Differences between transient neonatal diabetes mellitus subtypes can guide diagnosis and therapy.

OBJECTIVE: Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features. DESIGN: Retrospective analysis of the Italian data set of patients with TNDM. METHODS: Clinical features and treatment of 22 KATP/TNDM patients and 12 6q24/TNDM patients were compared. RESULTS: Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; -2.27 SD) than those with KATP mutations (4.0 weeks; -1.04 SD) (P = 0.009 and P = 0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 weeks vs 12 weeks) (P = 0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy. CONCLUSIONS: If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.

Systematic review of metformin use in obese nondiabetic children and adolescents.

OBJECTIVE: Childhood obesity has become epidemic and has been accompanied by an increase in prevalence of type 2 diabetes (T2DM) in youth. Addressing obesity and insulin resistance by drug treatment represents a rational strategy for the prevention of T2DM. A systematic review was performed to evaluate the effectiveness of metformin in reducing weight and ameliorating insulin resistance in obese nondiabetic children. METHODS: A PubMed database search was conducted, using 'metformin', 'obesity', 'insulin resistance', 'children', 'adolescents' as search terms. RESULTS: Eleven trials were included in the present review. Metformin was administered for 6-12 months at a dosage of 1,000-2,000 mg/daily, decreasing BMI by 1.1-2.7 compared with placebo or lifestyle intervention alone. Concomitantly, fasting insulin resistance improved after metformin therapy. Posttreatment follow-up was performed in one study, showing that after 1 year of discontinuation of therapy the decrease in BMI disappears. CONCLUSIONS: Short-term metformin treatment appears to moderately affect weight reduction in severely obese children and adolescents, with a concomitant improvement in fasting insulin sensitivity. Further studies with longer treatment period are needed to establish how much metformin can reduce weight and its real utility in preventing T2DM development in pediatric patients.

Obese children with low birth weight demonstrate impaired beta-cell function during oral glucose tolerance test.

OBJECTIVE: Epidemiological studies have shown an association between birth weight and future risk of type 2 diabetes, with individuals born either small or large for gestational age at increased risk. We sought to investigate the influence of birth weight on the relation between insulin sensitivity and beta-cell function in obese children. SUBJECTS AND METHODS: A total of 257 obese/overweight children (mean body mass index-sd score, 2.2 +/- 0.3), aged 11.6 +/- 2.3 yr were divided into three groups according to birth weight percentile: 44 were small for gestational age (SGA), 161 were appropriate for gestational age (AGA), and 52 were large for gestational age (LGA). Participants underwent a 3-h oral glucose tolerance test with glucose, insulin, and C-peptide measurements. Homeostasis model of assessment for insulin resistance, insulinogenic index, and disposition index were calculated to evaluate insulin sensitivity and beta-cell function. Glucose and insulin area under the curve (AUC) were also considered. One-way ANOVA was used to compare the three groups. RESULTS: SGA and LGA subjects had higher homeostasis model of assessment for insulin resistance than AGA subjects, but they diverged when oral glucose tolerance test response was considered. Indeed, SGA subjects showed higher glucose AUC and lower insulinogenic and disposition indexes. Insulin AUC was not different between groups, but when singular time points were considered, SGA subjects had lower insulin levels at 30 min and higher insulin levels at 180 min. CONCLUSIONS: SGA obese children fail to adequately compensate for their reduced insulin sensitivity, manifesting deficit in early insulin response and reduced disposition index that results in higher glucose AUC. Thus, SGA obese children show adverse metabolic outcomes compared to AGAs and LGAs.