title: The thyroid hormone-inactivating type III deiodinase is expressed in mouse and human beta-cells and its targeted inactivation impairs insulin secretion.
abstract: Deiodinases are selenoproteins that activate or inactivate thyroid hormone. During vertebrate development, these pathways control thyroid hormone action in a cell-specific fashion explaining how systemic thyroid hormone can affect local control of tissue embryogenesis. Here we investigated the role of the thyroid hormone-inactivating deiodinase (D3) in pancreatic islet function and glucose homeostasis. D3 expression was determined by real-time PCR, immunofluorescence, and enzyme activity. Embryonic and adult wild-type mice and Mice with targeted disruption of Dio3 gene (D3KO) as well as human fetal pancreas and adult islets were studied. Insulin secretion was evaluated in adult mouse isolated islets. We found Dio3 gene expression and protein highly expressed in embryonic and adult pancreatic islets, predominantly in β-cells in both humans and mice. However, mRNA levels were barely detectable for both the thyroid hormone-activating deiodinases types 1 and 2. D3KO animals were found to be glucose intolerant due to in vitro and in vivo impaired glucose-stimulated insulin secretion, without changes in peripheral sensitivity to insulin. D3KO neonatal (postnatal day 0) and adult pancreas exhibited reduced total islet area due to reduced β-cell mass, insulin content, and impaired expression of key β-cells genes. D3 expression in perinatal pancreatic β-cells prevents untimely exposure to thyroid hormone, the absence of which leads to impaired β-cell function and subsequently insulin secretion and glucose homeostasis. An analogous role is likely in humans, given the similar D3 expression pattern.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
authors.forename: Mayrin C
authors.initials: MC
authors.lastname: Medina
authors.forename: Judith
authors.initials: J
authors.lastname: Molina
authors.forename: Yelena
authors.initials: Y
authors.lastname: Gadea
authors.forename: Alberto
authors.initials: A
authors.lastname: Fachado
authors.forename: Monika
authors.initials: M
authors.lastname: Murillo
authors.forename: Gordana
authors.initials: G
authors.lastname: Simovic
authors.forename: Antonello
authors.initials: A
authors.lastname: Pileggi
authors.forename: Arturo
authors.initials: A
authors.lastname: Hernández
authors.forename: Helena
authors.initials: H
authors.lastname: Edlund
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Bianco
mesh_terms: D000818:Animals; D006801:Humans; D007328:Insulin / Q000032:analysis / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology*; D007453:Iodide Peroxidase / Q000032:analysis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D007328:Insulin; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase