Suppressor of cytokine signaling 3 (SOCS-3) is a negative feedback regulator of IFN-␥ signaling, shown up-regulated in mouse bone marrow cells by the proinflammatory cytokines interleukin-1␤ (IL-1␤), tumor necrosis factor-␣ (TNF-␣), and IFN-␥. IL-1␤ and IFN-␥ alone, or potentiated by TNF-␣, are cytotoxic to the insulin producing pancreatic ␤-cells and ␤-cell lines in vitro and suggested to contribute to the specific ␤-cell destruction in Type-1 diabetes mellitus (T1DM). Using a doxycycline-inducible SOCS-3 expression system in the rat ␤-cell line INS-1, we demonstrate that the toxic effect of both IL-1␤ or IFN-␥ at concentrations that reduced the viability by 50% over 3 days, was fully preventable when SOCS-3 expression was turned on in the cells. At cytokine concentrations or combinations more toxic to the cells, SOCS-3 overexpression yielded a partial protection. Whereas SOCS-3-mediated inhibition of IFN-␥ signaling is described in other cell systems, SOCS-3 mediated inhibition of IL-1␤ signaling has not previously been described. In addition we show that SOCS-3 prevention of IL-1␤-induced toxicity is accompanied by inhibited transcription of the inducible nitric oxide synthase (iNOS) by 80%, resulting in 60% decreased formation of the toxic nitric oxide (NO). Analysis of isolated native rat islets exposed to IL-1␤ revealed a naturally occurring but delayed up-regulated SOCS-3 transcription. Influencing SOCS-3 expression thus represents an approach for affecting cytokine-induced signal transduction at a proximal step in the signal cascade, potentially useful in future therapies aimed at reducing the destructive potential of ␤-cell cytotoxic cytokines in T1DM, as well as other cytokine-dependent diseases.

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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.

In spite of the majority of the patients being on multiple insulin injections, only 11% had HbA1c values below 8% and the prevalence of diabetic microvascular complications in kidneys, eyes and nerves was unacceptable high.

The objective of the present study was to describe the changes in glycaemic control based on data from the nationwide Danish Registry of Childhood Diabetes with valid haemoglobin A1c (HbA1c) readings centrally analysed between 1996 and 2006. The glycaemic control was assessed using generalized linear mixed models. Centre, age, diabetes duration, ethnicity, sex, self-monitoring of blood glucose, insulin regimens and hypoglycaemia was tested as explanatory variables. There were 9291 HbA1c recordings from 2705 children with T1D during the 10-yr period. The unadjusted mean HbA1c value in 1997 was 9.05% (95% CI +/- 0.82) and in 2006 was 8.20% (95% CI +/- 0.06). Mean HbA1c was significantly reduced over the years with a linear decrease of 0.08% per year (95% CI +/-0.011) (p < 0.0001). The decrease was unaffected by adjusting for number of injections, insulin/kg and use of insulin analogous. During the period, an increased frequency of self-monitored blood glucose was observed that was associated with a reduction in HbA1c (p < 0.0001). The percentage of children with severe hypoglycaemia decreased from 12.2 to 7.8% in those with HbA1c between 6 and 8%. Metabolic control in diabetic children has improved on a nationwide basis from the establishment of the national registry in 1996. The reduction in HbA1c was related to an increased number of self-monitoring of blood glucose values and a decrease in the number of hypoglycaemic events in those with the best metabolic control, whereas there were no association with the use of new analogous or insulin regimens.

A nationwide halving in rates of severe hypoglycemia was observed during the study period independent of the prevailing average HbA1c level. Changes in diabetes care and successful educational programs may have influenced the lower incidence rate of severe hypoglycemia.

Maternal sustained smoking during pregnancy is associated with lower risk of type 1 diabetes in children. This sheds new light on the potential intrauterine environmental origins of the disease.