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Bone mineral content in patients with congenital generalized lipodystrophy is unaffected by metreleptin replacement therapy.

ABSTRACT: Leptin alters bone and mineral metabolism in rodents, but this has not been verified in humans. PATIENTS with congenital generalized lipodystrophy (CGL) have low leptin due to deficient adipose mass and serve as models of leptin deficiency and replacement.To study the effects of recombinant human methionyl leptin (metreleptin) on bone mineral content (BMC) and mineral metabolism.An open-label nonrandomized study at the National Institutes of Health.Thirty-one patients with CGL (ages 4.3 to 46.7 y).Metreleptin (0.06 to 0.24 mg/kg/d) for 6 months to 11 years.BMC was assessed by dual-energy x-ray absorptiometry. SD scores (SDS) for BMC were calculated based on height, race, sex, and age using population normative data. Calcium, phosphorus, PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were measured at baseline and follow-up.At baseline, patients demonstrated significantly increased total body less head BMC (mean SDS, 1.8 ± 0.7), height (mean SDS, 1.3 ± 1.3), and lean mass index, defined as lean body mass per height squared (mean SDS, 1.5 ± 0.83), vs population normative data. No change in total body less head BMC was observed after metreleptin. Lean mass index decreased with metreleptin. Serum calcium decreased with metreleptin, but remained within normal limits. No changes were seen in phosphorus, PTH, or vitamin D.In contrast to rodent models, CGL patients have increased BMC in the leptin-deficient state, which does not change with leptin replacement. The high BMC in these patients is partially explained by high lean mass and tall stature.

SUBMITTER: Christensen JD

PROVIDER: S-EPMC4121033 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Bone mineral content in patients with congenital generalized lipodystrophy is unaffected by metreleptin replacement therapy.

Christensen John D JD Lungu Andreea O AO Cochran Elaine E Collins Michael T MT Gafni Rachel I RI Reynolds James C JC Rother Kristina I KI Gorden Phillip P Brown Rebecca J RJ

The Journal of clinical endocrinology and metabolism 20140729 8

<h4>Context</h4>Leptin alters bone and mineral metabolism in rodents, but this has not been verified in humans. PATIENTS with congenital generalized lipodystrophy (CGL) have low leptin due to deficient adipose mass and serve as models of leptin deficiency and replacement.<h4>Objective</h4>To study the effects of recombinant human methionyl leptin (metreleptin) on bone mineral content (BMC) and mineral metabolism.<h4>Design and setting</h4>An open-label nonrandomized study at the National Institu ...[more]

PMID: 25070319

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Project description:Abstract Background: Congenital generalized lipodystrophy (CGL) is a rare inherited disease characterized by widespread loss of subcutaneous fat and severe metabolic abnormalities. Metreleptin, a synthetic analog of leptin, is a treatment modality that has been shown to decrease fasting triglycerides, fasting glucose, and HbA1c. Metformin use in infants has only been described in a few case reports of CGL and Donohue syndrome (insulin receptor mutation), and there is no established dosing for this age group. We report metreleptin, insulin, and metformin use in an infant with type 1 CGL who presented with marked hypertriglyceridemia, hypoleptinemia, hyperglycemia, and transaminitis. Clinical Case: A 2-month-old African American female born SGA at term presented to her primary care physician for a well child check where she was noted to have poor weight gain, hyperphagia, and abdominal distension. She was subsequently admitted for failure to thrive with weight z-score of -2.17 and length z-score of -0.15. Initial labs were notable for triglycerides of 5,167 mg/dL, HDL 10 mg/dL, blood glucose 324 mg/dL, ALT 212 units/L, AST 215 units/L, and bicarbonate of 17 mmol/L. A random insulin level was elevated at 257 mcIU/mL. Adiponectin was undetectable and leptin was low at 0.3 ng/mL. Hemoglobin A1c was in diabetes mellitus range at 8.9%. She was started on detemir 1.0 units/kg/day on day 1 (titrated to a maximum dose of 4.4 units/kg/day) and metformin 50 mg/kg/day on day 3 of hospitalization. By day 4, triglycerides decreased to 758 mg/dL, AST to 119 units/L and ALT to 124 units/L. Pre-prandial glucoses improved ranging from 113 to 138 mg/dL. As her insurance denied coverage for detemir, she was discharged home on glargine 0.7 units/kg/day and metformin suspension. One month later, she was started on subcutaneous metreleptin, and glargine was discontinued. At 5 months of age, she had triglycerides 229 mg/dl, normal liver enzymes, and normal blood glucoses while on 0.056 mg/kg/day of subcutaneous metreleptin and metformin. Medications were well tolerated without side effects. She had improved growth and met all developmental milestones. Genetic evaluation revealed that she was homozygous for a pathogenic variant, c.589-2A>G; p.Gln196fs*228 (rs116807569), in the AGPAT2 gene. Conclusion: Leptin is important in regulation of lipid and glucose metabolism, and patients with CGL are deficient due to lack of adipose tissue. Metabolic abnormalities, including stabilization of glucoses and improved hypertriglyceridemia, in our patient markedly improved with initiation of metreleptin, metformin, and insulin. We present successful dosing of these treatment modalities without adverse reactions in an infant with CGL.

Project description:Lipodystrophies are extreme forms of metabolic syndrome. Metreleptin was approved in the United States for generalized lipodystrophy (GLD) but not partial lipodystrophy (PLD).The objective of the study was to test metreleptin's efficacy in PLD vs GLD and find predictors for treatment response.This was a prospective, single-arm, open-label study since 2000 with continuous enrollment. Current analysis included metreleptin treatment for 6 months or longer as of January 2014.The study was conducted at the National Institutes of Health (Bethesda, Maryland).Patients clinically diagnosed with lipodystrophy, leptin less than 8 ng/mL (males) or less than 12 (females), age older than 6 months, and one or more metabolic abnormalities (diabetes, insulin resistance, or hypertriglyceridemia) participated in the study.The interventions included sc metreleptin injections (0.06-0.24 mg/kg · d).Changes in glycated hemoglobin A1c (HbA1c) and triglycerides after 6 and 12 months of metreleptin were measured.Baseline metabolic parameters were similar in 55 GLD [HbA1c 8.4% ± 2.3%; triglycerides, geometric mean (25th, 75th percentile), 467 mg/dL (200, 847)] and 31 PLD patients [HbA1c 8.1% ± 2.2%, triglycerides 483 mg/dL (232, 856)] despite different body fat and endogenous leptin. At 12 months, metreleptin decreased HbA1c (to 6.4% ± 1.5%, GLD, P < .001; 7.3% ± 1.6%, PLD, P = .004) and triglycerides [to 180 mg/dL (106, 312), GLD, P < .001; 326 mg/dL (175, 478), PLD, P = .02]. HbA1c and triglyceride changes over time significantly differed between GLD and PLD. In subgroup analyses, metreleptin improved HbA1c and triglycerides in all GLD subgroups except those with baseline triglycerides less than 300 mg/dL and all PLD subgroups except baseline triglycerides less than 500 mg/dL, HbA1c less than 8%, or endogenous leptin greater than 4 ng/mL.In addition to its proven efficacy in GLD, metreleptin is effective in selected PLD patients with severe metabolic derangements or low leptin.

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Bone mineral content in patients with congenital generalized lipodystrophy is unaffected by metreleptin replacement therapy.

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Bone mineral content in patients with congenital generalized lipodystrophy is unaffected by metreleptin replacement therapy.

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