T3 Induces Both Markers of Maturation and Aging in Pancreatic β-Cells

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

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Previously, we showed that thyroid hormone (TH) triiodothyronine (T3) enhanced β-cell functional maturation through induction of Mafa High levels of T3 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 T3 increased p16Ink4a (a β-cell senescence marker and effector) mRNA in rodent and human β-cells. The kinetics of Mafa and p16Ink4a 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 p16Ink4a 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 p16Ink4a , whereas THRB1 bound to Mafa but not to p16Ink4a On a cellular level, T3 treatment accelerated cell senescence as shown by increased number of β-cells with acidic β-galactosidase activity. Our data show that T3 can simultaneously induce both maturation (Mafa) and aging (p16Ink4a ) 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 β-cells for replacement therapies in diabetes.

Original languageEnglish (US)
Pages (from-to)1322-1331
Number of pages10
JournalDiabetes
Volume67
Issue number7
DOIs
StatePublished - Jul 1 2018

Fingerprint

Protein Isoforms
Cell Aging
Triiodothyronine
Thyroid Hormones
Galactosidases
Thyroid Hormone Receptors
Chromatin Immunoprecipitation
Response Elements
Cell- and Tissue-Based Therapy
Transfection
Cell Differentiation
Mammals
Rodentia
Stem Cells
Cell Count
Messenger RNA
Genes
Therapeutics

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Aguayo-Mazzucato, C., Lee, T. B., Matzko, M., DiIenno, A., Rezanejad, H., Ramadoss, P., ... Bonner-Weir, S. (2018). T3 Induces Both Markers of Maturation and Aging in Pancreatic β-Cells. Diabetes, 67(7), 1322-1331. https://doi.org/10.2337/db18-0030

T3 Induces Both Markers of Maturation and Aging in Pancreatic β-Cells. / Aguayo-Mazzucato, Cristina; Lee, Terence B.; Matzko, Michelle; DiIenno, Amanda; Rezanejad, Habib; Ramadoss, Preeti; Scanlan, Thomas (Tom); Zavacki, Ann Marie; Larsen, P. Reed; Hollenberg, Anthony; Colton, Clark; Sharma, Arun; Bonner-Weir, Susan.

In: Diabetes, Vol. 67, No. 7, 01.07.2018, p. 1322-1331.

Research output: Contribution to journalArticle

Aguayo-Mazzucato, C, Lee, TB, Matzko, M, DiIenno, A, Rezanejad, H, Ramadoss, P, Scanlan, TT, Zavacki, AM, Larsen, PR, Hollenberg, A, Colton, C, Sharma, A & Bonner-Weir, S 2018, 'T3 Induces Both Markers of Maturation and Aging in Pancreatic β-Cells', Diabetes, vol. 67, no. 7, pp. 1322-1331. https://doi.org/10.2337/db18-0030
Aguayo-Mazzucato C, Lee TB, Matzko M, DiIenno A, Rezanejad H, Ramadoss P et al. T3 Induces Both Markers of Maturation and Aging in Pancreatic β-Cells. Diabetes. 2018 Jul 1;67(7):1322-1331. https://doi.org/10.2337/db18-0030
Aguayo-Mazzucato, Cristina ; Lee, Terence B. ; Matzko, Michelle ; DiIenno, Amanda ; Rezanejad, Habib ; Ramadoss, Preeti ; Scanlan, Thomas (Tom) ; Zavacki, Ann Marie ; Larsen, P. Reed ; Hollenberg, Anthony ; Colton, Clark ; Sharma, Arun ; Bonner-Weir, Susan. / T3 Induces Both Markers of Maturation and Aging in Pancreatic β-Cells. In: Diabetes. 2018 ; Vol. 67, No. 7. pp. 1322-1331.
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