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Extreme insulin resistance influences thyroid nodule growth in children
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Children with extreme insulin resistance due to lipodystrophy or an insulin receptor mutation had a high prevalence of thyroid nodules vs. children without the condition, independent of treatment with metreleptin therapy, according to findings published in The Journal of Clinical Endocrinology & Metabolism.
Syndromes of extreme insulin resistance include generalized or partial lipodystrophy and insulin receptor mutation syndromes, Rebecca J. Brown, MD, MHSc, a Lasker tenure track investigator with the National Institute of Diabetes and Digestive and Kidney Diseases at the NIH, and colleagues wrote in the study background. Treatments for both conditions typically include high-dose insulin and experimental metreleptin therapy (recombinant human methionyl leptin; Myalept, Aegerion).
“Children with syndromes of extreme insulin resistance have increased prevalence of thyroid nodules,” Brown told Endocrine Today. “Patients with biallelic mutations of the insulin receptor also had increased thyroid volume. These proliferative thyroid changes may reflect growth-promoting effects of high insulin levels.”Brown and colleagues analyzed thyroid ultrasound images and thyroid hormone level data from 81 children and adults with lipodystrophy and/or an insulin receptor mutation participating in studies on the natural history of insulin resistance or open-label interventional studies of metreleptin at the NIH. Researchers assessed thyroid structural abnormalities and hormone levels to determine whether insulin, insulin-like growth factor I and metreleptin therapy contribute to thyroid nodule growth and neoplasia.
Within the cohort, 42 patients had familial partial lipodystrophy, 27 had congenital generalized lipodystrophy, nine had acquired generalized lipodystrophy and three had atypical progeria. Among 11 patients with an insulin receptor mutation, five had homozygous or compound heterozygous mutations and six had heterozygous mutations. Sixty patients were prescribed metreleptin therapy. Participants with insulin receptor mutations had higher ambient insulin concentrations compared with those with lipodystrophy, according to researchers. Children with an insulin receptor mutation had a higher mean HbA1c vs. those with lipodystrophy (mean, 8.2% vs. 6.4%; P = .04); however, this trend was not observed in adults.
Researchers found that children with extreme insulin resistance were more likely to have thyroid nodules when compared with the published prevalence for children (16.7% vs. 2%; P = .0004), with no between-group differences when comparing children with or without an insulin receptor mutation. Three adults with lipodystrophy and one with an insulin receptor mutation were diagnosed with papillary thyroid carcinoma (age range, 18-40 years).
Researchers observed no between-group differences overall with respect to thyroid volume in patients with lipodystrophy vs. insulin receptor mutations (P = .3) or in analyses restricted to children only (P = .3). However, among patients with homozygous or compound heterozygous insulin receptor mutations, researchers noted that thyroid volume was larger when compared with patients with heterozygous insulin receptor mutations (P = .017) and when compared with participants with lipodystrophy (P = .046).
“Counter to our hypothesis, we found that only patients with [homozygous or compound heterozygous] insulin receptor mutations had elevated thyroid volume in comparison to patients with [heterozygous] mutations, lipodystrophy and healthy controls,” the researchers wrote. “We further hypothesized that metreleptin treatment might contribute to thyroid proliferation, but counter to our hypothesis, we did not observe an association between metreleptin treatment and thyroid size or nodularity.”
Participants with insulin receptor mutations had higher ambient insulin concentrations compared with those with lipodystrophy, according to researchers. Children with an insulin receptor mutation had a higher mean HbA1c vs. those with lipodystrophy but without the mutation (mean, 8.2% vs. 6.4%; P = .04); however, this trend was not observed in adults.
“Because thyroid nodules are a risk factor for thyroid cancer, patients with syndromes of extreme insulin resistance may benefit from increased surveillance for thyroid cancers,” Brown said. “Further research is needed on the molecular mechanisms leading to thyroid proliferative changes in patients with syndromes of extreme insulin resistance, as well as better estimates of the risk of thyroid cancer.” – by Regina Schaffer
For more information:
Rebecca J Brown, MD, MHSc , can be reached at the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10-CRC, Room 6-5942, 10 Center Drive, Bethesda, MD 20892; email: brownrebecca@niddk.nih.gov.
Disclosures: The authors report no relevant financial disclosures.
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