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Changes in insulin sensitivity during leptin replacement therapy in leptin-deficient patients

¹Center for Pharmacogenomics, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida; ²Serviço de Endocrinologia e Metabologia da Universidade Federal de Parana, Curitiba, Brazil; ³Behavioral Medicine Research Center, University of Miami, Miami, Florida; and ⁴Semel Institute, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California

Submitted 20 May 2008 ; accepted in final form 8 October 2008

Leptin replacement rescues the phenotype of morbid obesity and hypogonadism in leptin-deficient adults. However, leptin's effects on insulin resistance are not well understood. Our objective was to evaluate the effects of leptin on insulin resistance. Three leptin-deficient adults (male, 32 yr old, BMI 23.5 kg/m²; female, 42 yr old, BMI 25.1 kg/m²; female, 46 yr old, BMI 31.7 kg/m²) with a missense mutation of the leptin gene were evaluated during treatment with recombinant methionyl human leptin (r-metHuLeptin). Insulin resistance was determined by euglycemic hyperinsulinemic clamps and by oral glucose tolerance tests (OGTTs), whereas patients were on r-metHuLeptin and after treatment was interrupted for 2–4 wk in the 4th, 5th, and 6th years of treatment. At baseline, all patients had normal insulin levels, C-peptide, and homeostatic model assessment of insulin resistance index, except for one female diagnosed with type 2 diabetes. The glucose infusion rate was significantly lower with r-metHuLeptin (12.03 ± 3.27 vs. 8.16 ± 2.77 mg·kg^–1·min^–1, P = 0.0016) but did not differ in the 4th, 5th, and 6th years of treatment when all results were analyzed by a mixed model [F(1,4) = 0.57 and P = 0.5951]. The female patient with type 2 diabetes became euglycemic after treatment with r-metHuLeptin and subsequent weight loss. The OGTT suggested that two patients showed decreased insulin resistance while off treatment. During an off-leptin OGTT, one of the patients developed a moderate hypoglycemic reaction attributed to increased posthepatic insulin delivery and sensitivity. We conclude that, in leptin-deficient adults, the interruption of r-metHuLeptin decreases insulin resistance in the context of rapid weight gain. Our results suggest that hyperleptinemia may contribute to mediate the increased insulin resistance of obesity.

recombinant methionyl human leptin; euglycemic hyperinsulinemic clamp; homeostatic model assessment

This article has been cited by other articles:

				E. A. Oral and C. Burant Leptin and insulin resistance: good, bad, or still unclear? Am J Physiol Endocrinol Metab, February 1, 2009; 296(2): E394 - E395. [Full Text] [PDF]

				G. Paz-Filho, K. Esposito, B. Hurwitz, A. Sharma, C. Dong, V. Andreev, T. Delibasi, H. Erol, A. Ayala, M.-L. Wong, et al. Leptin and insulin sensitivity: reply to Oral and Burant Am J Physiol Endocrinol Metab, February 1, 2009; 296(2): E396 - E396. [Full Text] [PDF]