Efficacy of Metreleptin in Obese Patients With Type 2 Diabetes: Cellular and Molecular Pathways Underlying Leptin Tolerance
- Hyun-Seuk Moon1,
- Giuseppe Matarese2,
- Aoife M. Brennan1,
- John P. Chamberland1,
- Xiaowen Liu1,
- Christina G. Fiorenza1,
- Geetha H. Mylvaganam1,
- Luisa Abanni2,
- Fortunata Carbone2,
- Catherine J. Williams1,
- Alex M. De Paoli3,
- Benjamin E. Schneider4 and
- Christos S. Mantzoros1,5⇓
- 1Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
- 2Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Conisglio Nazionale delle Ricerche c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Napoli, Italy
- 3Amgen, Inc., Thousand Oaks, California
- 4Division of Minimally Invasive Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
- 5Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts
- Corresponding author: Christos S. Mantzoros, .
OBJECTIVE Metreleptin has been efficacious in improving metabolic control in patients with lipodystrophy, but its efficacy has not been tested in obese patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS We studied the role of leptin in regulating the endocrine adaptation to long-term caloric deprivation and weight loss in obese diabetic subjects over 16 weeks in the context of a double-blinded, placebo–controlled, randomized trial. We then performed detailed interventional and mechanistic signaling studies in humans in vivo, ex vivo, and in vitro.
RESULTS In obese patients with diabetes, metreleptin administration for 16 weeks did not alter body weight or circulating inflammatory markers but reduced HbA1c marginally (8.01 ± 0.93–7.96 ± 1.12, P = 0.03). Total leptin, leptin-binding protein, and antileptin antibody levels increased, limiting free leptin availability and resulting in circulating free leptin levels of ∼50 ng/mL. Consistent with clinical observations, all metreleptin signaling pathways studied in human adipose tissue and peripheral blood mononuclear cells were saturable at ∼50 ng/mL, with no major differences in timing or magnitude of leptin-activated STAT3 phosphorylation in tissues from male versus female or obese versus lean humans in vivo, ex vivo, or in vitro. We also observed for the first time that endoplasmic reticulum (ER) stress in human primary adipocytes inhibits leptin signaling.
CONCLUSIONS In obese patients with diabetes, metreleptin administration did not alter body weight or circulating inflammatory markers but reduced HbA1c marginally. ER stress and the saturable nature of leptin signaling pathways play a key role in the development of leptin tolerance in obese patients with diabetes.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db10-1791/-/DC1.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
- Received December 28, 2010.
- Accepted March 16, 2011.
- © 2011 by the American Diabetes Association.
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