| First Author | Fukaya M | Year | 2016 |
| Journal | Mol Endocrinol | Volume | 30 |
| Issue | 1 | Pages | 48-61 |
| PubMed ID | 26652732 | Mgi Jnum | J:234681 |
| Mgi Id | MGI:5790563 | Doi | 10.1210/me.2015-1176 |
| Citation | Fukaya M, et al. (2016) A20 Inhibits beta-Cell Apoptosis by Multiple Mechanisms and Predicts Residual beta-Cell Function in Type 1 Diabetes. Mol Endocrinol 30(1):48-61 |
| abstractText | Activation of the transcription factor nuclear factor kappa B (NFkB) contributes to beta-cell death in type 1 diabetes (T1D). Genome-wide association studies have identified the gene TNF-induced protein 3 (TNFAIP3), encoding for the zinc finger protein A20, as a susceptibility locus for T1D. A20 restricts NF-kappaB signaling and has strong antiapoptotic activities in beta-cells. Although the role of A20 on NF-kappaB inhibition is well characterized, its other antiapoptotic functions are largely unknown. By studying INS-1E cells and rat dispersed islet cells knocked down or overexpressing A20 and islets isolated from the beta-cell-specific A20 knockout mice, we presently demonstrate that A20 has broader effects in beta-cells that are not restricted to inhibition of NF-kappaB. These involves, suppression of the proapoptotic mitogen-activated protein kinase c-Jun N-terminal kinase (JNK), activation of survival signaling via v-akt murine thymoma viral oncogene homolog (Akt) and consequently inhibition of the intrinsic apoptotic pathway. Finally, in a cohort of T1D children, we observed that the risk allele of the rs2327832 single nucleotide polymorphism of TNFAIP3 predicted lower C-peptide and higher hemoglobin A1c (HbA1c) levels 12 months after disease onset, indicating reduced residual beta-cell function and impaired glycemic control. In conclusion, our results indicate a critical role for A20 in the regulation of beta-cell survival and unveil novel mechanisms by which A20 controls beta-cell fate. Moreover, we identify the single nucleotide polymorphism rs2327832 of TNFAIP3 as a possible prognostic marker for diabetes outcome in children with T1D. |
