Downregulation of Sirt3 contributes to β-cell dedifferentiation via FoxO1 in type 2 diabetic mellitus.

Publisher: Springer Verlag Country of Publication: Germany NLM ID: 9200299 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-5233 (Electronic) Linking ISSN: 09405429 NLM ISO Abbreviation: Acta Diabetol Subsets: MEDLINE

Publication: Berlin : Springer Verlag
Original Publication: Berlin : Springer International, c1991-

Diabetes Mellitus, Type 2*/metabolism ; Insulin-Secreting Cells*/metabolism ; Sirtuin 3*/genetics ; Sirtuin 3*/metabolism; Animals ; Mice ; Cell Dedifferentiation ; Down-Regulation ; Glucose/metabolism ; Insulin/metabolism

Aims: FoxO1 is an important factor in the β-cell differentiation in type 2 diabetes mellitus (T2DM). Sirt3 is found to be involved in FoxO1 function. This study investigated the role of Sirt3 in the β-cell dedifferentiation and its mechanism.
Methods: Twelve-week-old db/db mice and INS1 cells transfected with Sirt3-specific short hairpin RNA (shSirt3) were used to evaluate the dedifferentiation of β-cell. Insulin levels were measured by enzyme linked immunosorbent assay. The proteins of Sirt3, T-FoxO1, Ac-FoxO1 and differentiation indexes such as NGN3, OCT4, MAFA were determined by western blot or immunofluorescence staining. The combination of Sirt3 and FoxO1 was determined by the co-immunoprecipitation assay. The transcriptional activity of FoxO1 was detected by dual luciferase reporter assay.
Results: Both the in vivo and in vitro results showed that Sirt3 was decreased along with β-cell dedifferentiation and decreased function of insulin secretion under high glucose conditions. When Sirt3 was knocked down in INS1 cells, increased β-cell dedifferentiation and lowered insulin secretion were observed. This effect was closely related to the amount loss and the decreased deacetylation of FoxO1, which resulted in a reduction in transcriptional activity.
Conclusion: Downregulation of Sirt3 contributes to β-cell dedifferentiation in high glucose via FoxO1. Intervention of Sirt3 may be an effective approach to prevent β-cell failure in T2DM.
(© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

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81903681 National Natural Science Foundation of China; ZR-XY201502 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy

Keywords: Dedifferentiation; FoxO1; High glucose; Sirt3; T2DM; β-Cell

IY9XDZ35W2 (Glucose)
0 (Insulin)
0 (Sirt3 protein, mouse)
EC 3.5.1.- (Sirtuin 3)
0 (Foxo1 protein, mouse)

Date Created: 20231227 Date Completed: 20240327 Latest Revision: 20240329

20240329

10.1007/s00592-023-02221-w

38150004