Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

Development and validation of a predictive model for incident type 2 diabetes in middle-aged Mexican adults: the metabolic syndrome cohort.

BACKGROUND: Type 2 diabetes mellitus (T2D) is a leading cause of morbidity and mortality in Mexico. Here, we aimed to report incidence rates (IR) of type 2 diabetes in middle-aged apparently-healthy Mexican adults, identify risk factors associated to ID and develop a predictive model for ID in a high-risk population. METHODS: Prospective 3-year observational cohort, comprised of apparently-healthy adults from urban settings of central Mexico in whom demographic, anthropometric and biochemical data was collected. We evaluated risk factors for ID using Cox proportional hazard regression and developed predictive models for ID. RESULTS: We included 7636 participants of whom 6144 completed follow-up. We observed 331 ID cases (IR: 21.9 per 1000 person-years, 95%CI 21.37-22.47). Risk factors for ID included family history of diabetes, age, abdominal obesity, waist-height ratio, impaired fasting glucose (IFG), HOMA2-IR and metabolic syndrome. Early-onset ID was also high (IR 14.77 per 1000 person-years, 95%CI 14.21-15.35), and risk factors included HOMA-IR and IFG. Our ID predictive model included age, hypertriglyceridemia, IFG, hypertension and abdominal obesity as predictors (Dxy = 0.487, c-statistic = 0.741) and had higher predictive accuracy compared to FINDRISC and Cambridge risk scores. CONCLUSIONS: ID in apparently healthy middle-aged Mexican adults is currently at an alarming rate. The constructed models can be implemented to predict diabetes risk and represent the largest prospective effort for the study metabolic diseases in Latin-American population.

Higher Hepcidin Levels in Adolescents with Obesity Are Associated with Metabolic Syndrome Dyslipidemia and Visceral Fat.

Tightly regulated iron metabolism prevents oxidative stress. Hepcidin is a hormone that regulates iron flow in plasma; its production is induced by an iron overload and by inflammation. It inhibits iron entry into the circulation by blocking dietary absorption in the duodenum, the release of recycled iron from macrophages and the exit of stored iron from hepatocytes. Varied signals responding to iron stores, erythropoietic activity and host defense converge to regulate hepcidin production and thereby affect iron homeostasis. Although it is known that hepcidin increases when interleukin 6 (IL-6) increases, the relationship between hepcidin, dyslipidemia, insulin resistance (IR) and visceral adiposity index (VAI) in adolescents with obesity is unclear. In this cross-sectional study of 29 obese adolescents and 30 control subjects, we explored the difference of hepcidin, iron metabolism markers and IL-6 between obese and non-obese adolescents, and identified associations with inflammation, atherogenic dyslipidemia and IR. As compared to lean controls, obese participants showed 67% higher hepcidin: 14,070.8 ± 7213.5 vs. 8419.1 ± 4826.1 pg/mLc; 70% higher ferritin: 94.4 ± 82.4 vs. 55.1 ± 39.6 pg/mLa and 120% higher IL-6: 2.0 (1.1-4.9) vs. 0.9 (0.5-1.3) pg/mLd. Transferrin, soluble transferrin receptor and total body iron (as measured by sTFR/ferritin, log10 sTFR/ferritin ratio and sTFR/log ferritin ratios) were not different between the two cohorts. In the whole cohort, hepcidin correlated with VAI (r = 0.29a), sd-LDL (r = 0.31b), HOMA-IR (r = 0.29a) and IL-6 (r = 0.35c). In obese adolescents hepcidin correlated with TG (r = 0.47b), VLDL-C (r = 0.43b) and smaller LDL2 (r = 0.39a). Hepcidin elevation in adolescents with obesity is linked more to inflammation and metabolic alterations than to iron metabolism since the other markers of iron metabolism were not different between groups, except for ferritin. Studies addressing the long-term effects of higher hepcidin levels and their impact on subclinical anemia and iron status are warranted. a p < 0.05; b p < 0.01, c p < 0.001 dp < 0.0001.

Receptor soluble para productos finales de glicación avanzada y perfil lipídico como marcadores de riesgo cardiovascular en niños con obesidad / Soluble receptor for advanced glycation end products and lipid profile ratio as cardiovascular risk markers in children with obesity

Resumen Introducción: Se ha mostrado que la obesidad está asociada a niveles bajos de la forma soluble del receptor para productos finales de glicación avanzada (sRAGE). Objetivo: Evaluar los niveles de sRAGE y su asociación con el índice lipídico en niños con obesidad. Métodos: Estudio transversal de niños de seis a 11 años de edad con obesidad. Se evaluaron medidas antropométricas, glucosa, perfil lipídico, insulina y sRAGE; también se calculó índice de masa corporal, colesterol total/C-HDL, triglicéridos/glucosa, triglicéridos/C-HDL y HOMA-IR.] Resultados: Se estudiaron 80 niños, 50 % hombres y 50 % mujeres. Las mujeres presentaron mayor perímetro de cintura, HOMA-IR, triglicéridos/C-HDL y triglicéridos/glucosa. No se encontraron diferencias significativas en sRAGE. Al comparar las variables conforme a los terciles de la relación triglicéridos/C-HDL, en el tercil superior se encontraron mayores valores de colesterol total/HDL, triglicéridos/glucosa y sRAGE. Se observó correlación significativa entre sRAGE y HOMA-IR (p < 0.03) en los hombres y entre sRAGE, triglicéridos/C-HDL (p < 0.01) y triglicéridos/glucosa (p < 0.008) en las mujeres. Conclusiones: El sexo femenino mostró más factores de riesgo cardiovascular y mayor sRAGE en el tercil superior de triglicéridos/C-HDL. Se requieren más estudios para probar el posible efecto predictor de mayor riesgo para desarrollar complicaciones metabólicas y cardiovasculares.

Abstract Introduction: Obesity has been shown to be associated with low levels of soluble receptor for advanced glycation end products (sRAGE). Objective: To evaluate the levels of sRAGE and its association with the lipid index in children with obesity. Methods: Cross-sectional study of children with obesity aged between six and 11 years. Anthropometric measurements, glucose, lipid profile, insulin and sRAGE were evaluated; body mass index, total cholesterol/high-density cholesterol (TC/HDL-C), triglycerides/glucose (TG/glucose), and triglycerides/HDL-C (TG-HDL-C) ratios and HOMA-IR were also calculated. Results: Eighty children were studied, among which 50% were males and 50% females. Females had higher values for waist circumference, HOMA-IR, and TG/HDL-C and TG/glucose ratios. No significant differences were found for sRAGE. When the variables were compared according to TG/HDL-C ratio tertiles, higher TC/HDL, TG/glucose, and sRAGE values were found at upper tertile. A significant correlation was observed between sRAGE and HOMA-IR (p < 0.03) in males, and between sRAGE and TG/HDL-C (p < 0.01) and TG/glucose ratios (p < 0.008) in females. Conclusions: The female gender showed more cardiovascular risk factors and higher sRAGE at TG/HDL-C upper tertile. Further studies are required to test the possible predictive effect of higher risk for developing metabolic and cardiovascular complications.

Auditory impairment in patients with type 2 diabetes mellitus.

BACKGROUND: We assessed the auditory function of 94 patients with type 2 diabetes mellitus and 94 age- and sex-matched healthy subjects. METHODS: To study the influence of the clinical characteristics of the disease on the auditory function, after a clinical interview with ophthalmological assessment, subjects were evaluated using pure-tone audiometry, speech audiometry, auditory brainstem responses, the Michigan Diabetic Neuropathy Score and albuminuria. The mean age when diabetes was diagnosed was 42.8 +/- 6.5 years (mean +/- SD) and the time elapsed since diabetes diagnosis was 7.2 +/- 5.4 years. RESULTS: Forty-eight patients (62%) had HbA1c >8%; diabetic retinopathy was evident in 14 patients (14%) and microalbuminuria was identified in 12 patients. Compared to healthy subjects, diabetic patients showed an increase of the perception threshold at 8000 Hz (p <0.01), higher hearing levels to discriminate at least 90% of 10 monosyllables (p <0.01), and longer latencies of wave V, interwave I-V and interwave III-V (p <0.01). Significant correlation was found between the hearing threshold at 8 KHz and patient age, and the former and the time elapsed since the diabetes was diagnosed (p <0.001). CONCLUSIONS: Patients with type 2 diabetes mellitus can have subclinical hearing loss and impaired auditory brainstem response, independent of peripheral neuropathy, retinopathy or nephropathy.

Procedure to diagnose onychomycosis through changes in emissivity on infrared images.

A noninvasive, quick, reliable, and relatively cheap procedure for the diagnosis of onychomycosis is put forward. It is known that a nail may show an abnormal appearance, although only 50% of all the nails having such an appearance may owe it to the presence of onychomycosis; hence, adequate diagnosis of nail disease is needed for appropriate prescription of medication and treatment of the nail. In order to contribute to the process of improvement in the diagnosis, a procedure based on the analysis of medium-range infrared images is presented in which it is possible to observe energy changes mostly due to the changes in emissivity of the nail. As a nail is more affected by onychomycosis, such changes become more intense. Also, it was found that a nail without onychomycosis has a lower temperature than toe skin, but has a higher emission of energy. Fifty percent of the ailments that may a cause a fingernail or toenail to have an abnormal appearance are not considered in the present work.

Distribution of the homeostasis model assessment of insulin resistance in Mexican children and adolescents.

OBJECTIVE: Several cutoff points of the homeostasis model assessment of insulin resistance (HOMA-IR; varying from 2.5 to 4.0) have been suggested for diagnosing IR in youth. In this study, we determined the distribution of the HOMA-IR in Mexican children and adolescents. DESIGN AND METHODS: A total of 6132 children and adolescents from San Luis Potosi, León, Queretaro, and Durango, which are cities in central and northern Mexico, were enrolled in a population-based cross-sectional study. Eligible participants were apparently healthy children and adolescents aged 6-18 years. Pregnancy and the presence of chronic illnesses were exclusion criteria. RESULTS: A total of 3701 (60.3%) girls and 2431 (39.7%) boys were included in this study. In the overall population, the mean body mass index, insulin levels, and fasting glucose levels were 21.8±1.3 kg/m(2), 7.1±3.2 µU/ml, and 86.2±10.0 mg/dl respectively. The concentrations of insulin and fasting glucose gradually increased from 6 to 12 years of age, whereas the concentrations tended to plateau in the 13- to 18-year-old population. The absolute mean of the HOMA-IR was 2.89±0.7. The HOMA-IR gradually increased with age and reached a plateau at 13 years of age. CONCLUSIONS: Because the insulin concentrations, glucose levels, and HOMA-IR exhibited a gradual increase with age that was not related to obesity, our results suggested that the evaluation of IR in children should be based on percentiles of the HOMA-IR rather than a dichotomous value derived from a single cutoff point.

TSH and free thyroxine concentrations are associated with differing metabolic markers in euthyroid subjects.

OBJECTIVE: To examine the association between thyroid function and the components of the metabolic syndrome and insulin resistance in an Hispanic population. DESIGN: Cross-sectional study. METHODS: Subjects with no history of thyroid disease or diabetes were included. Thyroid function was stratified as euthyroid or subclinical hypothyroidism (SCH) status and subsequently by free thyroxine (FT(4)) and TSH tertiles. The association of the metabolic syndrome components (defined by 2004 Adult Treatment Panel III criteria) and insulin resistance with thyroid status, TSH, and FT(4) were examined. RESULTS: A total of 3148 subjects were analyzed. The prevalence of SCH was 8.3%. The prevalence of the metabolic syndrome was similar in euthyroid and SCH patients (31.6 vs 32.06%, P=0.89). Total cholesterol was higher in patients with SCH (5.51+/-1.19 vs 5.34+/-1.05 mmol/l, P<0.032). Serum TSH values showed a positive correlation (adjusted for age and sex) with total cholesterol, triglycerides, and waist circumference. In contrast, FT(4) showed a positive correlation with high-density lipoprotein cholesterol, and an inverse correlation with waist circumference, insulin, and HOMA-IR. CONCLUSION: SCH is not associated with an increased risk for the metabolic syndrome (as conceived as a diagnostic category defined by the National Cholesterol, Education Program, Adult Treatment Panel III criteria). Despite this, low thyroid function (even in the euthyroid state) predisposes to higher cholesterol, glucose, insulin, and HOMA-IR levels. The combined use of TSH and FT(4), compared with the assessment based on only FT(4), is a more convenient approach to evaluate the association between thyroid function and metabolic variables.

Tensión arterial en escolares de la Ciudad de León, Guanajuato y la correlación con sus variables somatométricas y la tensión arterial paterna / Systemic blood pressure in school children in Leon, Guanajuato, Mexico, and its correlation with somatometric variables and the blood pressure of their parents

Estudiamos la relación de la tensión arterial con las variables somatométricas y la tensión arterial de los padres en 350 escolares. Las cifras sistólica y diastólica, especialmente la primera, se asociaron con la edad y las variables somatométricas. La correlación más alta se obtuvo con el peso (r=0.569, P<0.001). El índice de masa corporal y la talla dieron coeficientes menores. La relación de la edad y del índice de masa corporal con las cifras tensionales fue lineal, sin diferencias por sexo. La tensión sistólica de los niños correlacionó con las cifras sistólicas de sus padres (r=0.156, P=0.009. Los niños cuya tensión arterial sistólica se encontraba en el cuartil superior, tenían mayor diferencia del índice de masa corporal (t=4.60, P<0.001) que el valor z del peso (t=4.24, P<0.001) y el peso (t=3.70, P<0.001). No había diferente tensión arterial entre quienes tenían antecedentes familiares de hipertensión arterial

Valoración de metotrexate en artritis reumatoide refractaria / Evaluation of methotrexate in refractory rheumatoid arthritis

Con el objeto de valorar la eficacia de metotrexate en el tratamiento de la artritis reumatoide refractaria, se realizará un estudio abierto prospectivo con 20 pacientes durante dos años. Se efectuarán valoraciones clínicas y de laboratorio cada dos meses, con opción a que el paciente tenga cita abierta ante la manifestación de cualquier efecto indeseable. Para fines estadísticos, las revisiones se realizarán al inicio del tratamiento y a los dos, cuatro, seis, 12, 18 y 24 meses de iniciado el estudio. En este informe preliminar se presentan los resultados obtenidos a los seis meses de tratamiento, con los diferentes parámetros evaluados. En casi todos los análisis efectuados hasta este corte, se concluye que metotrexate es un fármaco eficaz en este tipo de padecimiento. Asimismo, en este estudio se observó que metotrexate produce una tendencia a reducir el requerimiento diario de esteroides

Perceived psychologicasl stress in diabetes mellitus type 2 / Estrés psicológico percibido en diabetes mellitus tipo 2

Estudiamos los factores asociados al estrés psicosocial en pacientes con diabetes mellitus tipo 2. Se realizó un estudio en sección transversal en 105 pacientes, 27 hombres y 78 mujeres, cuya edad media es de 51.5 años (50.2-52.5, IC 95 por ciento) con 8.6 años desde el diagnóstico (7.3-9.8, IC 95 por ciento). Los pacientes tenían sobrepeso con índice de masa corporal (IMC) de 27.6 y la mayoría tenía descontrol metabólico aunque sin síntomas (media de glucosa 10.6 nmol/L y HbA1c de 9.2 por ciento). La hemoglobina glucosilada se asoció con el IMC (negativamente, p = 0.002). Dentro de los grupos, esta asociación con el IMC se encontró sólo en las mujeres y se explicó porqué la mujer obesa tiene menos años desde el diagnóstico que es un factor relacionado a mejor control metabólico. En el análisis de regresión múltiple el estrés percibido se asoció además con el por ciento de grasa corporal y con la glucosa en el grupo total, en las mujeres con años desde el diagnóstico (p = 0.02), y en los hombres con IMC (p = 0.03). No se encontró asociación entre estrés percibido y adherencia al tratamiento. Concluimos que en nuestro grupo, el estrés percibido se asoció con la obesidad y con el control metabólico.