Cytoplasmic islet cell antibodies remain valuable in defining risk of progression to type 1 diabetes in subjects with other islet autoantibodies

Abstract

The discovery of islet cell antibodies (ICAs) was the prelude to the understanding that type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease. The issue regarding whether or not the measurement of ICAs should be completely replaced by biochemical markers detecting islet autoantibodies (AAs) for the prediction of T1DM has been the subject of endless international debates. In light of this controversy, we assessed the current role of ICAs as a predictive marker for T1DM progression. We examined a cohort of 1484 first-degree relatives (FDRs) of T1DM probands from the Children's Hospital of Pittsburgh Registry. These relatives were consecutively enrolled between 1979 through 1984 and followed up to 22 yr. Serum obtained at the time of enrollment was assayed for ICAs, glutamic acid decarboxylase (GAD)65, insulin A (IA)-2 AA, and insulin AAs (IAAs). In FDRs who had ICAs in addition to GAD65 and IA-2 AAs, the cumulative risk of developing insulin-requiring diabetes was 80% at 6.7 yr of follow-up, whereas this risk in those with GAD65 and IA-2 AAs without ICAs was only 14% at 10 yr of follow-up (log rank: P < 0.00001). Cox regression analysis showed that diabetes risk was significantly associated with the presence of ICAs in both subjects with low titer and high titer GAD65 and IA-2 AAs. The addition of IAAs in GAD65 and IA-2 AA-positive relatives did not increase the cumulative risk for conversion to insulin-treated diabetes. We provide evidence that a subgroup of ICAs predicts a more rapid progression to insulin-requiring diabetes in GAD65 and IA-2 AA-positive relatives and should remain part of the assessment of T1DM risk for intervention trials. In addition, these findings provide impetus for efforts to identify a novel islet autoantigen(s) reactive with this ICA subset.

Primer: Immunity and Autoimmunity

“…There is convincing evidence that islet autoantibody responses against multiple islet autoantigens are associated with progression to overt disease (42). More recently, we provided evidence suggesting that a subset of cytoplasmic ICA is related to a more rapid progression to insulin-requiring diabetes in GAD65 and IA-2 antibody-positive relatives compared with relatives with GAD65 and IA-2 antibodies without ICA (44). We believe that this ICA response is more than likely caused by a subset of the ICA reacting with unidentified islet autoantigen(s).…”

The Heterogeneity of Diabetes

“…Recently, we provided evidence suggesting that a subset of cytoplasmic islet cell antibodies (ICAs) is related to a more rapid progression to insulin-requiring diabetes in GAD65-and IA-2 antibodypositive relatives as compared with relatives with GAD65 and IA-2 antibodies without ICA. This ICA reactivity more than likely is caused by a subset of ICA-recognizing unidentified islet autoantigen(s) (27). Although a pathogenic role of these islet autoantibodies has not been demonstrated, recent observations showed that injection of mice with IgG purified from type 1 diabetic patients induced bladder antibody-mediated dysfunction, which mimicked the effect of L-type voltage-gated calcium channel (VGCC) agonists (28).…”

Prediction of type 1 diabetes among siblings of affected children and in the general population

“…The first data on the predictive value of autoantibodies for type 1 diabetes were obtained by screening first-degree relatives of affected patients for islet cell antibodies (ICA), which represent a heterogeneous group of antibodies to a series of known islet antigens, including autoantibodies against islet antigen 2 (IA-2A) and GAD (GADA), as well as antibodies to one or more so far unidentified antigens [1]. More recent studies have indicated that while identifying first-degree relatives with an elevated disease risk, ICA screening could be replaced with screening for GADA and IA-2A [2], and accordingly current guidelines for the primary testing of this population recommend the measurement of GADA along with either IA-2A or autoantibodies against insulin (IAA) [3].…”