Cyclosporin Increases the Rate and Length of Remissions in Insulin-Dependent Diabetes of Recent Onset

Feutren, G.; Assan, R; Karsenty, Gérard; Rostu, H. Du; Sirmai, Jean; Papoz, L; Vialettes, B.; Vexiau, P.; Rodier, M.; Lallemand, A; Bach, Jean‐François

doi:10.1016/s0140-6736(86)91943-4

Cited by 421 publications

(179 citation statements)

References 21 publications

Supporting

Mentioning

165

Contrasting

Unclassified

Order By: Relevance

“…The morbidity associated with diabetes has encouraged research into ways to cure or prevent this chronic disease. Recent immunointervention trials have indicated that if such treatment is to be effective it should be initiated at the early stages of the disease [3,4], at a time where the residual Beta-cell mass is sufficient to fulfill insulin needs. Evidence has accumulated that despite its acute onset, Type 1 diabetes is preceded by a long prodromal period * Members of the Lyons' family study also include Prs EBerthez~-ne, R. Mornex, J. Tourniaire during which Beta-cells are progressively destroyed.…”

Section: Discussionmentioning

confidence: 99%

“…Immunosuppression had been found to be efficient in Type i diabetes when given at clinical presentation leading to an increase in the prevalence of complete remissions [3]. However, in order to prevent the disease, such treatment should be given earlier, at a time when the residual Beta-cell mass is sufficient to fulfill insulin needs.…”

Section: Discussionmentioning

confidence: 99%

“…Between January 1982 and October 1990, 708 first-degree relatives were enrolled in the screening programme, including 374 parents, 308 siblings, and 26 children of 228 Type i diabetic patients. The mean number of relatives per family tested was 3.1 [1][2][3][4][5][6][7]. This population was composed from 6 multiplex families.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Autoantibodies and genetic factors associated with the development of Type 1 (insulin-dependent) diabetes mellitus in first degree relatives of diabetic patients

et al. 1991

View full text Add to dashboard Cite

Summary.Factors associated with diabetes onset were analysed for their predictive value in 708 first-degree relatives of Type 1 (insulin-dependent) diabetic patients including 374 parents and 308 siblings of Type i diabetic patients. Relatives were prospectively followed for 2 304 subject years with blood samples for specific autoantibody evaluation. Islet cell cytoplasmic autoantibody titres were quantified in Juvenile Diabetes Foundation units with a threshold of positivity of 5 units. Insulin autoantibodies were determined using Tyr-A14 iodinated human insulin. HLA typing was performed in 92% of the relatives. During the time of study, 17 of 646 (2.6%) relatives showed islet cell antibodies. During follow-up, eight relatives developed diabetes, including six with high islet cell antibody titre. Taking titres above 20 units increased the positive predictive value from 35% to 75% whereas the presence of insulin autoantibodies did not increase the positive predictive value for the disease. Analysis of metabolic profiles months before the onset of diabetes by either oral or intravenous glucose loads, indicated a considerable level of heterogeneity with relatives with a high islet cell antibody titre who rapidly developed insulin-dependent diabetes, whereas others remained insulin-independent during the same observation period despite comparable titres. This study clearly indicates that initial islet cell antibody titre is not sufficient to predict individual outcome. Follow-up samples are clearly needed to monitor progression of the disease. Few relatives with persistent immunologic positivity progress to clinical Type 1 diabetes, suggesting that non-progressive and sub-clinical Beta-cell dysfunction is common. Despite current knowledge and available genetic and immune markers, early identification of the relatives progressing to clinical diabetes is still difficult and does not allow at the present time aggressive immunointervention at the prediabetic stage.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Autoantibodies and genetic factors associated with the development of Type 1 (insulin-dependent) diabetes mellitus in first degree relatives of diabetic patients

et al. 1991

View full text Add to dashboard Cite

show abstract

“…frequency of non-insulin requiring remission and on C-peptide levels [9,10]. The effect of cyclosporin on proinsulin levels is unknown.…”

mentioning

confidence: 99%

Proinsulin and C-peptide at onset and during 12 months cyclosporin treatment of Type 1 (insulin-dependent) diabetes mellitus

Snorgaard¹,

Hartling²,

Binder³

1990

Diabetologia

View full text Add to dashboard Cite

Smnmary. An increased proinsulin to C-peptide molar ratio at the onset of Type i (insulin-dependent) diabetes mellitus has been suggested. We studied fasting proinsulin levels and proinsulin/C-peptide ratios in the newly diagnosed diabetic subjects participating in the Canadian/European placebo controlled cyclosporin study at entry, during the one year treatment period and six months of follow-up. Available entry data from 176 out of the 188 allocated patients were compared to 60 age and weight matched control subjects. Fasting proinsulin was significantly elevated in male patients compared to male control subjects (p < 0.01), whereas the levels only tended to be elevated in female patients. The proinsulin/C-peptide ratio was three to fourfold elevated in the diabetic groups of both sexes, (p < 0.001). Further, proinsulin and C-peptide were studied in 83 cyclosporin and 86 placebo-treated subjects during the trial and follow-up. An additional increase of proinsulin/C-peptide ratio was observed during the first three months of placebo treatment. It remained constantly high for nine months and then declined to entry level. This pattern was not seen in the cyclosporintreated group, where the ratio was unchanged during the 12 months trial and follow-up. The effect of cyclosporin on the induction of non-insulin requiring remission was unrelated to fasting and glucagon stimulated C-peptide levels at entry, whereas 64% of the cyclosporin-treated against 28% of the placebo-treated subjects (p < 0.01) went into remission if the proinsulin/C-peptide ratio at entry was above 0.024. If the ratio was below 0.024 at entry, 42% and 33% went into noninsulin requiring remission, respectively (NS). We conclude that fasting proinsulin to C-peptide molar ratio is elevated at the onset of Type i diabetes mellitus. A further plateaushape elevation lasting nine months was seen during the remission period. Cyclosporin seems to inhibit or delay this development. The proinsulin/C-peptide ratio at diagnosis may show to be of value in the prediction of remission during cyclosporin treatment.

show abstract

“…Early human studies of immune intervention concentrated on the attempt to prolong beta-cell function in recently diagnosed patients requiring insulin therapy. Prospective randomised placebo controlled double-blind studies showed, for example, that Cyclosporin A can protect beta-cell function to the extent that some 25% of patients on Cyclosporin were able to control their diabetes on diet alone one year after diagnosis, as against 5 to 10% of controls [15,16]. Unfortunately this benefit does not persist, and the high rate of complications has limited this approach to therapy.…”

Section: Discussionmentioning

confidence: 99%

Intervening before the onset of Type 1 diabetes: baseline data from the European Nicotinamide Diabetes Intervention Trial (ENDIT)

Gale

Inte²

2003

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis To set up a clinical trial to establish whether nicotinamide can prevent or delay clinical onset of Type 1 diabetes.Method The European Nicotinamide Diabetes Intervention Trial is a randomised, double-blind, placebo-controlled intervention trial undertaken in 18 European countries, Canada and the USA.Entry criteria were a first-degree family history of Type 1 diabetes, age 3-40 years, confirmed islet cell antibody (ICA) levels greater than or equal to 20 JDF units, and a non-diabetic OGTT; the study group was further characterised by intravenous glucose tolerance testing, measurement of antibodies to GAD, IA-2 and insulin and HLA class II genotyping.Results ICA screening was carried out in approximately 30,000 first-degree relatives. A total of 1004 individuals fulfilled ICA criteria for eligibility, and 552 (288 male) were randomised to treatment. Of these, 331 were aged less than 20 years (87% siblings and 13% offspring of the proband with diabetes) and 221 were 20 years of age or more (76% parents, 21% siblings and 3% offspring). Oral glucose tolerance was normal in 500 and impaired in 52 (9.4%), and first phase 1 insulin response in the IVGTT was below the 10 th centile in 34%. Additional islet autoantibodies were identified in 354 trial entrants. Diabetes-associated HLA class II haplotypes were found in 84% of the younger age group and 80% of the older group. The protective haplotype HLA-DQA1*0102-DQB1*0602 was found in 10% overall.Conclusions/interpretation ENDIT has shown that a trial of an intervention designed to halt or delay progression to Type 1 diabetes can be carried out on a multinational collaborative basis, as and when potentially safe and effective forms of intervention become available. Primary screening with biochemically defined autoantibodies will substantially reduce the number of lower risk individuals to be included in future intervention trials Europe includes countries with the highest incidence of Type 1 (insulin-dependent) diabetes mellitus in the world. These rates continue to rise rapidly, and the EURODIAB TIGER Concerted Action has shown an annual 3 to 4% increase in the incidence of childhood diabetes across our continent [1]. In Finland, it is estimated that childhood diabetes is now four times as common as 2 it was in the 1950s [2]. There is currently no means of preventing or curing this disorder. Type 1 diabetes can, however, be predicted by screening for islet autoantibodies, and both animal and human pilot studies suggest that prevention is possible. The US Diabetes Prevention Trial-Type 1 (DPT-1) has recently reported experience with parenteral insulin therapy in high risk relatives of an individual with Type 1 diabetes [3]. Here we show baseline data from a trial of high-dose oral nicotinamide, and demonstrate that a candidate preventive measure can be tested successfully on a multinational collaborative basis. MethodsStudy Design ENDIT is a randomised, double-blind, placebo controlled trial designed to test whether daily oral administration of hi...

show abstract

Cyclosporin Increases the Rate and Length of Remissions in Insulin-Dependent Diabetes of Recent Onset

Cited by 421 publications

References 21 publications

Autoantibodies and genetic factors associated with the development of Type 1 (insulin-dependent) diabetes mellitus in first degree relatives of diabetic patients

Autoantibodies and genetic factors associated with the development of Type 1 (insulin-dependent) diabetes mellitus in first degree relatives of diabetic patients

Proinsulin and C-peptide at onset and during 12 months cyclosporin treatment of Type 1 (insulin-dependent) diabetes mellitus

Intervening before the onset of Type 1 diabetes: baseline data from the European Nicotinamide Diabetes Intervention Trial (ENDIT)

Contact Info

Product

Resources

About