Context: Acquired generalized lipodystrophy (AGL) is marked by severe insulin resistance and hypertriglyceridemia. Rarely, AGL and type 1 diabetes (T1D) coexist.

Objective: To describe the response to leptin therapy in patients with coexisting AGL and T1D, and to document the autoimmune diseases associated with AGL.

Design: Open-label prospective study.

Setting: Clinical Research Center of the National Institutes of Health.

Patients: 50 patients with generalized or partial lipodystrophy (acquired or congenital); 2 patients had both AGL and T1D.

Intervention: 12 months of recombinant human leptin administration to achieve high normal serum concentrations.

Results: 2 patients had both AGL and T1D. The first was diagnosed with T1D at age 8 years. Beginning at age 11 years, he developed generalized lipodystrophy, elevated transaminases, and poor glycemic control (HbA_1c 10.7%) despite markedly increased insulin requirements (3.3–5 U/kg/day). Further evaluation revealed hypoleptinemia and hypertriglyceridemia. At age 15 years, leptin therapy was initiated and after 1 year, his insulin requirements fell to 1 U/kg/day, his glycemic control improved (HbA_1c 8.4%), and both his triglycerides and transaminases normalized. The second patient developed concurrent AGL and T1D at age 6 years. Despite insulin doses of up to 32 U/kg/day, she developed poor glycemic control (HbA_1c 10.6%), hypertriglyceridemia (2984 mg/dl), elevated transaminases, and nonalcoholic steatohepatitis. At age 13 years, leptin therapy was started and after 1 year, her glycemic control improved (HbA_1c 7.3%) and her insulin requirements decreased (17 U/kg/day). Her triglycerides remained elevated, but were improved (441 mg/dL).

Conclusions: Long-term recombinant leptin therapy is effective in treating the insulin resistance of patients with the unusual combination of T1D and AGL.