Metreleptin-mediated improvements in insulin sensitivity are independent of food intake in humans with lipodystrophy
Rebecca J. Brown, Areli Valencia, Megan Startzell, Elaine Cochran, Peter J. Walter, H. Martin Garraffo, Hongyi Cai, Ahmed M. Gharib, Ronald Ouwerkerk, Amber B. Courville, Shanna Bernstein, Robert J. Brychta, Kong Y. Chen, Mary Walter, Sungyoung Auh, Phillip Gorden
Rebecca J. Brown, Areli Valencia, Megan Startzell, Elaine Cochran, Peter J. Walter, H. Martin Garraffo, Hongyi Cai, Ahmed M. Gharib, Ronald Ouwerkerk, Amber B. Courville, Shanna Bernstein, Robert J. Brychta, Kong Y. Chen, Mary Walter, Sungyoung Auh, Phillip Gorden
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Clinical Research and Public Health Endocrinology Metabolism

Metreleptin-mediated improvements in insulin sensitivity are independent of food intake in humans with lipodystrophy

Abstract

BACKGROUND. Recombinant leptin (metreleptin) ameliorates hyperphagia and metabolic abnormalities in leptin-deficient humans with lipodystrophy. We aimed to determine whether metreleptin improves glucose and lipid metabolism in humans when food intake is held constant. METHODS. Patients with lipodystrophy were hospitalized for 19 days, with food intake held constant by a controlled diet in an inpatient metabolic ward. In a nonrandomized, crossover design, patients previously treated with metreleptin (n = 8) were continued on metreleptin for 5 days and then taken off metreleptin for the next 14 days (withdrawal cohort). This order was reversed in metreleptin-naive patients (n = 14), who were reevaluated after 6 months of metreleptin treatment on an ad libitum diet (initiation cohort). Outcome measurements included insulin sensitivity by hyperinsulinemic-euglycemic clamp, fasting glucose and triglyceride levels, lipolysis measured using isotopic tracers, and liver fat by magnetic resonance spectroscopy. RESULTS. With food intake constant, peripheral insulin sensitivity decreased by 41% after stopping metreleptin for 14 days (withdrawal cohort) and increased by 32% after treatment with metreleptin for 14 days (initiation cohort). In the initiation cohort only, metreleptin decreased fasting glucose by 11% and triglycerides by 41% and increased hepatic insulin sensitivity. Liver fat decreased from 21.8% to 18.7%. In the initiation cohort, changes in lipolysis were not independent of food intake, but after 6 months of metreleptin treatment on an ad libitum diet, lipolysis decreased by 30% (palmitate turnover) to 35% (glycerol turnover). CONCLUSION. Using lipodystrophy as a human model of leptin deficiency and replacement, we show that metreleptin improves insulin sensitivity and decreases hepatic and circulating triglycerides and that these improvements are independent of its effects on food intake. TRIAL REGISTRATION. ClinicalTrials.gov NCT01778556 FUNDING. This research was supported by the intramural research program of the NIDDK.

Authors

Rebecca J. Brown, Areli Valencia, Megan Startzell, Elaine Cochran, Peter J. Walter, H. Martin Garraffo, Hongyi Cai, Ahmed M. Gharib, Ronald Ouwerkerk, Amber B. Courville, Shanna Bernstein, Robert J. Brychta, Kong Y. Chen, Mary Walter, Sungyoung Auh, Phillip Gorden

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Figure 4

Decreases in triglycerides and liver fat were independent of food intake in humans with lipodystrophy while on metreleptin.

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Decreases in triglycerides and liver fat were independent of food intake...
(A) Triglyceride levels in leptin initiation subjects and leptin withdrawal subjects while off, on, or after 6 months on metreleptin. The dotted line indicates the upper limit of normal (150 mg/dl). (B) Liver fat percentage measured by MRS. The dotted line indicates the upper limit of normal (5%). (C) Glycerol Ra in plasma. (D) Palmitate Ra in plasma. Data shown represent the mean ± SEM or the geometric mean ± 95% CI (triglycerides). The study was powered to detect differences between the off- versus on-leptin state (black versus white bars) during constant food intake. *P < 0.05, by 2-tailed t test or Wilcoxon matched pairs, signed-rank test between each pair of time points, based on data distribution. #P < 0.05, by linear mixed model for all 3 time points, with post-hoc pairwise Bonferroni correction in the leptin initiation cohort.