The P2 promoter of the IGF1 gene is a major epigenetic locus for GH responsiveness.

Short children using growth hormone (GH) to accelerate their growth respond to this treatment with a variable efficacy. The causes of this individual variability are multifactorial and could involve epigenetics. Quantifying the impact of epigenetic variation on response to treatments is an emerging challenge. Here we show that methylation of a cluster of CGs located within the P2 promoter of the insulin-like growth factor 1 (IGF1) gene, notably CG-137, is inversely closely correlated with the response of growth and circulating IGF1 to GH administration. For example, variability in CG-137 methylation contributes 25% to variance of growth response to GH. Methylation of CGs in the P2 promoter is negatively associated with the increased transcriptional activity of P2 promoter in patients' mononuclear blood cells following GH administration. Our observation indicates that epigenetics is a major determinant of GH signaling (physiology) and of individual responsiveness to GH treatment (pharmacoepigenetics).

Decrease in clinical hypoglycemia in young children with type 1 diabetes treated with free-mixed aspart and detemir insulin: an open labeled randomized trial.

OBJECTIVE: To compare the effectiveness of a free-mix of aspart (A) and detemir (D) insulins (ADIM) with a commonly used premixed fixed-ratio aspart and neutral protamine Hagedorn (NPH) insulin mixture (ANIM) in young children with type 1 diabetes (T1D) treated with twice-daily injections. The trial thus compares not only D vs. NPH, but also flexible, personalized insulin preparations vs. a fixed premixed preparation. RESEARCH DESIGN AND METHODS: This single-center, open-label, randomized trial included 82 children with T1D. Patients stayed on ANIM for 1 yr of optimization of disease management, then were randomized to either ANIM (N = 41) or ADIM (N = 41) for another year. OUTCOMES: Frequency of severe or symptomatic episodes, glycated hemoglobin A1c (HbA1c), and blood glucose (BG) values. RESULTS: Compared with ANIM, ADIM decreases symptomatic hypoglycemia by approximately 2 fold (p < 0.001) and severe hypoglycemia by 7-10 fold (p = 0.04). ADIM somewhat reduced BG variation. Mean HbA1c was comparable on ADIM (7.9 ± 0.8 %; 63 ± 9 mmol/mol) and ANIM (8.2 ± 0.7 %; 66 ± 8 mmol/mol). CONCLUSIONS: Using a free-mixing preparation of aspart and detemir insulin decreases hypoglycemia in young children with type 1 diabetes.

[Growth Hormone-Insulin Growth Factor I (GH-IGF-I) axis and growth]. / L'axe GH-IGF-I dans la croissance.

Normal human linear growth results from an evolutionary process expressing the sum effect of multiple genes. The growth hormone (GH) - insulin like growth factor (IGF)-I axis is one of the main actors in the growth process. Defects in this axis can be responsible for short or tall stature. Short stature is defined as smaller than - 2 standard deviations (SD). It is a very common reason for consultation in pediatrics; indeed, 2.5 % of children are concerned. Multiple causes make diagnosis difficult. In this article, we detail the most common constitutional causes of small size, including those related to a defect in the GH-IGF-I axis. Then, we report, the first results of the clinical and genetic study conducted on 213 patients with gigantism. Tall stature is defined by a height superior to 2 SD. Finally, recent work linking epigenetics and growth - via signaling pathways of GH-IGF-I axis - will be presented.

Vascular placental abnormalities and newborn death in a pregnant diabetic woman with familial partial lipodystrophy type 3: a possible role for peroxisome proliferator-activated receptor γ.

The peroxisome proliferator-activated receptor protein gamma (PPARγ), a nuclear receptor involved in adipocyte differentiation, energy homoeostasis and fat storage, can lead, in rare cases of coding mutations, to familial partial lipodystrophy type 3 (FPLD3) with severe insulin resistance. PPARγ is also highly expressed in the syncytiotrophoblast and extravillous cytotrophoblast cells. It has a key role in trophoblast invasion, as shown by studies in vitro, but its precise role during placentation remains to be elucidated, and fetomaternal outcomes of FPLD3 pregnancies also need to be assessed. This report is of a novel missense heterozygous mutation of PPARγ identified during pregnancy in a young diabetic woman who, at 3weeks of amenorrhoea, prematurely delivered a baby who died 24 h later. Histopathological analysis revealed important vascular placental abnormalities. The presence of the PPARγ mutation in placental tissues in the absence of fetal malformations and maternal hypertension suggests that FPLP3 pregnancies may be at high-risk, especially if the fetus has inherited the mutation. It also supports a physiological role for PPARγ during placentation.

[Post-menopausal ovarian hyperthecosis]. / Hyperthécose ovarienne post-ménopausique.

Ovarian hyperthecosis is infrequent but it represents the first cause of post-menopausal hyperandrogenia. Pathophysiology of ovarian hyperthecosis remains poorly understood but the metabolic syndrome observed in most patients suggests that insulin resistance associated with high, postmenopausal LH levels, might play a role as in polycystic ovarian syndrome. We report here four patients who presented post-menopausal hyperandrogenia. Although high, tumoral, plasma testosterone levels, lack of focused radiological lesions except enlarged ovaries, associated to the metabolic syndrome, suggested ovarian hyperthecosis. Bilateral annexectomy allowed histological confirmation of hyperthecosis showing specific luteinized stromal cells and led to the complete suppression of the inappropriate androgen secretion.