Author:
Beltrand Jacques,Lahlou Najiba,Le Charpentier Tifenn,Sebag Guy,Leka Sofia,Polak Michel,Tubiana-Rufi Nadia,Lacombe Didier,de Kerdanet Marc,Huet Frederic,Robert Jean-Jacques,Chevenne Didier,Gressens Pierre,Lévy-Marchal Claire
Abstract
ContextRecently, in a 4-month proof-of-concept trial, beneficial metabolic effects were reported in non-diabetic children with Berardinelli–Seip congenital lipodystrophy (BSCL); this information prompted us to hypothesize that long-term leptin-replacement therapy might improve or reverse the early complications of the disease in these patients.Patients and methodsA 28-month trial was implemented in eight patients. Efficacy assessment was based on a decrease in serum triglyceride concentrations, and/or a decrease in liver volume and/or an increase in insulin sensitivity of at least 30% respectively. The response was defined as follows: total (3/3 positive criteria), partial (1 or 2/3), or negative (0/3). Anti-leptin antibodies were measured with a radiobinding assay, and a neutralizing effect was assessed in primary cultures of embryonic neurons incubated with an apoptotic agent (N-methyl-d-aspartate) and the patient serum, with or without leptin.ResultsA negative or partial response to treatment was observed in five of eight patients even when leptin dosages were increased. A displaceable leptin binding was detectable in all patients after 2 months of treatment. At 28 months, binding was higher in the patients with a negative response than in the total responders, and it paralleled both the increase in leptin dosage and serum leptin concentrations. Co-incubation of embryonic neurons with serum from two patients with a negative response inhibited the neuroprotective effect of leptin.ConclusionUnder leptin therapy, patients with BSCL may develop a resistance to leptin, which could be partly of immunological origin, blunting the previously reported beneficial effects.
Subject
Endocrinology,General Medicine,Endocrinology, Diabetes and Metabolism
Cited by
50 articles.
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