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Thyroid hormone promotes postnatal rat pancreatic ?-cell development and glucose-responsive insulin secretion through MAFA.

ABSTRACT: Neonatal ? cells do not secrete glucose-responsive insulin and are considered immature. We previously showed the transcription factor MAFA is key for the functional maturation of ? cells, but the physiological regulators of this process are unknown. Here we show that postnatal rat ? cells express thyroid hormone (TH) receptor isoforms and deiodinases in an age-dependent pattern as glucose responsiveness develops. In vivo neonatal triiodothyronine supplementation and TH inhibition, respectively, accelerated and delayed metabolic development. In vitro exposure of immature islets to triiodothyronine enhanced the expression of Mafa, the secretion of glucose-responsive insulin, and the proportion of responsive cells, all of which are effects that were abolished in the presence of dominant-negative Mafa. Using chromatin immunoprecipitation and electrophoretic mobility shift assay, we show that TH has a direct receptor-ligand interaction with the Mafa promoter and, using a luciferase reporter, that this interaction was functional. Thus, TH can be considered a physiological regulator of functional maturation of ? cells via its induction of Mafa.

SUBMITTER: Aguayo-Mazzucato C

PROVIDER: S-EPMC3636623 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Thyroid hormone promotes postnatal rat pancreatic β-cell development and glucose-responsive insulin secretion through MAFA.

Aguayo-Mazzucato Cristina C Zavacki Ann Marie AM Marinelarena Alejandra A Hollister-Lock Jennifer J El Khattabi Ilham I Marsili Alessandro A Weir Gordon C GC Sharma Arun A Larsen P Reed PR Bonner-Weir Susan S

Diabetes 20130110 5

Neonatal β cells do not secrete glucose-responsive insulin and are considered immature. We previously showed the transcription factor MAFA is key for the functional maturation of β cells, but the physiological regulators of this process are unknown. Here we show that postnatal rat β cells express thyroid hormone (TH) receptor isoforms and deiodinases in an age-dependent pattern as glucose responsiveness develops. In vivo neonatal triiodothyronine supplementation and TH inhibition, respectively, ...[more]

PMID: 23305647

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Project description:ContextPatients with mutations of the insulin receptor gene (INSR) have extreme insulin resistance and are at risk for early morbidity and mortality from diabetes complications. A case report suggested that thyroid hormone could improve glycemia in INSR mutation in part by increasing brown adipose tissue (BAT) activity and volume.ObjectiveTo determine if thyroid hormone increases tissue glucose uptake and improves hyperglycemia in INSR mutation.DesignSingle-arm, open-label study of liothyronine.SettingNational Institutes of Health.ParticipantsPatients with homozygous (n = 5) or heterozygous (n = 2) INSR mutation.InterventionLiothyronine every 8 hours for 2 weeks (n = 7); additional 6 months' treatment in those with hemoglobin A1c (HbA1c) > 7% (n = 4).OutcomesWhole-body glucose uptake by isotopic tracers; tissue glucose uptake in muscle, white adipose tissue (WAT) and BAT by dynamic [18F] fluorodeoxyglucose positron emission tomography/computed tomography; HbA1c.ResultsThere was no change in whole-body, muscle, or WAT glucose uptake from baseline to 2 weeks of liothyronine. After 6 months, there was no change in HbA1c (8.3 ± 1.2 vs 9.1 ± 3.0%, P = 0.27), but there was increased whole-body glucose disposal (22.8 ± 4.9 vs 30.1 ± 10.0 µmol/kg lean body mass/min, P = 0.02), and muscle (0.7 ± 0.1 vs 2.0 ± 0.2 µmol/min/100 mL, P < 0.0001) and WAT glucose uptake (1.2 ± 0.2 vs 2.2 ± 0.3 µmol/min/100 mL, P < 0.0001). BAT glucose uptake could not be quantified because of small volume. There were no signs or symptoms of hyperthyroidism.ConclusionLiothyronine administered at well-tolerated doses did not improve HbA1c. However, the observed increases in muscle and WAT glucose uptake support the proposed mechanism that liothyronine increases tissue glucose uptake. More selective agents may be effective at increasing tissue glucose uptake without thyroid hormone-related systemic toxicity.Clinical Trial Registration Number: NCT02457897; https://clinicaltrials.gov/ct2/show/NCT02457897.

Dataset Information

Thyroid hormone promotes postnatal rat pancreatic ?-cell development and glucose-responsive insulin secretion through MAFA.

Publications

Thyroid hormone promotes postnatal rat pancreatic β-cell development and glucose-responsive insulin secretion through MAFA.

Similar Datasets

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