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A cross-sectional sample of 185 children and adolescents (boys and girls) from 1 to 17 years of age were recruited in the Pediatric Diabetes Clinic (PDC) of the third-level Mexican High-Specialty Regional Bajío Hospital (Hospital Regional de Alta Especialidad del Bajío, HRAEB) located in León, Guanajuato (México) between March 2008 and April 2015. All participants were Mexican-Hispanic. Patients were included in the study if they had recently been diagnosed with DM and had verified pancreatic autoimmunity. Exclusion criteria were neonatal or secondary diabetes (i.e., diabetes associated with the use of steroids or stressful situations).
This study is a part of the protocol included in the “Cohort of Mexican Children with Diabetes (CMC-DM)”. CMC-DM is registered with ClinicalTrials.gov, identifier: NCT02722655. The study protocol was reviewed and approved by the Research Committee of the High-Specialty Regional Bajio Hospital and by the Ethics Committee of the High-Specialty Regional Bajio Hospital. Approval number: CI-HRAEB-2015-018. The patients and their parents signed a written informed agreement and consent form, respectively, when they were enrolled in the study.
A physical examination was conducted by a pediatric endocrinologist and included an acanthosis nigricans evaluation based on a modified quantitative scale,[13] described by Burke et al., and puberty staging according to the Tanner Scale. Systolic and diastolic blood pressure (SBP and DBP) were manually measured twice in the right arm using a sphygmomanometer (Riester, Jungingen, Germany) with the appropriate sized cuff while the subject was resting, and the average of the two measurements was used in the analysis. Hypertension was defined as SBP or DBP in the 95th percentile or greater for sex, age and height. [14] Body weight was measured while the children wore light clothing and no shoes. Height was measured with the children standing in an upright position using a Seca stadimeter. Body mass index (BMI) was calculated dividing body weight (kg) by the square of height (m). Body weight, height and BMI percentiles were determined for age and sex according to the Centers for Disease Control (CDC) growth charts. Abdominal waist circumference (WC) was measured in the middle axillary line at the point between the lower edge of the ribs and the top of the iliac crest, and the corresponding percentiles were calculated according to data tables pertaining to Mexican children. [15] Overweight/obese children were defined as children <2 years old with a BMI in the 95th percentile or greater and children aged 2 years or older with a BMI in the 85th percentile or greater.
Blood samples were collected after an overnight fast when glucose metabolism was stable and the children did not present with acute illness or infection. Fasting C-peptide (FCP) was measured using a chemiluminescence microparticle immunoassay (ARCHITECT SYSTEM, Abbott, IL, USA). Intra- and inter-assay coefficients of variation were less than 10%. The pancreatic β-cell reserve was defined as FCP ≥0.2 nmol/L. [16] Serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) were measured using dry chemistry with colorimetric methods (Vitros 3350; Ortho Clinical Diagnostic, Johnson & Johnson). Low-density lipoprotein cholesterol (LDL-C) levels were calculated using the Friedewald formula. [17] HbA1C was determined using high-performance liquid chromatography with a DS-5 Analyzer (Drew Scientific, Inc. Miami, FL, USA). High-sensitivity C-reactive protein (hs-CRP) was measured by quantitative immunoturbidimetric determination (CRP Vario 6K26-30 and 6K26-41; Abbott Laboratories Inc. USA). Insulin sensitivity (IS) was calculated using the equation developed and validated with the euglycemic-hyperinsulinemic clamp used in the SEARCH diabetes in youth study. [18] The following equation was used to measure IS: IS = exp [4.64725–0.02032 x waist (cm) - 0.09779 x [HbA1C(%)] - 0.00235 x TG (mg/dL)]. According to this surrogate measurement, insulin resistance (IR) was defined as IS <8.15 and no insulin resistance (NIR) was defined as IS ≥8.15. [19] FCP levels were adjusted by IS; FCP when IS <8.15 and FCP when IS≥8.15.
Antibodies against glutamic acid decarboxylase 65 (GAD-65) were measured using an ELISA kit (from AccuDiag™, CA, USA) with a sensitivity and specificity of 85% and 87.1%, respectively (antibody-positive was defined as levels >1.05). Anti-insulin antibodies (IAA) were measured using ELISA kits (BioSystems S.A. Barcelona, Spain) with a sensitivity and specificity of 86.7% and 98.7%, respectively (antibody-positive was defined as levels >10 U/mL). Anti-islet cell antibodies (AICA) were evaluated using indirect immunofluorescence methods (monkey pancreas section, BioSystems S.A. Barcelona, Spain) with a sensitivity and specificity of 65% and 100%, respectively. Pancreatic autoimmunity was defined as at least one of three autoantibody-positive results.
Diagnosis and classification of diabetes: DM was diagnosed based on ADA criteria. [1] The classification of DM types was made as follows: T1ADM: non-overweight/obese and positive pancreatic autoimmunity,T1BDM: non-overweight/obese and negative pancreatic autoimmunity,T2DM: overweight/obese and negative pancreatic autoimmunity,T1.5DM: overweight/obese and positive pancreatic autoimmunity.
Data were analyzed using R statistical software. [20] Descriptive statistics were calculated for clinical, anthropometric and biochemical variables grouped by the type of DM, and the values were compared using the Kruskal-Wallis test or the chi-squared test depending on the variable type. The sample size of each group allowed for the detection of a ≥10% difference in any assessment (type I error alpha = 0.05 and type II error beta = 0.80). In all cases, 95% confidence intervals were constructed, and an alpha = 0.05 was considered significant.
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