Carmen Mazza

Clinical‐etiologic correlation in children with Prader‐Willi syndrome (PWS): An interdisciplinary study

Prader‐Willi syndrome (PWS) is a multisystemic disorder caused by the loss of expression of paternally transcribed genes within chromosome 15q11‐q13. Most cases are due to paternal deletion of this region; the remaining cases result from maternal uniparental disomy (UPD) and imprinting defects. To better understand the phenotypic variability of PWS, a genotype–phenotype correlation study was performed in 91 children with PWS. Patients were diagnosed by Southern Blot Methylation assay and genetic subtypes were established using FISH and microsatellite analyses. Fifty‐nine subjects with deletion (31/28 males/females; mean age 3.86 years), 30 with UPD (14/16 males/females; mean age 3.89 years) and 2 girls with a presumed imprinting defect (mean age 0.43 yrs) were identified. For correlation purposes patients were grouped as “deleted” and “non‐deleted.” An increased maternal age was found in the UPD group. Four of Holms criteria were more frequently present in the deleted group: need for special feeding techniques, sleep disturbance, hypopigmentation, and speech articulation defects. Concerning cognitive assessments, only 9.52% of subjects with deletion had Full‐Scale IQ (FSIQ) ≥70, while 61.53% of subjects without deletion had FSIQ ≥70. Similar results were found in behavioral measures. Sleep disorders and carbohydrate metabolism were systematically assessed. Polysomnoghaphic studies revealed a higher frequency of central events with desaturations ≥10% in the deleted group (P = 0.020). In summary, the phenotype was significantly different between both groups in certain parameters related to the CNS. These results might be related to the differences in brain gene expression of the genetic subtypes.

Prevalence of type 2 diabetes mellitus and impaired glucose tolerance in obese Argentinean children and adolescents.

The aim of this study was to evaluate the prevalence of type 2 diabetes mellitus (DM2) and impaired glucose tolerance (IGT) in obese children and adolescents and to examine insulin resistance and insulin secretion. We studied 427 asymptomatic obese patients. DM2 and IGT were diagnosed by an oral glucose tolerance test. Insulin resistance and P-cell function were assessed by using homeostasis model assessment (HOMA), insulin/glucose index (I/GI), fasting insulin and insulin sensitivity index (ISI-composite). Thirty patients showed IGT (7%) and seven had DM2 (1.6%). The mean age was 10.7 +/- 3.5 years, the diabetic group being significantly older than the normal group (p < 0.01). The mean body mass index was 30 +/- 5.3 kg/m2 without significant differences between groups. beta-Cell function declined significantly in the patients with IGT and DM2, and insulin resistance increased significantly. Given the rather high prevalence of glucose metabolism impairment, children with obesity should undergo glucose tolerance testing for appropriate therapeutic intervention.

Characterization of Alterations in Carbohydrate Metabolism in Children with Prader-Willi Syndrome

OBJECTIVE To study carbohydrate metabolism and insulin sensitivity and secretion in children and adolescents with Prader-Willi syndrome (PWS) compared with multifactorial obesity (MO) controls. PATIENTS AND METHODS Seventy-five patients with PWS and 395 controls with MO were studied by oral glucose tolerance test. Insulin resistance (IR) and beta-cell function were assessed by homeostasis model assessment (HOMA), insulin glucose index, fasting insulin and insulin sensitivity index. RESULTS The incidence of diabetes mellitus was 0% in PWS and 1.5% in MO, while carbohydrate intolerance was 9.3% in the former group and 7.6% in the latter (NS); basal insulin level (12 +/- 8.2 vs 22.3 +/- 25 mU/ml) and HOMA-IR (2.47 +/- 1.6 vs 4.18 +/- 5.05) were lower in PWS (p = 0.004 and 0.04, respectively), whereas HOMA beta-cell index was lower in PWS than in MO (59 +/- 42 vs 102 +/- 119, p = 0.03). ISI Composite was higher in PWS compared to MO (6 +/- 5.7 vs 4.18 +/- 5.05, p = 0.04). CONCLUSION Patients with PWS presented lower insulin resistance and a dissociation between beta-cell secretion and the degree of obesity.

Assessment of risk factors of poor metabolic control in type 1 diabetic children assisted in a public hospital in Argentina

Objective:  To evaluate predictive risk variables of poor diabetes control that are present at the onset of the disease.

No Evidence of Association of CTLA-4 -318 C/T, 159 C/T, 3′ STR and SUMO4 163 AG Polymorphism with Autoimmune Diabetes

Autoimmune diabetes is an organ specific and multifactorial disorder including insulin dependent diabetes mellitus (Type 1 Diabetes) and latent autoimmune diabetes in adults (LADA), which progresses to insulin dependency because of the beta cells destruction. Several polymorphisms in different genes have been associated with diabetes. The CTLA4 gene is considered a down regulator of T cell function, and the SUMO4 gene encodes a small ubiquitin-like modifier implicated in the intensity and duration of the immune response. We selected 62 LADA patients, 123 patients with Type 1 diabetes patients and 136 unrelated volunteers to study CTLA4 -318 C/T, 159 C/T, 3′ STR and SUMO4 163 A/G polymorphisms by PCR. There was a statistical difference significant in the frequency of the allele 209pb for the 3′STR between LADA and Type 1 diabetes patients but not with respect the normal group, the frequencies were found to be 6.9%, 1.0% and 1.9%, respectively. However, no association with either of the polymorphisms has been found in the studied population. The knowledge of the several susceptibility loci in autoimmune diabetes will enhanced the prediction of individuals at high risk of developing the disease in order to establish the best treatment and the prevention of autoimmune diabetes.

Combined measurement of diabetes mellitus immunological markers: an assessment of its benefits in adult-onset patients.

The convenience of combining the measurement of antibodies to glutamic acid decru·boxylase (GADA), protein tyrosine phosphatase (IA-2A), and autoantibodies to insulin (IAA) in diabetic patients was assessed. We analysed 71 type l and 11 5 adult-onset diabetic patient. The latter were grouped into three categories according to the time of evolution to insulin dependence. The main findings were as follows: (i) in type I diabetes, the combined analysis of GADA and IA-2A showed a sensitivity of 87.4% and was not appreciably improved by adding IAA; (ii) out of 31 adults who required insulin immediately or wi thin the first two years of diagnosis, 41.9, 29.0, and 6.5% were positive for at least one, two or all three, and all three markers, respectively; GADA was the most prevalent (35.5%) and IA-2A the least represented (16.1%); (iii) 34 adult patients with slow evolution to insulin dependence bowed a completely different profile: 5.9% were GADA positive and 23.5% were IAA positive and no double or triple positivity was observed as all patients were IA-2A negative; and (iv) 50 type 2 patients who had not required insulin treatment showed a low incidence of GADA (4%) as the only marker present. We conclude that a combined double-antigen test for GADA and TA-2A is a useful strategy for prospective screening of type I diabetes. However, in adults, the profile of individual markers di scloses the course to insulin dependence. There fore, it seems advisable to measure the markers separately, to allow a better classification of these patients, and help define their treatment.

Evaluation of two dietary treatments in obese hyperinsulinemic adolescents

Abstract Hyperinsulinemia increases the risk of cardiovascular disease in obese children. Only a few treatments are available to decrease insulin resistance. The reduction of hyperinsulinemia by dietary means would be a simple, physiologic and economic way to reduce the risk of metabolic disease. Objective: To compare the effects of two low-energy diets on serum insulin concentrations and weight loss in obese hyperinsulinemic adolescents. Materials and methods: Eighty-six randomly assigned insulin-resistant obese adolescents completed a 16 week calorie-restricted diet. The experimental diet had a reduced glycemic index designed to evoke a low insulin response (LIR), with carbohydrates and proteins ingested in separate meals. The control diet was a conventional (CD) with similar proportions (60%, 20% and 20%). Variables studied were blood glucose and insulin concentrations after an oral glucose load, body mass index, waist circumference, and insulin resistance (homeostasis model assessment, HOMA). Results: Mean weight [±Standard Deviation (SD)] was significantly reduced after the LIR (–0.53±0.5) and the CD (–0.54±0.4), but a greater decrease of waist circumference (cm) was observed after the LIR (–9.1±4.8 vs. –6.6±4.6, p=0.02). Fasting insulin concentrations (–17.9±27.9 vs. –9.4±14.8, p=0.01) and HOMA dropped significantly more after the LIR than after the CD (–3.5±4.9SD vs. –2.4±1SD, p<0.0001). Conclusions: The LIR diet reduces serum insulin concentrations and waist circumference more than conventional treatment and appears to be a promising alternative to a conventional diet in insulin-resistant obese adolescents. Long-term follow-up is needed to evaluate the maintenance of weight loss and metabolic parameters.

Waist-to-height ratio as a marker of low-grade inflammation in obese children and adolescents

Abstract Background: The epidemic of childhood obesity is associated with early atherosclerosis. Several reports have related this event to low-grade inflammation described in obesity. CRP and IL6 are markers that correlate with adiposity. The waist-to-height ratio (WtHR) is an anthropometric marker associated with insulin resistance and inflammation. The objective of this study was to assess the correlation between WtHR, metabolic complications and pro-inflammatory factors in obese children and adolescents. Methods: Weight, height, waist circumference, glycemia, insulin, CRP, TNF-α and IL-6 were measured in the baseline sample in 280 patients 6–19 years of age with overweight or obesity (OW/OB) and 112 normal-weight controls. Logistic regression was performed using WtHR as an independent variable. p>0.05 STATA11. Results: Mean WtHR was 0.6±0.06 in OW/OB and 0.43±0.02 in controls (p<0.01). WtHR was increased in 93% of the OW/OB vs. 2% of the controls. In the OW/OB inflammatory markers were significantly increased (p<0.01) compared to the controls (CRP 2.2 vs. 0.8; Il-6 2.9 vs. 2.1; and TNF-α 6.2 vs. 5.5). In the WtHR>0.5, insulin resistence and inflammatory markers were significantly increased (p<0.01) compared to the WtHR<0.5 (HOMA 3.4 vs. 1.4; CRP 2.3 vs. 0.6; Il-6 2.9 vs. 2.1; and TNF-α 6.4 vs. 5.55). In logistic regression, a significant independent association was found between WtHR with CRP (OR1.47), IL6 (OR1.60) and TNF-α (OR1.79). Conclusions: Obese children and adolescents have high inflammatory markers that may increase cardiovascular risk. WtHR is associated with low-grade inflammation and may be considered a relevant anthropometric marker in the clinical practice.

Impact of maternal nutritional status before and during pregnancy on neonatal body composition: A cross-sectional study.

BACKGROUND The existence of early factors which, acting during critical periods of intrauterine or immediate postnatal development, determine long-term health has become increasingly recognized. Both high and low birth weight have been associated with cardiovascular risk factors in adulthood. Therefore, body composition at birth rather than birth weight may be a marker to predict future diseases. Maternal weight previous to and gained during pregnancy is associated with intrauterine fetal growth. OBJECTIVE To evaluate the correlation between maternal nutritional status before and during pregnancy and neonatal body composition. MATERIAL AND METHODS We studied consecutive mother-child pairs at delivery at an Argentinean public hospital during 5 months period, evaluating maternal and neonatal anthropometry before 24h of life as well as the history of the mother before and during pregnancy. Neonatal body composition was calculated according to a mathematical formula based on skinfold thickness measurement validated in newborns. RESULTS Mothers of newborns with high body fat mass were more frequently obese (72.7% versus 35.1%, p 0.005), and more frequently showed weight gain above 18kg during pregnancy (76.4% versus 31%, p 0.03). CONCLUSIONS Our findings confirm the hypothesis that maternal obesity before pregnancy is highly correlated with neonatal fat mass in the first hours of life.

Association between insulin resistance and risk of complications in children and adolescents with type 1 diabetes.

BACKGROUND It has been hypothesized that insulin resistance may be involved in the development of type 1 diabetes complications and early diagnosis would be important for their prevention. Our aim was to study insulin resistance in our population of children with type 1 diabetes and to identify associated early risk factors for micro- and macrovascular complications. METHODS A descriptive, cross-sectional study was conducted including 150 children with type 1 diabetes. Anthropometric, bioelectric impedance, carotid Doppler ultrasonography, electromyography, and conduction velocity studies were performed. Baseline plasma glucose, lipid profile, uric acid, plasma thyrotropin, glycosylated hemoglobin A1C, and microalbuminuria were assessed. More insulin-resistant patients were defined as those having an estimated glucose disposal rate (eGDR) value below the first quartile. RESULTS Clinically manifest microvascular complications were not found in any of the patients. More insulin-resistant patients had a greater sub scapular fold thickness, a higher incidence of obesity (12% vs. 1.7% p 0.007), higher fructosamine levels (496 vs. 403 p<0.00019, and a higher incidence of altered lipid metabolism (70% vs. 39% p 0.0007). CONCLUSION In the subgroup of patients with lower eGDR there were more children with lipid disorders, obesity, and worse diabetic control, which, if not corrected, may lead to development of micro- and macrovascular complications.