{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T00:47:08Z","timestamp":1793234828523,"version":"4.5.0"},"reference-count":27,"publisher":"American Diabetes Association","issue":"6","license":[{"start":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T00:00:00Z","timestamp":1630022400000},"content-version":"vor","delay-in-days":3751,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,6,1]]},"abstract":"<jats:sec>\n                  <jats:title>OBJECTIVE<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                  <jats:p>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\u2013controlled, randomized trial. We then performed detailed interventional and mechanistic signaling studies in humans in vivo, ex vivo, and in vitro.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>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 \u00b1 0.93\u20137.96 \u00b1 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 \u223c50 ng\/mL. Consistent with clinical observations, all metreleptin signaling pathways studied in human adipose tissue and peripheral blood mononuclear cells were saturable at \u223c50 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/db10-1791","type":"journal-article","created":{"date-parts":[[2011,5,26]],"date-time":"2011-05-26T21:55:04Z","timestamp":1306446904000},"page":"1647-1656","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":132,"title":["Efficacy of Metreleptin in Obese Patients With Type 2 Diabetes: Cellular and Molecular Pathways Underlying Leptin Tolerance"],"prefix":"10.2337","volume":"60","author":[{"given":"Hyun-Seuk","family":"Moon","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Matarese","sequence":"additional","affiliation":[{"name":"Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Conisglio Nazionale delle Ricerche c\/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universit\u00e0 di Napoli Federico II, Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aoife M.","family":"Brennan","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Chamberland","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowen","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina G.","family":"Fiorenza","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geetha H.","family":"Mylvaganam","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Abanni","sequence":"additional","affiliation":[{"name":"Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Conisglio Nazionale delle Ricerche c\/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universit\u00e0 di Napoli Federico II, Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fortunata","family":"Carbone","sequence":"additional","affiliation":[{"name":"Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Conisglio Nazionale delle Ricerche c\/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universit\u00e0 di Napoli Federico II, Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine J.","family":"Williams","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical 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