HUMAN-LEUKOCYTE ANTIGEN IDENTITY AND DQ RISK ALLELES IN AUTOANTIBODY-POSITIVE SIBLINGS OF CHILDREN WITH IDDM ARE ASSOCIATED WITH REDUCED EARLY INSULIN-RESPONSE

To investigate the relationship between human leukocyte antigen (HLA)- associated genetic factors and the development of beta-cell dysfunctio n, we performed sequential intravenous glucose tolerance tests (IVGTTs ) on 81 islet cell antibody (ICA)-positive and/or insulin antoantibody -positive healthy siblings of children with newly diagnosed insulin-de pendent diabetes mellitus (IDDM). A lower glucose disappearance rate ( k(g)) (P < 0.05) and decreased first-phase insulin response (FPIR) (P < 0.05) were observed on multiple occasions in HLA-identical siblings compared with the haploidentical or nonidentical ones, Siblings carryi ng the DQB10302/0201, -0302/x, or -0201/x genotype also had lower FPI Rs (P less than or equal to 0.05) at several time points than those wi th no DQB1 risk genotype. When all IVGTTs were taken into account, DQB 10302/0201 heterozygous siblings had an abnormally low FPIR (<45 mU/l ; 3rd percentile) in at least one test more often than did siblings wi th no DQB1 risk genotype (50.0% vs, 6.1%; P = 0.001), Siblings carryin g either the DQB10602 or the DQB1*0603 protective allele had lower se rum peak ICA and glutamic acid decarboxylase (GAD)(65) antibody levels (P = 0.023 and 0.007, respectively) and higher FPIRs on several occas ions (P < 0.05) than those with the DQB1 risk genotypes, Progression t o IDDM was related to both HLA identity and the presence of the DQB10 302/0201 genotype, Normal K-g and FPIR levels were observed in sibling s who were positive for only insulin autoantibody, and none of them de veloped IDDM, Serum ICA concentrations were inversely correlated with K-g (r(s) = -0.41; P < 0.001) and FPIR. (r(s) = -0.52; P < 0.001) in t he first IVGTT, suggesting that high serum levels of ICA could to some extent be nsed as an indicator of impaired insulin-secretory capacity in the beta-cells. We conclude that both HLA identity and the presenc e of DQB1 risk genotype were associated with a decreased early insulin response to intravenous glucose in ICA(+) siblings of diabetic childr en, HLA identity was also associated with impaired glucose tolerance.