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A20 Inhibits β-Cell Apoptosis by Multiple Mechanisms and Predicts Residual β-Cell Function in Type 1 Diabetes

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DOI

  1. Changes in the lipidome in type 1 diabetes following low carbohydrate diet: Post-hoc analysis of a randomized crossover trial

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. The Rac2 GTPase contributes to cathepsin H-mediated protection against cytokine-induced apoptosis in insulin-secreting cells

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Characterization of plasma lipidomics in adolescent subjects with increased risk for type 1 diabetes in the DiPiS cohort

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Long Noncoding RNAs in Diabetes and β-Cell Regulation

    Research output: Chapter in Book/Report/Conference proceedingBook chapterResearchpeer-review

  5. Increased levels of inflammatory factors are associated with severity of polyneuropathy in type 1 diabetes

    Research output: Contribution to journalJournal articleResearchpeer-review

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Activation of the transcription factor nuclear factor kappa B (NFkB) contributes to β-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-κB signaling and has strong antiapoptotic activities in β-cells. Although the role of A20 on NF-κB 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 β-cell-specific A20 knockout mice, we presently demonstrate that A20 has broader effects in β-cells that are not restricted to inhibition of NF-κB. 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 β-cell function and impaired glycemic control. In conclusion, our results indicate a critical role for A20 in the regulation of β-cell survival and unveil novel mechanisms by which A20 controls β-cell fate. Moreover, we identify the single nucleotide polymorphism rs2327832 of TNFAIP3 as a possible prognostic marker for diabetes outcome in children with T1D.

Original languageEnglish
JournalMolecular Endocrinology
Volume30
Issue number1
Pages (from-to)48-61
Number of pages14
ISSN0888-8809
DOIs
Publication statusPublished - 2016

ID: 45943726