Type I diabetes mellitus: a predictable autoimmune disease with interindividual variation in the rate of beta cell destruction

A large body of data generated during the past two decades has led to the ability to predict the development of Type I diabetes in the majority of relatives of diabetics. In particular we have recently proposed a dual parameter linear model to aid in predicting the onset of diabetes [years to diabetes = 1.5 + .03(IVGTT insulin secretion) - 0.008 (concn of insulin autoantibodies)]. The concentration of insulin autoantibodies in prediabetics appears to remarkably correlate with the age at which diabetes develops and the rate at which islet cell antibody-positive individuals progress to diabetes. Children developing diabetes before Age 5 often express more than 1000 nU/ml of such antibodies with the upper limit of normal of 39 nU/ml. Each prediabetic appears to be set at a characteristic level of insulin autoantibodies which does not consistently vary prior to the development of diabetes. During the prodromal phase preceding diabetes first phase insulin secretion is progressively lost, and the combination of insulin release which appears to reflect beta cell damage and the level of insulin antibodies accounts for more than 75% of the variation in time to diabetes over a 6-year interval. A subset of NOD mice also expresses insulin autoantibodies, and in addition essentially all NOD mice, but not F1 crosses of NOD by BALB/c, have antibodies to a target antigen of a RIN islet line protein (termed "polar antibodies"). In addition patients but not NOD mice have cytoplasmic islet cell antibodies which appear to react with a glycolipid islet target antigen. In the NOD mice the inheritance of disease is multigenic with a gene on chromosome 9, linked to the T cell marker theta, determining the bulk of islet cell destruction. In crosses of NOD mice with a series of normal strains, inheritance overt diabetes is correlated with inheritance of the NOD's unique I-A beta gene, though the bulk of islet destruction and insulitis can occur independent of MHC inheritance. Until the additional genes outside of the MHC, associated with the development of Type I diabetes, are identified for man, the NOD mouse, and the BB rat, one can only speculate concerning pathogenic mechanisms. To date islet cell destruction appears to be independent of polymorphic genes acting at the level of the islet target, and crucially dependent upon bone marrow precursor cells.