Ethnic differences in beta cell adaptation to insulin resistance in obese children and adolescents.

AIMS/HYPOTHESIS: The prevalence of altered glucose metabolism in obese children and adolescents is growing at a significant rate, especially in ethnic minorities. It is not clear whether young people of different ethnic backgrounds differ in their adaptive mechanisms to obesity-related insulin resistance. The aim of this study was to evaluate the early insulin response and insulin clearance in response to an oral glucose load in obese children and adolescents. METHODS: Seven hundred and nine obese children and adolescents underwent an OGTT. Indices of the early insulin response and insulin clearance were compared in participants of White European, African American and Hispanic origin. RESULTS: Participants of the three ethnic groups demonstrated similar mechanisms of adaptation to increasing insulin resistance, but with different magnitudes. African American subjects had a greater early insulin response and decreased insulin clearance than their White European and Hispanic counterparts. This happened regardless of whether the cohort was divided by glucose tolerance level or by level of insulin sensitivity. IGT across ethnic groups was characterised by a marked decline in the acute insulin response in the context of severe insulin resistance and very low insulin clearance. CONCLUSIONS/INTERPRETATION: In obese children and adolescents, mechanisms of adaptation to obesity related to insulin resistance are similar across ethnic groups. The greater early insulin response needed to maintain glucose tolerance in young people of ethnic minorities may partially explain their greater tendency to develop type 2 diabetes.

Microalbuminuria in pediatric obesity: prevalence and relation to other cardiovascular risk factors.

BACKGROUND: Microalbuminuria (MA) has emerged as a strong predictor of cardiovascular (CV) events, even in nondiabetic adults. While the mechanisms behind this association remain to be established, most studies suggest that MA is the result of increased vascular leakage denoting endothelial dysfunction associated with early vasculopathy. OBJECTIVE: To examine if a urine albumin creatinine ratio (UACR) in the microalbuminuric range is related to metabolic markers of CV risk in obese and pre-diabetic youth recruited from an obesity clinic. METHODS: MA was defined as a UACR between 2.0 and 20 mg/mmol. Subjects with gross proteinuria (UACR>20 mg/mmol) were excluded from the study. Analyses were performed to assess the relationship of MA and markers of CV risk, including body mass index (BMI), % body fat, blood pressure (BP), lipid profile, inflammatory markers, insulin sensitivity indexes and degrees of oral glucose tolerance. MA was also correlated with risk factor constellations unique to the metabolic syndrome, a distinct CV risk entity. RESULTS: Postchallenge alterations in glucose metabolism and overall loss in insulin sensitivity were strongly and positively correlated with the presence of MA (P = 0.002 and 0.01, respectively). Neither the metabolic syndrome nor any of the individual CV risk factors examined were associated with MA. CONCLUSIONS: These data suggest that early glucose toxicity, as reflected by postchallenge elevations in plasma glucose even below the diagnostic cutoff for diabetes mellitus may contribute to the presence of MA. Whether MA is equally as predictive of CV disease in youth, as in adulthood, remains to be investigated.

Fabry disease: thirty-five mutations in the alpha-galactosidase A gene in patients with classic and variant phenotypes.

BACKGROUND: Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from mutations in the alpha-galactosidase A (alpha-Gal A) gene located at Xq22.1. To determine the nature and frequency of the molecular lesions causing the classical and milder variant Fabry phenotypes and for precise carrier detection, the alpha-Gal A lesions in 42 unrelated Fabry hemizygotes were determined. MATERIALS AND METHODS: Genomic DNA was isolated from affected probands and their family members. The seven alpha-galactosidase A exons and flanking intronic sequences were PCR amplified and the nucleotide sequence was determined by solid-phase direct sequencing. RESULTS: Two patients with the mild cardiac phenotype had missense mutations, I9IT and F113L, respectively. In 38 classically affected patients, 33 new mutations were identified including 20 missense (MIT, A31V, H46R, Y86C, L89P, D92Y, C94Y, A97V, R100T, Y134S, G138R, A143T, S148R, G163V, D170V, C202Y, Y216D, N263S, W287C, and N298S), two nonsense (Q386X, W399X), one splice site mutation (IVS4 + 2T-->C), and eight small exonic insertions or deletions (304del1, 613del9, 777del1, 1057del2, 1074del2, 1077del1, 1212del3, and 1094ins1), which identified exon 7 as a region prone to gene rearrangements. In addition, two unique complex rearrangements consisting of contiguous small insertions and deletions were found in exons 1 and 2 causing L45R/H46S and L120X, respectively. CONCLUSIONS: These studies further define the heterogeneity of mutations causing Fabry disease, permit precise carrier identification and prenatal diagnosis in these families, and facilitate the identification of candidates for enzyme replacement therapy.

Fabry disease: twenty-three mutations including sense and antisense CpG alterations and identification of a deletional hot-spot in the alpha-galactosidase A gene.

Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from mutations in the alpha-galactosidase A gene at Xq22.1. To determine the nature and frequency of the molecular lesions causing the classical and milder variant Fabry phenotypes, and for precise carrier detection in Fabry families, the alpha-galactosidase A coding and flanking intronic sequences from 23 unrelated Fabry hemizygotes were analyzed. In patients with the classic phenotype, 16 new missense and nonsense mutations and four small exonic gene rearrangements were identified: C52S, C56F, E59K, L89R, R100K, R112H, L131P, A143P, G144V, C172Y, D244N, N272K, A288D, W81X, Q99X, Q157X, R301X, 25del1, 333del18, 358del6, and 1020del1. The R112H mutation at a CpG dinucleotide resulted in residual activity and a mild variant phenotype while the R112C lesion caused the classic disease manifestations, defining a genotype/phenotype correlation for sense and antisense mutations at the same CpG dinucleotide. In addition, two complex rearrangements, each involving two mutational events, occurred in classic hemizygotes. Both rearrangements resulted in missense mutations that did not change the reading frame. Notably, three of the deletions occurred within 11 codons in exon 2, thereby defining a 'hot-spot' for deletions. These studies revealed that most mutations in the alpha-galactosidase A gene causing Fabry disease were private, that codons 111-122 defined a deletion hot-spot, and that different substitutions of the same codon resulted in markedly different disease phenotypes.