/genética , Diabetes Mellitus Tipo 2/genética , Variación Genética , Polimorfismo de Nucleótido Simple , Pueblo Asiatico/genética , China , Cartilla de ADN , Diabetes Mellitus Tipo 2/epidemiología , Humanos , Japón , Corea (Geográfico) , TaiwánRESUMEN
AIMS/HYPOTHESIS: Hypertension, obesity, impaired glucose tolerance and dyslipidaemia are metabolic abnormalities that often cluster together more often than expected by chance alone. Since these metabolic variables are highly heritable and are at least partially genetically determined, the clustering of defects in these traits implies that pleiotropic effects, where a common set of genes influences more than one trait simultaneously, are likely. METHODS: We conducted bivariate linkage analyses for highly correlated traits, aiming to dissect the genetic architecture affecting these traits, in 411 Chinese families participating in the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance Study. RESULTS: We confirmed the pleiotropic effects of the locus at 37 cM on chromosome 20 on the following pairs: (1) fasting insulin and insulin AUC (empirical p = 0.0006); (2) fasting insulin and homeostasis model assessment of beta cell function (HOMA-beta) (empirical p = 0.0051); and (3) HOMA of insulin resistance (IR) and HOMA-beta (empirical p = 0.0044). In addition, the peak logarithm of the odds (LOD) scores of linkage between a chromosomal locus and a trait for the pair fasting insulin and HOMA-IR rose to 5.10 (equivalent LOD score in univariate analysis, LOD([1]) = 4.01, empirical p = 8.0 x 10(-5)) from 3.67 and 3.42 respectively for these two traits in univariate analysis. Additional significant linkage evidence, not shown in single-trait analysis, was identified at 45 cM on chromosome 16 for the pair 1 h insulin and the AUC for insulin, with a LOD score of 4.29 (or LOD([1]) = 3.27, empirical p = 2.0 x 10(-4)). This new locus is also likely to harbour the common genes regulating these two traits (p = 1.73 x 10(-6)). CONCLUSIONS/INTERPRETATION: These data help provide a better understanding of the genomic structure underlying the metabolic syndrome.
Asunto(s)
Pueblo Asiatico/genética , Genoma Humano , Hipertensión/genética , Resistencia a la Insulina/genética , Adulto , Análisis de Varianza , Glucemia/metabolismo , Índice de Masa Corporal , HDL-Colesterol/genética , Cromosomas Humanos Par 20/genética , Salud de la Familia , Ayuno , Femenino , Ligamiento Genético/genética , Genotipo , Humanos , Hipertensión/sangre , Escala de Lod , Masculino , Síndrome Metabólico/genética , Persona de Mediana Edad , Fenotipo , Sitios de Carácter Cuantitativo/genéticaRESUMEN
The purpose of the study is to compare surrogate estimates of insulin sensitivity with a directly measured insulin sensitivity index, steady-state plasma glucose (SSPG) from insulin suppression test (IST), in subjects with hypertension. Two hundred and twenty-eight hypertensive patients who received IST for SSPG were included for analysis. Estimates from fasting measurements alone, homeostasis model assessment for insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI)), and indices from fasting and/or 2 h samples (ISI(0,120) and ISI(TX)) were calculated. In addition to Pearson and partial correlations, variance-component models were used to test the relationship between surrogate estimates of insulin sensitivity and SSPG. A large proportion of variance owing to covariates in the variance-component models indicated the goodness of model fit, irrespective of the independence among variables. SSPG was positively correlated with logarithmic transformation (Log) (HOMA-IR) and negatively correlated with QUICKI, Log (ISI(0,120)) and ISI(TX) (all P<0.0001). Log (ISI(0,120)) seemed to have a better correlation with SSPG (r=-0.72) than other measures in partial correlation. The proportion of variance owing to all covariates of Log (ISI(0,120)) and ISI(TX) were larger than those of Log (HOMA-IR) and QUICKI in the variance-component models. After adjustments for demographic and obesity covariates, the proportion of variance explained by Log (ISI(0,120)) were largest among the surrogate measures in the variance-component models. Our results showed that ISI(0,120) and ISI(TX) correlated better with SSPG than those used fasting measures alone (HOMA-IR and QUICKI). Log (ISI(0,120)) currently showing the strongest association with SSPG than other estimates is adaptable for use in large studies of hypertension.
Asunto(s)
Técnica de Clampeo de la Glucosa/métodos , Hipertensión/fisiopatología , Resistencia a la Insulina , Adulto , Análisis de Varianza , Pueblo Asiatico , Glucemia/análisis , Diabetes Mellitus/sangre , Femenino , Humanos , Hipertensión/sangre , Insulina/sangre , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Sensibilidad y EspecificidadRESUMEN
AIMS/HYPOTHESIS: The gene encoding solute carrier family 2, facilitated glucose transporter, member 10 (SLC2A10, previously known as glucose transporter 10 [GLUT10]) is a promising candidate gene for type 2 diabetes since it is highly expressed in liver and pancreas and is located on human chromosome region 20q12-q13.1, a region previously shown to harbour type 2 diabetes susceptibility genes. We investigated whether the SLC2A10 gene could be a type 2 diabetes susceptibility gene in the Taiwanese population. SUBJECTS AND METHODS: Sequencing of SLC2A10 gene from 48 diabetic subjects detected short tandem repeat polymorphisms in the promoter region, but did not detect any other sequence variants or new single-nucleotide polymorphisms (SNPs) other than those already in the SNPper database ( http://snpper.chip.org ) (30 June 2005). RESULTS: Using these genetic polymorphisms, we divided the SLC2A10 gene into four distinct linkage disequilibrium blocks and performed a case-control association study in a group of type 2 diabetes subjects (n = 375) and normoglycaemic individuals (n=377). The HapD (A-G-T-C) haplotype in block 3, a rare haplotype, which consisted of four SNPs (rs3092412, rs2235491, rs2425904 and rs1059217), was modestly associated with type 2 diabetes with a haplotype score of -2.95567 (p = 0.012 with the haplotype-specific test). CONCLUSIONS/INTERPRETATION: Our results suggest that SLC2A10 genetic variations do not appear to be major determinants for type 2 diabetes susceptibility in the Taiwanese population.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , Anciano , Secuencia de Bases , Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Exones , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Variación Genética , Hemoglobina Glucada/análisis , Humanos , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Taiwán , Triglicéridos/sangreRESUMEN
BACKGROUND AND AIM: Gliclazide-modified release (gliclazide MR) is a new formulation of the sulfonylurea gliclazide designed for once-daily administration. The hydrophilic matrix of hypromellose-based polymer in the new formulation induces a progressive drug release, which parallels the 24-h glycaemic profile in type 2 diabetic patients. The aim of this study was to compare the efficacy and safety of gliclazide MR (once-daily administration) versus gliclazide (twice-daily administration) in Chinese type 2 diabetic patients. MATERIALS AND METHODS: Sixty-three type 2 diabetic Chinese patients who had been on diet control alone or on treatment with metformin or on low dose of sulfonylurea were randomized to either gliclazide MR taken once daily or gliclazide taken twice daily. Dosage of metformin was maintained throughout the study, and the sulfonylurea was stopped. The dose of gliclazide MR was increased at 1-month intervals from 30 mg to 120 mg, while that of gliclazide from 80 mg to 320 mg until metabolic control was achieved [fasting plasma glucose (FPG) < or = 7.7 mmol/l] or the maximum dose reached. Efficacy was mainly evaluated by levels of haemoglobin A1c (HbA1c) and FPG. RESULTS: The mean baseline characteristics of the full analysis set 1 (FAS1) (HbA1c, n = 58) and the FAS2 (FPG, n = 61) were comparable in both groups. The levels of HbA1c decreased similarly in both groups over the treatment period: -1.6 +/- 1.6% (p < 0.001) on gliclazide MR (n = 31) and -1.6 +/- 1.4% (p < 0.001) on gliclazide (n = 27). Decrease in HbA1c was observed irrespective of pre-existing therapy for diabetes: -2.3 +/- 1.5% for patients on diet alone; -0.6 +/- 1.3% for patients switched from sulfonylurea to study drug and -1.4 +/- 0.8% for patients on metformin in combination with study drug. FPG decreased significantly from 177.5 +/- 63.5 to 136.7 +/- 42.2 (p < 0.001, n = 32) on gliclazide MR and not significant from 188.2 +/- 62.6 to 163.7 +/- 67.9 (p = 0.059, n = 29) on gliclazide. Both treatments were very well tolerated with no major hypoglycaemic episodes requiring external assistance; only three patients experienced mild hypoglycaemic episodes. CONCLUSIONS: Once-daily gliclazide MR showed a better trend in improving blood glucose control in comparison with gliclazide in type 2 diabetic Chinese patients irrespective of the pre-existing anti-diabetic treatment. The safety profiles of gliclazide MR and gliclazide were similar with a small number of patients having reported hypoglycaemic episodes. Once-daily dosing with gliclazide MR should improve patient compliance, an important factor in long-term glycaemic control.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Gliclazida/administración & dosificación , Hipoglucemiantes/administración & dosificación , Adulto , Anciano , Pueblo Asiatico/etnología , Glucemia/metabolismo , Preparaciones de Acción Retardada , Diabetes Mellitus Tipo 2/etnología , Método Doble Ciego , Ayuno/sangre , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
AIM: Apolipoprotein AV (APOA5) is an important determinant of plasma triglyceride concentration. This study aimed to investigate the relationship of an amino acid substitution at position 182 (G182C) of the apolipoprotein AV (APOA5) gene with triglyceride concentration in a Taiwanese population. METHODS: This study enrolled two cohorts: non-diabetic subjects (112 males and 89 females) aged 50.3+/-11.0 years (mean+/-sd) and diabetic subjects (106 males and 96 females) aged 62.1+/-10.3 years. The relationship between the G182C polymorphism (rs 2075291) and plasma triglycerides was examined. Demographic and metabolic parameters including age, sex, body mass index, fasting plasma glucose and total cholesterol were also obtained. RESULTS: The G182C polymorphism was a determinant of plasma triglycerides in both non-diabetic (P=0.022) and diabetic (P=0.003) groups, independent of age, gender, fasting plasma glucose, body mass index and total cholesterol. In the diabetic group, this genetic polymorphism interacts significantly (P=0.032) with fasting plasma glucose concentration on plasma triglycerides after adjustment for age, sex, body mass index and total cholesterol. CONCLUSIONS: In conclusion, the G182C polymorphism of the APOA5 gene affects plasma triglycerides in both non-diabetic and diabetic populations. The observed interaction of gene and glycaemic control further indicates a multifactorial nature of clinical phenotypes in subjects with Type 2 diabetes.
Asunto(s)
Apolipoproteínas/genética , Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleótido Simple/genética , Triglicéridos/sangre , Adulto , Anciano , Apolipoproteína A-V , Apolipoproteínas A , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , TaiwánRESUMEN
This study aimed at elucidating the effects of interferon (IFN)-alpha on glucose metabolism in patients with chronic hepatitis B and C infections. Twenty-eight biopsy-proven patients with chronic hepatitis B (ten cases) and hepatitis C (18 cases) were given IFN-alpha for a total of 24 weeks. The patients received a 75 g oral glucose tolerance test (OGTT), glucagon stimulation test, tests for type 1 diabetes-related autoantibodies and an insulin suppression test before and after IFN-alpha therapy. Ten of the 28 patients responded to IFN-alpha therapy. Steady-state plasma glucose of the insulin suppression test decreased significantly in responders (13.32+/-1.48 (S.E.M.) vs 11.33+/-1.19 mmol/l, P=0.0501) but not in non-responders (12.29+/-1.24 vs 11.11+/-0.99 mmol/l, P=0.2110) immediately after completion of IFN-alpha treatment. In the oral glucose tolerance test, no significant difference was observed in plasma glucose in either responders (10.17+/-0.23 vs 10.03+/-0.22 mmol/l) or non-responders (10.11+/-0.22 vs 9.97+/-0.21 mmol/l) 3 Months after completion of IFN-alpha treatment. However, significant differences were noted in C-peptide in both responders (2.90+/-0.13 vs 2.20+/-0.09 nmol/l, P=0.0040) and non-responders (2.45+/-0.11 vs 2.22+/-0.08 nmol/l, P=0.0287) before vs after treatment. The changes of C-peptide in an OGTT between responders and non-responders were also significantly different (P=0.0028), with responders reporting a greater reduction in C-peptide. No case developed autoantibodies during the treatment. In patients who were successfully treated with IFN-alpha, insulin sensitivity improved and their plasma glucose stayed at the same level without secreting as much insulin from islet beta-cells.
Asunto(s)
Hepatitis B Crónica/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Resistencia a la Insulina , Islotes Pancreáticos/metabolismo , Adulto , Alanina Transaminasa/sangre , Análisis de Varianza , Autoanticuerpos/sangre , Glucemia/metabolismo , Péptido C/sangre , Distribución de Chi-Cuadrado , ADN Viral/sangre , Diabetes Mellitus Tipo 1/inmunología , Femenino , Glucagón , Prueba de Tolerancia a la Glucosa , Antígenos e de la Hepatitis B/sangre , Hepatitis B Crónica/sangre , Hepatitis B Crónica/inmunología , Hepatitis C Crónica/sangre , Hepatitis C Crónica/inmunología , Homeostasis , Humanos , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Interferón-alfa , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: The human adiponectin gene has been implicated in the pathophysiology of obesity, type II diabetes mellitus, dyslipidemia and atherosclerosis. Investigation of the physiological functions of the adiponectin gene in humans was mainly conducted at the levels of plasma proteins or DNA polymorphisms. The depot-specific adiponectin mRNA levels also could be relevant to these physiological functions. OBJECTIVES: The relation between the adipose depot-specific adiponectin mRNA expression levels and various metabolic factors, including BMI, fasting plasma glucose, insulin, triglycerides (TGs) and HDL-cholesterol and insulin resistance index by HOMA, was investigated among 66 nondiabetic women using quantitative real-time PCR. RESULTS: The subcutaneous relative adiponectin mRNA levels (SRAmR) correlated significantly with the omental relative adiponectin mRNA levels (ORAmR) (gamma=0.468, P=0.0001). The SRAmR correlated inversely with the fasting plasma glucose with a borderline significance (gamma=-0.35, P=0.058). On the other hand, the ORAmR correlated negatively with serum TG levels with the adjustment for age (gamma=-0.33, P=0.007) or age plus BMI (gamma=-0.27, P=0.027). CONCLUSION: These results indicate that the adiponectin mRNA levels in different adipose depots were at least related to certain phenotypes of metabolic syndrome. The expression levels of adiponectin in the omental adipose depots are related to TG metabolism.
Asunto(s)
Tejido Adiposo/metabolismo , Péptidos y Proteínas de Señalización Intercelular , Proteínas/metabolismo , ARN Mensajero/metabolismo , Abdomen , Adiponectina , Adulto , Envejecimiento/fisiología , Glucemia/metabolismo , Índice de Masa Corporal , HDL-Colesterol/metabolismo , Humanos , Insulina/metabolismo , Resistencia a la Insulina , Persona de Mediana Edad , Reacción en Cadena de la PolimerasaRESUMEN
AIMS/HYPOTHESIS: Genetic interactions in modulating the phenotypes of a complex trait, such as insulin sensitivity, were usually taken for granted. However, this has not been commonly shown. Previous studies have suggested that both PPARgamma2 and adiponectin genes could influence insulin sensitivity. Therefore it is likely that they could modulate insulin sensitivity through gene to gene interactions. METHODS: We genotyped 1793 subjects of Chinese and Japanese descendents from 601 hypertensive families recruited in Sapphire study for a T94G in the adiponectin gene exon 2 and the PPARgamma2 Pro12Ala polymorphisms. Serum insulin concentrations and insulin resistance index (HOMA(IR)) were used as the markers of insulin sensitivity. RESULTS: We found that the T allele of adiponectin gene was associated with a higher Ins60 and higher area under curve of insulin (AUCi) in OGTT utilizing all subjects in a mixed model that corrected for family effects. Important interactions between adiponectin and PPARgamma2 genotypes were found in fasting insulin concentrations (Ins0), insulin concentrations at 2-h (Ins120) in OGTT and insulin resistance index (HOMA(IR)). The main effects of the PPARgamma2 genotypes were in the plasma glucose concentrations in OGTT. In contrast, the main effects of adiponectin genotypes were in every insulin variable, including Ins0, Ins60, Ins120, AUCi and HOMA(IR). The subjects carrying the adiponectin G allele and the PPARgamma2 Ala12 allele seemed to be more insulin sensitive. CONCLUSION/INTERPRETATION: These results showed that adiponectin is a genetic factor associated with insulin sensitivity. Interactions with PPARgamma2 genotypes modified this association.