The complicated clinical course in a case of atypical lipodystrophy after development of neutralizing antibody to metreleptin: treatment with setmelanotide.
2020
Adipose tissue
Adolescent/young adult
Alanine aminotransferase
Amenorrhoea
Anion gap
Antinuclear antibody
Apolipoprotein A-1*
Apolipoprotein B*
Appetite*
BMI
Beta-hydroxybutyrate
C-peptide (blood)
Cholesterol:HDL ratio*
Cirrhosis
Complement 4*
DEXA scan
DNA sequencing
Diabetes mellitus type 1
Diabetic ketoacidosis
Diet
Fat loss*
Fatigue
Female
Fenofibrate
Fluid repletion
Food intake*
GADA
Gamma-glutamyl transpeptidase*
Glucose (blood)
Haemoglobin A1c
Hand contractures*
Histopathology
Hyperglycaemia
Hyperlipidaemia*
Hypertriglyceridaemia*
Hypoglycaemia
Hypogonadism
Hypoleptinaemia*
Insulin
Insulin resistance
Ketones (plasma)
Ketones (urine)
Leptin
Leptin*
Lipodystrophy
Liver biopsy
Liver fat*
Liver function
MRI
March
Metformin
Metreleptin*
Mixed meal test*
Nonalcoholic steatohepatitis*
Novel treatment
Obesity
Paediatrics
Pancreatitis
Pioglitazone
Plasmapheresis
Polydipsia
Prednisone
Radioimmunoassay
Scoliosis
Setmelanotide*
Tanner scale
Thiazolidinediones
Triglycerides
United States
Visceral fat*
Vision - blurred
Weight
White
Journal
Endocrinology, diabetes & metabolism case reports
ISSN: 2052-0573
Titre abrégé: Endocrinol Diabetes Metab Case Rep
Pays: England
ID NLM: 101618943
Informations de publication
Date de publication:
25 Mar 2020
25 Mar 2020
Historique:
received:
11
02
2020
accepted:
05
03
2020
pubmed:
28
3
2020
medline:
28
3
2020
entrez:
28
3
2020
Statut:
aheadofprint
Résumé
A patient with atypical partial lipodystrophy who had a transient initial response to metreleptin experienced acute worsening of her metabolic state when neutralizing antibodies against metreleptin appeared. Because her metabolic status continued to deteriorate, a therapeutic trial with melanocortin-4 receptor agonist setmelanotide, that is believed to function downstream from leptin receptor in the leptin signaling system, was undertaken in an effort to improve her metabolic status for the first time in a patient with lipodystrophy. To achieve this, a compassionate use (investigational new drug application; IND) was initiated (NCT03262610). Glucose control, body fat by dual-energy X-ray absorptiometry and MRI, and liver fat by proton density fat fraction were monitored. Daily hunger scores were assessed by patient filled questionnaires. Although there was a slight decrease in hunger scales and visceral fat, stimulating melanocortin-4 receptor by setmelanotide did not result in any other metabolic benefit such as improvement of hypertriglyceridemia or diabetes control as desired. Targeting melanocortin-4 receptor to regulate energy metabolism in this setting was not sufficient to obtain a significant metabolic benefit. However, complex features of our case make it difficult to generalize these observations to all cases of lipodystrophy. It is still possible that melanocortin-4 receptor agonistic action may offer some therapeutic benefits in leptin-deficient patients. A patient with atypical lipodystrophy with an initial benefit with metreleptin therapy developed neutralizing antibodies to metreleptin (Nab-leptin), which led to substantial worsening in metabolic control. The neutralizing activity in her serum persisted for longer than 3 years. Whether the worsening in her metabolic state was truly caused by the development of Nab-leptin cannot be fully ascertained, but there was a temporal relationship. The experience noted in our patient at least raises the possibility for concern for substantial metabolic worsening upon emergence and persistence of Nab-leptin. Further studies of cases where Nab-leptin is detected and better assay systems to detect and characterize Nab-leptin are needed. The use of setmelanotide, a selective MC4R agonist targeting specific neurons downstream from the leptin receptor activation, was not effective in restoring metabolic control in this complex patient with presumed diminished leptin action due to Nab-leptin. Although stimulating the MC4R pathway was not sufficient to obtain a significant metabolic benefit in lowering triglycerides and helping with her insulin resistance as was noted with metreleptin earlier, there was a mild reduction in reported food intake and appetite. Complex features of our case make it difficult to generalize our observation to all leptin-deficient patients. It is possible that some leptin-deficient patients (especially those who need primarily control of food intake) may still theoretically benefit from MC4R agonistic action, and further studies in carefully selected patients may help to tease out the differential pathways of metabolic regulation by the complex network of leptin signaling system.
Identifiants
pubmed: 32213649
doi: 10.1530/EDM-19-0139
pii: EDM190139
pmc: PMC7159256
doi:
pii:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK072488
Pays : United States
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