Aims/hypothesis We investigated the long-term impact of diabetic ketoacidosis (DKA) at onset on metabolic regulation and residual beta cell function in a Danish population with type 1 diabetes. Methods The study is based on data from DanDiabKids, a Danish national diabetes register for children. The register provides clinical and biochemical data on patients with type 1 diabetes diagnosed in 1996-2009 and then followed-up until 1 January 2012. Repeated-measurement models were used as statistical methods.Results The study population comprised 2,964 children <18 years. The prevalence of DKA at diagnosis was 17.9%. Of the total subjects, 8.3% had mild, 7.9% had moderate and 1.7% had severe DKA. DKA (moderate and severe) was associated with increased HbA 1c (%) levels (0.24; 95% CI 0.11, 0.36; p=0.0003) and increased insulin dose-adjusted HbA 1c (IDAA 1c , 0.51; 95% CI 0.31, 0.70; p<0.0001) during followup, after adjustment for covariates. Children without a family history of diabetes were more likely to present with DKA (19.2% vs 8.8%, p<0.0001); however, these children had a lower HbA 1c (%) level over time (−0.35; 95% CI −0.46, −0.24; p<0.0001). Continuous subcutaneous insulin infusion (CSII) was associated with a long-term reduction in HbA 1c , changing the effect of DKA, after adjustment for covariates (p<0.0001). Conclusions/interpretation DKA at diagnosis was associated with poor long-term metabolic regulation and residual beta cell function as assessed by HbA 1c and IDAA 1c, respectively; however, CSII treatment was associated with improvement in glycaemic regulation and residual beta cell function, changing the effect of DKA at onset in our population.

Despite improvements in metabolic control over a decade the prevalence of severe hypoglycemic events remained unchanged. More intensive treatments such as insulin pump therapy and multiple daily injections on a national level seems to be a protective factor for developing severe hypoglycemia up to 2009.

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.

The levels of the Arg variant of the ZnT8 autoantibodies are associated with higher levels of stimulated C-peptide after diagnosis of T1D and during follow-up. Carriers of the TT genotype of the SLC30A8 gene predict lower stimulated C-peptide levels 12 months after diagnosis.