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.

The coactivator CRTC1 promotes cell proliferation and transformation via AP-1.

Regulation of gene expression in response to mitogenic stimuli is a critical aspect underlying many forms of human cancers. The AP-1 complex mediates the transcriptional response to mitogens, and its deregulation causes developmental defects and tumors. We report that the coactivator CRTC1 cyclic AMP response element-binding protein (CREB)-regulated transcription coactivator 1 is a potent and indispensable modulator of AP-1 function. After exposure of cells to the AP-1 agonist 12-O-tetradecanoylphorbol-13-acetate (TPA), CRTC1 is recruited to AP-1 target gene promoters and associates with c-Jun and c-Fos to activate transcription. CRTC1 consistently synergizes with the proto-oncogene c-Jun to promote cellular growth, whereas AP-1-dependent proliferation is abrogated in CRTC1-deficient cells. Remarkably, we demonstrate that CRTC1-Maml2 oncoprotein, which causes mucoepidermoid carcinomas, binds and activates both c-Jun and c-Fos. Consequently, ablation of AP-1 function disrupts the cellular transformation and proliferation mediated by this oncogene. Together, these data illustrate a novel mechanism required to couple mitogenic signals to the AP-1 gene regulatory program.

Insulin gene mutations as cause of diabetes in children negative for five type 1 diabetes autoantibodies.

OBJECTIVE: Heterozygous, gain-of-function mutations of the insulin gene can cause permanent diabetes with onset ranging from the neonatal period through adulthood. The aim of our study was to screen for the insulin gene in patients who had been clinically classified as type 1 diabetic but who tested negative for type 1 diabetes autoantibodies. RESEARCH DESIGN AND METHODS: We reviewed the clinical records of 326 patients with the diagnosis of type 1 diabetes and identified seven probands who had diabetes in isolation and were negative for five type 1 diabetes autoantibodies. We sequenced the INS gene in these seven patients. RESULTS: In two patients whose diabetes onset had been at 2 years 10 months of age and at 6 years 8 months of age, respectively, we identified the mutation G(B8)S and a novel mutation in the preproinsulin signal peptide (A(Signal23)S). CONCLUSIONS: Insulin gene mutations are rare in absolute terms in patients classified as type 1 diabetic (0.6%) but can be identified after a thorough screening of type 1 diabetes autoantibodies.