Background: Lack of leptin is implicated in insulin resistance and other metabolic abnormalities in generalized lipodystrophy, however, the efficacy, safety and underlying mechanisms of leptin-replacement therapy in patients with generalized lipodystrophy remain unclear.

Methods: Seven Japanese patients with generalized lipodystrophy, two acquired and five congenital type, were treated with the physiologic replacement dose of recombinant leptin during an initial four-month hospitalization followed by out-patient follow up for up to 36 months.

Results: The leptin-replacement therapy with the twice-daily injection dramatically improved fasting glucose (mean ± SE: 172 ± 20 to 120 ± 12 mg/dl, P < 0.05) and triglyceride levels (mean ± SE: 700 ± 272 to 260 ± 98 mg/dl, P < 0.05) within one week. The leptin-replacement therapy reduced insulin resistance evaluated by euglycemic clamp method, and augmented insulin secretion at glucose tolerance test with different responses between acquired and congenital types. Improvement of the fatty liver was also observed. The efficacy and safety of the once-daily injection were comparable to those of the twice-daily injection. The leptin-replacement therapy ameliorated macro- and micro-albuminuria and showed no deterioration of neuropathy and retinopathy of these patients. The leptin-replacement therapy is beneficial to diabetic complications and lipodystrophic ones. Two patients developed anti-leptin antibodies but not neutralizing antibodies. The therapy was well tolerated and its effects were maintained for up to 36 months without any notable adverse effects such as hypoglycemia, high blood pressure or reduction of bone mineral density.

Conclusions: The present study demonstrates the efficacy and safety of the long-term leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy.