Efficacy of metreleptin in obese patients with type 2 diabetes: Cellular and molecular pathways underlying leptin tolerance
Open accessAbstract
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 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. CONCLUSIONS: 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.
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In adults with hyperleptinemia and leptin resistance, administration of metreleptin showed marginal benefits with a reduction in glycated hemoglobin.
“In adults with hyperleptinemia and leptin resistance administration of metreleptin showed marginal benefits with a reduction in glycated hemoglobin [43].”
From Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions (2021) · cites this paper as [43]
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Obesity-Related Asthma: Immune Regulation and Potential Targeted Therapies
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Intranasal Neuropeptide Administration To Target the Human Brain in Health and Disease
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New advances in the treatment of generalized lipodystrophy: role of metreleptin
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Cellular and Molecular Activities of IP6 in Disease Prevention and Therapy
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Leptin but not adiponectin is related to type 2 diabetes mellitus in obese adolescents
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Metreleptin and generalized lipodystrophy and evolving therapeutic perspectives
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Leptin-activity blockers: development and potential use in experimental biology and medicine
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Leptin attenuates oxidative stress and neuronal apoptosis in hyperglycemic condition
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Therapeutic use of recombinant methionyl human leptin
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RetractedLeptin in Relation to the Lipodystrophy-Associated Metabolic Syndrome
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Glucose-lowering therapies in type 2 diabetes: Opportunities and challenges for peptides
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Current and Emerging Treatment Options in Diabetes Care
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Neuroimaging and neuroendocrine insights into food cravings and appetite interventions in obesity
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Diurnal Variation of Sweet Taste Recognition Thresholds Is Absent in Overweight and Obese Humans
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- Authors
- Moon, H.-S., Matarese, G., Brennan, A. M., Chamberland, J. P., Liu, X., Fiorenza, C. G., Mylvaganam, G. H., Abanni, L., Carbone, F., Williams, C. J., De Paoli, A. M., Schneider, B. E., & Mantzoros, C. S.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Institute for Experimental Endocrinology and Oncology (IT)
- Amgen, Inc., Thousand Oaks, California
- Corresponding author
- Mantzoros, Christos S.
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2011-05-21
- Volume
- 60
- Issue
- 6
- Pages
- 1647-1656
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3114380
- OpenAlex
- W2169893368
- Cited by
- 151
- References
- 28
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 7 · 2023: 14 · 2022: 9 · 2021: 10 · 2020: 5 · 2019: 6 · 2018: 12 · 2017: 12 · 2016: 9 · 2015: 12 · 2014: 16 · 2013: 17 · 2012: 8
- FWCI
- 11.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- U.S. Department of Veterans Affairs
- Amgen
- Amylin Pharmaceuticals
- Beth Israel Deaconess Medical Center
- Harvard Catalyst (M01-RR-01032)
- National Institutes of Health (DK58785)
- National Institute on Aging (R01AG032030, AG032030.)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK079929, DK-081913, R01DK058785, F32DK064550, R56DK058785, DK 79929, DK 58785, K24DK081913, F32-DK64550-01A1)
- National Center for Research Resources (M01-RR-01032, M01RR001032, UL1RR025758)
- FP7 Ideas: European Research Council (202579)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- metreleptin, leptin resistance, type 2 diabetes, obesity, leptin signaling, endoplasmic reticulum stress, STAT3 phosphorylation, adipocytes, HbA1c, caloric restriction, weight loss, adipose tissue, inflammatory markers
- MeSH terms
- Adult, Body Weight, Cells, Cultured, Diabetes Mellitus, Type 2, Double-Blind Method, Enzyme-Linked Immunosorbent Assay, Female, Glycated Hemoglobin, Humans, Immunohistochemistry, Male, Middle Aged, Obesity, Phosphorylation, Blotting, Western, Signal Transduction, Adipocytes, Leptin, STAT3 Transcription Factor, Receptors, Leptin
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