[Fluticasone propionate in children and infants with asthma]. / Propionate de fluticasone dans l'asthme de l'enfant et du nourrisson.

The known efficacy of fluticasone propionate in adults, comparable at half-dosage of corticosteroids has been validated by the market authorization (MA) and by the national and international guidelines for beclomethasone. This could be partly explained by its pharmacological properties, affinity for glucocorticosteroid receptors, lung deposition and lipophilicity. The limited systemic adverse events is due to its low bioavailability, optimal hepatic clearance, high plasma protein binding. The efficacy in asthmatic children has been confirmed in clinical studies showing a "plateau" efficacy between 100 and 200 microg/d for the majority of children. Most children are controlled by such dosages: the added value of increasing posology on asthma control exists but is small. A high off-label posology does not allow more quickly asthma control and therefore is not justified. A twice daily dosing is more efficient, particularly for initiation of maintenance therapy, than a once daily dosing. A literature survey confirms that, at MA recommended daily doses in children (100-200 microg), fluticasone propionate has no clinically significant effect either on hypothalamic-pituitary-adrenal (HPA) axis (basal function or stimulation tests), bone or growth velocity. However, high daily doses (higher to 500 microg/day) for long periods expose to systemic adverse effects with measurable consequences on growth rate, bone density (decreasing biochemical makers of bone formation) and HPA function. Several cases of adrenal insufficiency that may have led to acute adrenal crisis have been reported in 4- to 10-year-old children receiving fluticasone propionate in doses between 500 to 2000 microg daily. In case of surgery or infection, a preventive treatment of adrenal insufficiency with hydrocortisone should be proposed for children treated for more than 6 months with such high daily doses. Such children need definitely an advice from paediatricians specialized in chest diseases as well as in endocrinology. It is important to recall that the clinical benefit of daily doses of inhaled corticosteroids higher than recommended is low and that the good use of inhaled corticosteroids particularly in children lays on the careful search of the minimal efficient daily doses.

Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy.

Sporadic persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or nesidioblastosis is a heterogeneous disorder characterized by profound hypoglycemia due to inappropriate hypersecretion of insulin. An important diagnostic goal is to distinguish patients with a focal hyperplasia of islet cells of the pancreas (FoPHHI) from those with a diffuse abnormality of islets (DiPHHI) because management strategies differ significantly. 16 infants with sporadic PHHI resistant to diazoxide and who underwent pancreatectomy were investigated. Selective pancreatic venous sampling coupled with peroperative surgical examination and analysis of extemporaneous frozen sections allowed us to identify 10 cases with FoPHHI and 6 cases with DiPHHI. We show here that in cases of FoPHHI, but not those of DiPHHI, there was specific loss of maternal alleles of the imprinted chromosome region 11p15 in cells of the hyperplastic area of the pancreas but not in normal pancreatic cells. This somatic event is consistent with a proliferative monoclonal lesion. It involves disruption of the balance between monoallelic expression of several maternally and paternally expressed genes. Thus, we provide the first molecular explanation of the heterogeneity of sporadic forms of PHHI such that it is possible to perform only partial pancreatectomy, limited to the focal somatic lesion, so as to avoid iatrogenic diabetes in patients with focal adenomatous hyperplasia.

The development of hyperglycaemia in patients with insulin-resistant generalized lipoatrophic syndromes.

Insulin resistance is present in patients suffering from lipoatrophic syndromes long before the onset of diabetes mellitus. Thus, the decreased peripheral glucose disposal may not be the only mechanism of hyperglycaemia. The kinetic parameters of glucose homeostasis were evaluated in six young females aged 15, 16, 18, 19 and 24 years with generalized lipoatrophy; one patient was studied both at 12 and 15 years. Insulin resistance was evaluated in vivo by the hyperinsulinaemic euglycaemic clamp (3-4 insulin infusion rates from 1 to 100 mU/kg.min). All patients showed a rightward shift of the dose-response curve, indicating decreased insulin sensitivity. In two patients, maximal glucose disposal was moderately decreased, while in five patients it was dramatically reduced (3.6-6.9 mg/kg.min). Fasting plasma glucose was variable (4.3-18.3 mmol/l) and did not correlate with peripheral glucose disposal rates. Hepatic glucose production, measured by infusion of [6,6-2H] glucose, varied from 1.7 to 8.3 mg/kg.min and was significantly correlated with fasting plasma glucose. The overproduction of glucose despite basal hyperinsulinism suggested hepatic insulin resistance, which was confirmed by the abnormal response to constant unlabelled glucose infusion (2 mg/kg.min) in five patients. In conclusion, impaired glucose tolerance seems to develop in generalized lipoatrophy with aggravated peripheral insulin resistance. The present data show that fasting hyperglycaemia is mainly the consequence of increased hepatic glucose production.

Insulin resistance and excess weight in adolescent insulin-dependent diabetic girls.

Insulin dependent diabetic adolescent girls show a tendency towards excess weight. The relationship between insulin resistance and body mass index (BMI) was investigated in 23 Type 1 adolescents aged 13-20 yr. These patients body mass indexes spanned from 19.8 to 30.5. Excess weight was evaluated using Z-scores, corrected for age with reference to french standards. 9 patients with a Z-score greater than 2 were considered as obese. Insulin sensibility was measured using the hyperinsulinaemic euglycaemic clamp (insulin infusion rate, 1 mU kg-1 min-1). The mean glucose infusion rate during the clamp was low in the diabetic girls (2.29 +/- 1.35 mg kg-1 min-1), confirming the existence of insulin resistance. However, the degree of insulin resistance was not correlated with the excess in weight (glucose infusion rate, 2.23 +/- 1.24 vs 2.33 +/- 1.46 mg kg-1 min-1 in the obese and the non-obese patients, respectively). None of the factors which influence on insulin sensitivity could explain this lack of correlation, the obese patients showing greater daily insulin doses (1.36 +/- 0.22 vs 1.22 +/- 0.25 unit kg-1 day-1) and worse metabolic control (Hba1C, 10.9 +/- 1.4 vs 10.2 +/- 2.0%). Insulin resistance was significantly correlated with free fatty acid levels during the clamp.