Efficacy of Metreleptin in Obese Patients With Type 2 Diabetes: Cellular and Molecular Pathways Underlying Leptin Tolerance

• Published in: Diabetes (New York, N.Y.) Vol. 60; no. 6; pp. 1647 - 1656
• Main Authors: Moon, Hyun-Seuk, Matarese, Giuseppe, Brennan, Aoife M., Chamberland, John P., Liu, Xiaowen, Fiorenza, Christina G., Mylvaganam, Geetha H., Abanni, Luisa, Carbone, Fortunata, Williams, Catherine J., De Paoli, Alex M., Schneider, Benjamin E., Mantzoros, Christos S.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.06.2011
• Subjects: Adipocytes - drug effects; Adipocytes - metabolism; Adult; Biological and medical sciences; Biopsy; Blotting, Western; Body fat; Body Weight - drug effects; Cells, Cultured; Diabetes; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Diabetes. Impaired glucose tolerance; Diet; Double-Blind Method; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endoplasmic reticulum; Enzyme-Linked Immunosorbent Assay; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Glycated Hemoglobin - metabolism; Humans; Immunohistochemistry; Insulin resistance; Leptin - analogs & derivatives; Leptin - blood; Leptin - immunology; Leptin - therapeutic use; Male; Medical sciences; Metabolic diseases; Metabolism; Middle Aged; Obesity; Obesity - blood; Obesity - drug therapy; Phosphorylation - drug effects; Receptors, Leptin - blood; Research design; s in Diabetes; Signal Transduction - drug effects; STAT3 Transcription Factor - metabolism; Weight control; Endocrinopathy; Type 2 diabetes; Human; Obesity; Leptin; Nutrition disorder; Tolerance; Metabolic diseases; Adipokine; Nutritional status
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db10-1791

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. 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. In obese patients with diabetes, metreleptin administration for 16 weeks did not alter body weight or circulating inflammatory markers but reduced HbA(1c) 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. In obese patients with diabetes, metreleptin administration did not alter body weight or circulating inflammatory markers but reduced HbA(1c) 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.