Immunologic and Genetic Factors in Type

Under normal physiologic conditions, the entry of glucose into beta cells triggers the secretion of insulin (1) (Fig. 1). The released insulin is carried in the blood to peripheral tissues where it binds to insulin receptors, which are members of the receptor tyrosine kinase family. This initiates a cascade of transmembrane events resulting in the uptake of glucose by cells and its metabolism into energy or storage as glycogen (2). Defects anywhere along the beta cell-peripheral tissue pathway can result in hyperglycemia, but at the clinical level there are two major forms of diabetes: type 1 diabetes, previously known as juvenile or insulin-dependent diabetes, and type 2 diabetes, previously known as adult or non-insulin-dependent diabetes. Type 1 diabetes is caused by an absolute deficiency in the production of insulin as a result of destruction of pancreatic beta cells. About one million people in the United States suffer from this form of the disease. Type 2 diabetes is the more common form of the disease and afflicts about 16 million people. It is the result of a double defect: inadequate or inappropriate secretion of insulin by beta cells and resistance to the action of insulin in both peripheral tissues (e.g. muscle, adipose tissues) and beta cells. Insulin resistance occurs at the postinsulin receptor level and may be the result of a defect in any one of several genes or pathways as recently demonstrated in transgenic and knock-out mice (1, 2). The precise defect(s) in the human, however, is still not known. Over the last few years, evidence has accumulated that type 1 diabetes is an autoimmune disease or at least has a major autoimmune component. The evidence comes from three sources: the presence of an inflammatory infiltrate (insulitis) in the islets; a strong linkage between type 1 diabetes and certain alleles of the major histocompatibility complex (MHC); and autoantibodies that react with islet cell autoantigens. The purpose of this article on type 1 diabetes is to review some of this evidence with emphasis on the immunological and genetic factors involved in prediction of disease and destruction of beta cells.