The Thyroid Hormone-Inactivating Type III Deiodinase Is Expressed in Mouse and Human β-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.

Thyroid hormones in fetal growth and prepartum maturation

“…Knockout of the Dio3 gene causes perinatal thyrotoxicity and partial lethality at or before birth (Hernandez et al 2006). Birth weight is normal in the live mutant pups but there are abnormalities in the pancreatic b-cells, retina, and hypothalamus at birth with a more severe growthrestricted phenotype developing with increasing postnatal age (Hernandez et al 2006, Ng et al 2010, Medina et al 2011, Ueta et al 2012. The tissue-specific patterns of imprinting and expression of Dio3 suggest that this deiodinase has both paracrine and endocrine actions in preventing feto-placental over exposure to thyroid hormones at critical stages of development.…”

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…This is also observed in animal models of transgenic Dio2 expression in the heart (273,274). In contrast, D3 inactivation results in localized increase in thyroid hormone signaling as evidenced in the D3 KO mouse (64,239,(275)(276)(277)(278)(279).…”

Hypothyroidism Impairs Human Stem Cell–Derived Pancreatic Progenitor Cell Maturation in Mice

“…Maternal hypothyroidism caused impaired insulin secretion in neonatal rats as well as glucose intolerance and b-cell dysfunction in adult offspring (9). Systemic knockout of Dio3 (the enzyme required for intracellular inactivation of thyroid hormones) caused significantly reduced islet area and pancreatic insulin content compared with wild-type mice at birth as well as glucose intolerance and impaired insulin secretion during adulthood (10). Triiodothyronine (T3) has also been shown to have prosurvival effects on adult b-cells by protecting mice from streptozotocin-induced b-cell death and diabetes (11).…”