Predictive markers of type 1 diabetes in sibs of diabetic patients

الملخص EN

Background: Different genetic, autoimmune, and metabolic markers could be employed for prediction of type1diabetes (T1D) in individuals at high risk of disease.

The genome-wide search identified more than 15 chromosomal regions that may contribute to the genetic predisposition to T1D.

Over 90 percent of patients with type 1 diabetes carry DR4, DQB*0302 and / or DR3, DQB*0201.

Multiple islet autoantibody positivity is currently believed to best predict progression to TID, of these autoimmune markers islet cell cytoplasmic antibodies (ICA) and antibodies to glutamic acid decarboxylase (GAD A).

A reduced first phase insulin release (FPIR) to intravenous glucose is perceived as a sign of far-advanced deterioration of beta cell function during the development of TID.

The aim of this study was to identify the sibs at high risk of development TID depending on the presence of multiple auto antibodies and HLA DQB1 alleles known to predispose to TID as well as reduced FPIR with ultimate goals of prevention of TID in these sibs. Methods: Forty-nine sibs of patients with TID as well as 27 diabetic children (for comparison) were analyzed for glutamic acid decarboxylate antibodies (GAD), islet cell autoantibodies (ICA).

All subjects performed HLA studies searching for the presence of DQB1 alleles related to genetic susceptibility for TID: HLA DQB1 0201 and HLA DQB1 0302.

FPIR was done for 15 sibs having one or two positive antibodies.

Twenty healthy controls for GAD Ab and six for FPIR were also included. Results: Mean age of siblings was 6.94 ± 3.19 yr, 26 females (53.06%) and 23 males (46.93%).

Nine sibs out of 49 (18.4%) showed positive GAD antibodies and 16 / 49 sibs (32.7%) were positive for IC antibodies.

Of these, five sibs only (10%) showed positive both antibodies.

While in diabetics 18 / 27 (66.7%) showed positive GAD antibodies and 19 / 27 diabetics (70.4%) had positive IC antibodies, 15 (55.6%) of them had positive both antibodies.

Twenty-six sibs (53.1%) had the HLA DQB1 0201 while 21 sibs (42.9%) had the HLA DQB1 0302 alleles, 15 of them (30.6%) had both alleles.

However in diabetics, 23 / 27 (85%) had positive HLA 0201 allele and 15 / 27 (55.6%) had positive HLA 0302 and 14 of them (51.85%) had both alleles. FPIR was performed for 15 sibs (12 were positive for one antibody and 3 were positive for two antibodies), 7 sibs had preserved FPIR and 8 sibs were in the high risk group with reduced FPIR less than the 5th percentile.

We found that the mean level of FPIR in sibs with two positive antibodies was significantly lower than those with one positive antibody (46.13 mU / L ± 3.33 Vs 151.84 mU / L ± 100.84 respectively) with P-value <0.005.

Also we found that 7/ 8 of sibs having FPIR below the 5th percentile have the two studied predisposing DQB1 alleles and the remaining one has one predisposing allele. Conclusion: we conclude that sibs of type 1 diabetics had variable combinations of immune, genetic and metabolic factors.

Longer follow-up period is needed to test the sensitivity and specificity of these markers in prediction of diabetes.