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

Gilberto Paz-Filho, Karin Esposito, Barry Hurwitz, Anil Sharma, Chuanhui Dong, Victor Andreev, Tuncay Delibasi, Halil Erol, Alejandro Ayala, Ma Li Wong, Julio Licinio

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)E1401-E1408
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number6
StatePublished - Dec 2008


  • Euglycemic hyperinsulinemic clamp
  • Homeostatic model assessment
  • Recombinant methionyl human leptin

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism


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