Immune intervention at diagnosis - Should we treat children to preserve beta-cell function?
Department of Molecular and Clinical Science, Division of Pediatrics and Diabetes Research Centre, Faculty of Health Sciences, Linköping, Sweden.Pediatric Diabetes (Impact Factor: 2.57). 11/2007; 8 Suppl 6(s6):34-9. DOI: 10.1111/j.1399-5448.2007.00299.x
Type 1 diabetes (T1D) is characterized by loss of beta-cell function. If beta-cell function can be preserved, it will lead to improved metabolic balance with improved quality of life and fewer acute and late complications, and if residual insulin secretion improves well enough, then that could lead to complete remission and even cure of the disease. Several efforts to save residual beta-cell function have been made for more than three decades without success. Proof of principle has been possible, and it seems clear that immune suppression or immune modulation, in fact, can stop the destructive process and thereby preserve beta-cell function. However, the effect seen in adult patients with T1D have been minimal or absent in diabetic children who seem to have another or at least more aggressive disease process. Furthermore, the immune interventions have had too serious and common adverse events in comparison to the scarce-positive effect. Recent more specific immune modulation with anti-CD3 monoclonal antibodies seems more encouraging with at least postponement of the C-peptide decline, but unfortunately still with common and quite threatening adverse effects. Even more promising are the autoantigen therapies, of which glutamic acid decarboxylase (GAD) vaccination has shown good results with impressive preservation of residual insulin secretion in 10- to 18-year-old type 1 diabetic patients with recent onset. In patients with short diabetes duration at intervention the effect was remarkable. Furthermore, these effects were achieved with no adverse events. Future studies will show whether the good effect seen so far can be confirmed. If so there is hope that GAD vaccination will cause remission and even cure and prevention of T1D will then no longer be just a dream.
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ABSTRACT: Considerable advances have been made in insulin pharmacology and pharmacotherapeutics in the 77 years since its discovery by Frederick Banting and Charles Best at the University of Toronto. Nevertheless, even the most sophisticated regimens of diabetes management still do not replace insulin in a physiological manner, i.e. by portal secretion in precise amounts to respond to ingested nutrients and other secretogogues. It is for these reasons that insulin remains just one of many facets of optimal diabetes care. Further advances in the next few years can be expected to change some aspects of insulin therapeutics. However, in the absence of perfect physiological replacement, the goal of diabetes management remains the balancing of the different components of therapy in order to achieve the best possible metabolic control.Diabetes, nutrition & metabolism 05/1999; 12(2):86-95.
Article: Personalized Medicine for DiabetesJournal of diabetes science and technology 05/2008; 2(3):335-41. DOI:10.1177/193229680800200301
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ABSTRACT: In mouse models of diabetes, prophylactic administration of insulin reduced incidence of the disease. We investigated whether administration of nasal insulin decreased the incidence of type 1 diabetes, in children with HLA genotypes and autoantibodies increasing the risk of the disease. At three university hospitals in Turku, Oulu, and Tampere (Finland), we analysed cord blood samples of 116 720 consecutively born infants, and 3430 of their siblings, for the HLA-DQB1 susceptibility alleles for type 1 diabetes. 17 397 infants and 1613 siblings had increased genetic risk, of whom 11 225 and 1574, respectively, consented to screening of diabetes-associated autoantibodies at every 3-12 months. In a double-blind trial, we randomly assigned 224 infants and 40 siblings positive for two or more autoantibodies, in consecutive samples, to receive short-acting human insulin (1 unit/kg; n=115 and n=22) or placebo (n=109 and n=18) once a day intranasally. We used a restricted randomisation, stratified by site, with permuted blocks of size two. Primary endpoint was diagnosis of diabetes. Analysis was by intention to treat. The study was terminated early because insulin had no beneficial effect. This study is registered with ClinicalTrials.gov, number NCT00223613. Median duration of the intervention was 1.8 years (range 0-9.7). Diabetes was diagnosed in 49 index children randomised to receive insulin, and in 47 randomised to placebo (hazard ratio [HR] 1.14; 95% CI 0.73-1.77). 42 and 38 of these children, respectively, continued treatment until diagnosis, with yearly rates of diabetes onset of 16.8% (95% CI 11.7-21.9) and 15.3% (10.5-20.2). Seven siblings were diagnosed with diabetes in the insulin group, versus six in the placebo group (HR 1.93; 0.56-6.77). In all randomised children, diabetes was diagnosed in 56 in the insulin group, and 53 in the placebo group (HR 0.98; 0.67-1.43, p=0.91). In children with HLA-conferred susceptibility to diabetes, administration of nasal insulin, started soon after detection of autoantibodies, could not be shown to prevent or delay type 1 diabetes.The Lancet 10/2008; 372(9651):1746-55. DOI:10.1016/S0140-6736(08)61309-4 · 45.22 Impact Factor
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