| First Author | Aguayo-Mazzucato C | Year | 2018 |
| Journal | Diabetes | Volume | 67 |
| Issue | 7 | Pages | 1322-1331 |
| PubMed ID | 29625991 | Mgi Jnum | J:264811 |
| Mgi Id | MGI:6188483 | Doi | 10.2337/db18-0030 |
| Citation | Aguayo-Mazzucato C, et al. (2018) T3 Induces Both Markers of Maturation and Aging in Pancreatic beta-Cells. Diabetes 67(7):1322-1331 |
| abstractText | Previously, we showed that thyroid hormone (TH) triiodothyronine (T3) enhanced beta-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 p16(Ink4a) (a beta-cell senescence marker and effector) mRNA in rodent and human beta-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, T3 treatment accelerated cell senescence as shown by increased number of beta-cells with acidic beta-galactosidase activity. Our data show that T3 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 beta-cells for replacement therapies in diabetes. |
