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Leptin-Replacement Therapy for Lipodystrophy
Open accessAbstract
BACKGROUND: The adipocyte hormone leptin is important in regulating energy homeostasis. Since severe lipodystrophy is associated with leptin deficiency, insulin resistance, hypertriglyceridemia, and hepatic steatosis, we assessed whether leptin replacement would ameliorate this condition. METHODS: Nine female patients (age range, 15 to 42 years; eight with diabetes mellitus) who had lipodystrophy and serum leptin levels of less than 4 ng per milliliter (0.32 nmol per milliliter) received recombinant methionyl human leptin (recombinant leptin). Recombinant leptin was administered subcutaneously twice a day for four months at escalating doses to achieve low, intermediate, and high physiologic replacement levels of leptin. RESULTS: During treatment with recombinant leptin, the serum leptin level increased from a mean (+/- SE) of 1.3 +/- 0.3 ng per milliliter to 11.1 +/- 2.5 ng per milliliter (0.1 +/- 0.02 to 0.9 +/- 0.2 nmol per milliliter). The absolute decrease in the glycosylated hemoglobin value was 1.9 percent (95 percent confidence interval, 1.1 to 2.7 percent; P=0.001) in the eight patients with diabetes. Four months of therapy decreased average triglyceride levels by 60 percent (95 percent confidence interval, 43 to 77 percent; P<0.001) and liver volume by an average of 28 percent (95 percent confidence interval, 20 to 36 percent; P=0.002) in all nine patients and led to the discontinuation of or a large reduction in antidiabetes therapy. Self-reported daily caloric intake and the measured resting metabolic rate also decreased significantly with therapy. Overall, recombinant leptin therapy was well tolerated. CONCLUSIONS: Leptin-replacement therapy improved glycemic control and decreased triglyceride levels in patients with lipodystrophy and leptin deficiency. Leptin deficiency contributes to the insulin resistance and other metabolic abnormalities associated with severe lipodystrophy.
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“Energy expenditure was assessed by indirect calorimetry in all patients before and after leptin treatment and was found to be slightly, but not significantly, lower in all patients after leptin treatment (1,660 ± 108 kcal/day before treatment versus 1,403 ± 62 kcal/day after treatment, P = 0.08).”
From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [5]
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“At the time of the postleptin treatment study, all patients had their antidiabetic medication discontinued (5).”
From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [5]
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“The improved glycemic control could be attributed to a marked increase in their insulin responsiveness, as reflected by an almost fourfold increase in the rate of glucose infusion required to maintain euglycemia during the clamp”
From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [5]
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In the citing paper
“Energy intake was monitored in patient NIH-6, and leptin treatment caused an approximately 50% reduction in energy intake, from 2,017 kcal/day before treatment to 962 kcal/day after 3 months of treatment.”
From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [5]
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“More recently, Arioglu Oral et al. found that human recombinant leptin therapy reduced hyperglycemia and hypertriglyceridemia and increased the rate of glucose disappearance during an intravenous insulin tolerance test in nine lipodystrophic patients (5).”
From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [5]
In the citing paper
“Marked effects of leptin in reducing food intake in lipodystrophic patients and others have also been noted (35).”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [35]
In the citing paper
“Previous studies had shown that leptin treatment can improve glucose homeostasis in patients with lipodystrophy (21) and in children treated with leptin on a long-term basis (8, 9).”
From Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults (2004) · cites this paper as [21]
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“Several lines of evidence from both humans and rodent models suggest that leptin deficiency contributes to insulin resistance and diabetes in this setting (139, 168, 169).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [139]
In the citing paper
“leptin therapy has been examined in several clinical trials in patients with lipodystrophy and these have demonstrated significant improvements in glycemia, dyslipidemia and hepatic steatosis (89, 90, 139, 142).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [139]
In the citing paper
“First in rodent models (5) and then in preliminary short-term studies in humans (6), it was shown that recombinant leptin administration could ameliorate dyslipidemia, insulin resistance, and diabetes.”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [6]
In the citing paper
“Although pair feeding may lead to some improvement in the metabolic profile compared with the ad lib state, it does not correct the metabolic abnormalities to the same extent as leptin replacement.”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [6]
In the citing paper
“Moreover, leptin dramatically improves insulin sensitivity in human lipodystrophy and in lipodystrophic mouse models which are characterized by low serum leptin levels and by severe insulin resistance (Oral et al., 2002; Petersen et al., 2002; Shimomura et al., 1999).”
From Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons (2009) · cites this paper as Oral et al., 2002
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Metadata
- Authors
- Oral, E. A., Simha, V., Ruiz, E., Andewelt, A., Premkumar, A., Snell, P., Wagner, A. J., DePaoli, A. M., Reitman, M. L., Taylor, S. I., Gorden, P., & Garg, A.
- Affiliations
- National Institutes of Health (US)
- The University of Texas Southwestern Medical Center (US)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- Amgen (United States) (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2002-02-21
- Volume
- 346
- Issue
- 8
- Pages
- 570-578
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2084310603
- Cited by
- 1,247
- References
- 44
- Citations by year
- 2026: 18 · 2025: 37 · 2024: 38 · 2023: 41 · 2022: 41 · 2021: 46 · 2020: 31 · 2019: 44 · 2018: 31 · 2017: 55 · 2016: 46 · 2015: 50 · 2014: 57 · 2013: 56 · 2012: 50
- FWCI
- 24.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-54387, R01DK054387)
- National Center for Research Resources (M01RR000633, M01 RR00633)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- leptin replacement therapy, lipodystrophy, leptin deficiency, recombinant human leptin, insulin resistance, hypertriglyceridemia, hepatic steatosis, glycemic control, diabetes mellitus, liver volume, resting metabolic rate, energy intake
- MeSH terms
- Adolescent, Adult, Basal Metabolism, Blood Glucose, Energy Intake, Diabetes Mellitus, Female, Glycated Hemoglobin, Humans, Injections, Subcutaneous, Insulin Resistance, Lipodystrophy, Liver, Liver Function Tests, Prospective Studies, Triglycerides, Leptin, Diabetes Complications
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