T 3 induces both markers of maturation and aging in pancreatic b-cells

Cristina Aguayo-Mazzucato, Terence B. Lee, Michelle Matzko, Amanda DiIenno, Habib Rezanejad, Preeti Ramadoss, Thomas Scanlan, Ann Marie Zavacki, P. Reed Larsen, Anthony Hollenberg, Clark Colton, Arun Sharma, Susan Bonner-Weir

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Previously, we showed that thyroid hormone (TH) triiodothyronine (T 3 ) enhanced b-cell functional maturation through induction of Mafa. High levels of T 3 have been linked to decreased life span in mammals and low levels to lengthened life span, suggesting a relationship between TH and aging. Here, we show that T 3 increased p16 Ink4a (a b-cell senescence marker and effector) mRNA in rodent and human b-cells. The kinetics of Mafa and p16 Ink4a induction suggested both genes as targets of TH via TH receptors (THRs) binding to specific response elements. Using specific agonists CO23 and GC1, we showed that p16 Ink4a expression was controlled by THRA and Mafa by THRB. Using chromatin immunoprecipitation and a transient transfection yielding biotinylated THRB1 or THRA isoforms to achieve specificity, we determined that THRA isoform bound to p16 Ink4a , whereas THRB1 bound to Mafa but not to p16 Ink4a . On a cellular level, T 3 treatment accelerated cell senescence as shown by increased number of b-cells with acidic b-galactosidase activity. Our data show that T 3 can simultaneously induce both maturation (Mafa) and aging (p16 Ink4a ) effectors and that these dichotomous effects are mediated through different THR isoforms. These findings may be important for further improving stem cell differentiation protocols to produce functional b-cells for replacement therapies in diabetes.

Original languageEnglish (US)
Pages (from-to)1322-1331
Number of pages10
JournalDiabetes
Volume67
Issue number7
DOIs
StatePublished - Jul 2018

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Aguayo-Mazzucato, C., Lee, T. B., Matzko, M., DiIenno, A., Rezanejad, H., Ramadoss, P., Scanlan, T., Zavacki, A. M., Larsen, P. R., Hollenberg, A., Colton, C., Sharma, A., & Bonner-Weir, S. (2018). T 3 induces both markers of maturation and aging in pancreatic b-cells Diabetes, 67(7), 1322-1331. https://doi.org/10.2337/db18-0030