Leptin therapy for partial lipodystrophy linked to a PPAR-gamma mutation.
OBJECTIVE
Partial lipodystrophy (PL) is most commonly characterized by loss of subcutaneous fat in the extremities with preservation of truncal fat and is associated with insulin resistance, diabetes and hyperlipidaemia. Recombinant human leptin (r-metHuLeptin) therapy has been shown to be effective in treating metabolic abnormalities associated with congenital or acquired generalized lipodystrophy and PL associated with lamin A/C (LMNA) gene mutations or highly active antiretroviral therapy (HAART). Our aim was to assess the effectiveness of leptin therapy in treating metabolic complications of PL associated with heterozygous peroxisome proliferator activated receptor gamma (PPARG) mutations. This is the first report to detail the clinical response of a patient with PL due to a PPARG mutation treated with r-metHuLeptin.


METHODS
A 36-year-old female with PL associated with a heterozygous PPARG mutation complicated by poorly controlled diabetes and severe, refractory hypertriglyceridaemia was enrolled in a National Institutes of Health (NIH) protocol to evaluate the role of r-metHuLeptin in lipodystrophy. The patient received escalating doses of r-metHuLeptin until a dose 0.12 mg/kg/day was reached. Metabolic parameters, including serum chemistries, fasting blood glucose, glycated haemoglobin (HbA1c), lipid profile, an oral glucose tolerance test (OGTT), an insulin tolerance test (ITT), liver volume, percentage body fat and energy expenditure were followed at regular time intervals over 18 months of therapy.


RESULTS
Eighteen months of r-MetHuLeptin therapy was associated with a marked improvement in glucose homeostasis as evidenced by normalization of the fasting blood glucose (baseline = 8.3 mmol/l; 18 months = 4.9 mmol/l), lowering of HbA1c (baseline = 9.9%; 18 months = 7.2%) and improved tolerance to an oral glucose load. In addition, a striking amelioration in the patient's refractory, severe hypertriglyceridaemia was observed (baseline = 21.15 mmol/l; 18 months = 5.96 mmol/l).


CONCLUSIONS
r-MetHuLeptin is effective in treating metabolic complications associated with PL due to PPARG mutations. In the context of previously published work, our findings suggest that the response to r-MetHuLeptin is independent of the aetiology in lipodystrophy.
Guettier
Jean-Marc
JM
Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Park
Jean Y
JY
Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Cochran
Elaine K
EK
Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Poitou
Christine
C
INSERM, U872 Equipe 7 Paris; Université Pierre et Marie Curie-Paris6, Centre de Recherche des Cordeliers, UMRS872, Paris.
Basdevant
Arnaud
A
INSERM, U872 Equipe 7 Paris; Université Pierre et Marie Curie-Paris6, Centre de Recherche des Cordeliers, UMRS872, Paris.|AP/HP, Department d'Endocrinologie, hôpital Pitié Salpétrière, Paris.
Meier
Muriel
M
INSERM, U680, Paris.|Université Pierre et Marie Curie-Paris6, Faculté de Médecine, UMRS680, Paris, France.
Clément
Karine
K
INSERM, U872 Equipe 7 Paris; Université Pierre et Marie Curie-Paris6, Centre de Recherche des Cordeliers, UMRS872, Paris.|AP/HP, Department d'Endocrinologie, hôpital Pitié Salpétrière, Paris.
Magré
Jocelyne
J
INSERM, U680, Paris.|Université Pierre et Marie Curie-Paris6, Faculté de Médecine, UMRS680, Paris, France.
Gorden
Phillip
P
Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
D000328:Adult; D005260:Female; D006801:Humans; D020738:Leptin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008060:Lipodystrophy / Q000188:drug therapy* / Q000235:genetics*; D047495:PPAR gamma / Q000235:genetics*; D016896:Treatment Outcome
D020738:Leptin; D047495:PPAR gamma; C122136:recombinant methionyl human leptin