Maternal inheritance of an inactive type III deiodinase gene allele affects mouse pancreatic β-cells and disrupts glucose homeostasis

Mayrin C. Medina, Tatiana L. Fonesca, Judith Molina, Alberto Fachado, Melany Castillo, Liping Dong, Renata Soares, Arturo Hernández, Diego A Caicedo-Vierkant, Antonio C. Bianco

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Abstract

Dio3 is the most distal gene of the imprinted Dlk1-Dio3 gene locus and is expressed according to parental origin. Dio3 encodes the type 3 deiodinase (D3), a thioredoxin-fold like containing sel-enoenzyme that inactivates thyroid hormone and dampens thyroid hormone signaling. Here we used heterozygous animals with disruption of the Dio3 gene to study the allelic expression pattern of Dio3 in pancreatic β-cells and the metabolic phenotype resulting from its inactivation. Adult heterozygous mice with disruption of the Dio3 gene with maternal inheritance of the inactive Dio3 allele exhibited a total loss of D3 activity in isolated pancreatic islets, approximately 30% reduction in total pancreatic islet area, a marked decrease in insulin2 mRNA and in vivo glucose intolerance. In contrast, inheritance of the inactive Dio3 allele from the father did not affect D3 activity in isolated pancreatic islets and did not result in a pancreatic phenotype. Furthermore, exposure of pancreatic explants, D3-expressing MIN6-C3 cells or isolated pancreatic islets to 100 nM T 3 for 24 hours reduced insulin2 mRNA by approximately 50% and the peak of glucose-induced insulin secretion. An unbiased analysis of T 3-treated pancreatic islets revealed the down-regulation of 21 gene sets (false discovery rate q value < 25%) involved in nucleolar function and transcription of rRNA, ribonucleotide binding, mRNAtranslation, and membrane organization. We conclude that the Dio3 gene is preferentially expressed from the maternal allele in pancreatic islets and that the inactivation of this allele is sufficient to disrupt glucose homeostasis by reducing the pancreatic islet area, insulin2 gene expression, and glucose-stimulated insulin secretion.

Original languageEnglish
Pages (from-to)3160-3171
Number of pages12
JournalEndocrinology
Volume155
Issue number8
DOIs
StatePublished - Jan 1 2014

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Islets of Langerhans
Homeostasis
Alleles
Glucose
Genes
Thyroid Hormones
Insulin
Phenotype
Ribonucleotides
Iodide Peroxidase
Messenger RNA
Thioredoxins
Glucose Intolerance
iodothyronine deiodinase type III
Maternal Inheritance
Fathers
Down-Regulation
Mothers
Gene Expression
Membranes

ASJC Scopus subject areas

  • Endocrinology

Cite this

Medina, M. C., Fonesca, T. L., Molina, J., Fachado, A., Castillo, M., Dong, L., ... Bianco, A. C. (2014). Maternal inheritance of an inactive type III deiodinase gene allele affects mouse pancreatic β-cells and disrupts glucose homeostasis. Endocrinology, 155(8), 3160-3171. https://doi.org/10.1210/en.2013-1208

Maternal inheritance of an inactive type III deiodinase gene allele affects mouse pancreatic β-cells and disrupts glucose homeostasis. / Medina, Mayrin C.; Fonesca, Tatiana L.; Molina, Judith; Fachado, Alberto; Castillo, Melany; Dong, Liping; Soares, Renata; Hernández, Arturo; Caicedo-Vierkant, Diego A; Bianco, Antonio C.

In: Endocrinology, Vol. 155, No. 8, 01.01.2014, p. 3160-3171.

Research output: Contribution to journalArticle

Medina, MC, Fonesca, TL, Molina, J, Fachado, A, Castillo, M, Dong, L, Soares, R, Hernández, A, Caicedo-Vierkant, DA & Bianco, AC 2014, 'Maternal inheritance of an inactive type III deiodinase gene allele affects mouse pancreatic β-cells and disrupts glucose homeostasis', Endocrinology, vol. 155, no. 8, pp. 3160-3171. https://doi.org/10.1210/en.2013-1208
Medina, Mayrin C. ; Fonesca, Tatiana L. ; Molina, Judith ; Fachado, Alberto ; Castillo, Melany ; Dong, Liping ; Soares, Renata ; Hernández, Arturo ; Caicedo-Vierkant, Diego A ; Bianco, Antonio C. / Maternal inheritance of an inactive type III deiodinase gene allele affects mouse pancreatic β-cells and disrupts glucose homeostasis. In: Endocrinology. 2014 ; Vol. 155, No. 8. pp. 3160-3171.
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AU - Fonesca, Tatiana L.

AU - Molina, Judith

AU - Fachado, Alberto

AU - Castillo, Melany

AU - Dong, Liping

AU - Soares, Renata

AU - Hernández, Arturo

AU - Caicedo-Vierkant, Diego A

AU - Bianco, Antonio C.

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AB - Dio3 is the most distal gene of the imprinted Dlk1-Dio3 gene locus and is expressed according to parental origin. Dio3 encodes the type 3 deiodinase (D3), a thioredoxin-fold like containing sel-enoenzyme that inactivates thyroid hormone and dampens thyroid hormone signaling. Here we used heterozygous animals with disruption of the Dio3 gene to study the allelic expression pattern of Dio3 in pancreatic β-cells and the metabolic phenotype resulting from its inactivation. Adult heterozygous mice with disruption of the Dio3 gene with maternal inheritance of the inactive Dio3 allele exhibited a total loss of D3 activity in isolated pancreatic islets, approximately 30% reduction in total pancreatic islet area, a marked decrease in insulin2 mRNA and in vivo glucose intolerance. In contrast, inheritance of the inactive Dio3 allele from the father did not affect D3 activity in isolated pancreatic islets and did not result in a pancreatic phenotype. Furthermore, exposure of pancreatic explants, D3-expressing MIN6-C3 cells or isolated pancreatic islets to 100 nM T 3 for 24 hours reduced insulin2 mRNA by approximately 50% and the peak of glucose-induced insulin secretion. An unbiased analysis of T 3-treated pancreatic islets revealed the down-regulation of 21 gene sets (false discovery rate q value < 25%) involved in nucleolar function and transcription of rRNA, ribonucleotide binding, mRNAtranslation, and membrane organization. We conclude that the Dio3 gene is preferentially expressed from the maternal allele in pancreatic islets and that the inactivation of this allele is sufficient to disrupt glucose homeostasis by reducing the pancreatic islet area, insulin2 gene expression, and glucose-stimulated insulin secretion.

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