Elif Arioglu Oral, M.D., Vinaya Simha, M.D., Elaine Ruiz, N.P., Alexa Andewelt, B.S., Ahalya Premkumar, M.D., Peter Snell, Ph.D., Anthony J. Wagner, Ph.D., Alex M. DePaoli, M.D., Marc L. Reitman, M.D., Ph.D., Simeon I. Taylor, M.D., Ph.D., Phillip Gorden, M.D., and Abhimanyu Garg, M.D.
Background The adipocyte hormone leptin is important in regulatingenergy homeostasis. Since severe lipodystrophy is associatedwith leptin deficiency, insulin resistance, hypertriglyceridemia,and hepatic steatosis, we assessed whether leptin replacementwould ameliorate this condition.
Methods Nine female patients (age range, 15 to 42 years; eightwith diabetes mellitus) who had lipodystrophy and serum leptinlevels of less than 4 ng per milliliter (0.32 nmol per milliliter)received recombinant methionyl human leptin (recombinant leptin).Recombinant leptin was administered subcutaneously twice a dayfor four months at escalating doses to achieve low, intermediate,and high physiologic replacement levels of leptin.
Results During treatment with recombinant leptin, the serumleptin level increased from a mean (±SE) of 1.3±0.3ng per milliliter to 11.1±2.5 ng per milliliter (0.1±0.02to 0.9±0.2 nmol per milliliter). The absolute decreasein the glycosylated hemoglobin value was 1.9 percent (95 percentconfidence interval, 1.1 to 2.7 percent; P=0.001) in the eightpatients with diabetes. Four months of therapy decreased averagetriglyceride levels by 60 percent (95 percent confidence interval,43 to 77 percent; P<0.001) and liver volume by an averageof 28 percent (95 percent confidence interval, 20 to 36 percent;P=0.002) in all nine patients and led to the discontinuationof or a large reduction in antidiabetes therapy. Self-reporteddaily caloric intake and the measured resting metabolic ratealso decreased significantly with therapy. Overall, recombinantleptin therapy was well tolerated.
Conclusions Leptin-replacement therapy improved glycemic controland decreased triglyceride levels in patients with lipodystrophyand leptin deficiency. Leptin deficiency contributes to theinsulin resistance and other metabolic abnormalities associatedwith severe lipodystrophy.
Source Information
From the Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases (E.A.O., E.R., A.A., M.L.R., S.I.T., P.G.), and the Clinical Center (A.P.), National Institutes of Health, Bethesda, Md.; the University of Texas Southwestern Medical Center at Dallas, Dallas (V.S., P.S., A.G.); and Amgen, Thousand Oaks, Calif. (A.J.W., A.M.D.).
Address reprint requests to Dr. Oral at the National Institute of Diabetes and Digestive and Kidney Diseases, Diabetes Branch, Bldg. 10, Rm. 8D20, Bethesda, MD 20892-1770, or at elif_arioglu{at}nih.gov.
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