Leptin therapy for partial lipodystrophy linked to a PPAR-gamma mutation

Abstract

Aims/hypothesis: 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).

Conclusion: 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.

Fig. 1

Detection of a heterozygous PPARG mutation that cosegregates with insulin resistance and dyslipidaemia (a) Direct sequencing of genomic DNA from the proband. The asterisk indicates the single base pair (C to T) substitution that results in an arginine to cysteine exchange at codon 425 of PPAR-γ2. (b) Family pedigree and electrophoretic pattern of digested PCR fragment containing the heterozygous R425C mutation demonstrating cosegregation of metabolic abnormalities with the mutation. Carriers of the PPARG mutation have diabetes and dyslipidaemia as indicated by grey fill. The proband is indicated by black fill and an asterisk. M, molecular weight marker; ND, nondigested PCR product; C1 and C2, digested PCR products from controls 1 and 2; J, A, D, F and H, digested PCR products from the proband and first-degree relatives.

Fig. 2

Clinical features of the proband Photographs show partial loss of fat affecting the upper (a) and lower extremities as well as the gluteal regions (b and c). Facial (a), truncal and mammary fat (d) is present. Hyperandrogenism is evidenced by muscular hypertrophy in the lower limbs (b and c) and abdomen (d) as well as by coarse terminal hair on the chest and lower abdomen (d). Features of insulin resistance include the presence of acanthosis nigricans in the neck and axilla (a). Skin changes consistent with a previous history of eruptive xanthomas are also apparent (a and c).

Fig. 3

Clinical course on r-metHuLeptin Fasting glucose, HbA1c and triglycerides levels over 18 months of leptin therapy. Medications used to treat both diabetes and dyslipidaemia prior to the start of leptin therapy are indicated (doses: miglitol 100 mg/day, glimepiride 6 mg/day, rosiglitazone 8 mg/day, ciprofibrate 100 mg/day). No medication changes besides leptin dose adjustments were made during this time period.

Fig. 4

Insulin tolerance test (ITT). Fasting glucose response to intravenous insulin (0·2 U/kg) at baseline (filled diamonds) and 12 months (filled squares) of r-metHuLeptin treatment. Slope of the response and absolute decrease in serum glucose at 12 months suggest improvement in insulin responsiveness. Calculated rates of glucose disposal (K_ITT) at baseline and 12 months were 1·6%/min and 4·8%/min, respectively. Normal fasting blood glucose precluded testing at 18 months.

Fig. 5

Oral glucose tolerance test (OGTT). Glucose and insulin response to 1·75 g/kg oral dextrose challenge. Improved glucose tolerance and a robust insulin response are seen after 18 months of r-metHuLeptin treatment (filled diamonds).