DIABETES mellitus is simply defined on the basis of hyperglycemia. It is, however, a highly heterogeneous disease. A major advance was made in the late 1960s when insulin-dependent diabetes mellitus (IDDM, type 1) was distinguished from non-insulin-dependent diabetes mellitus (NIDDM, type 2). Another milestone was the realization in the 1970s that in most cases IDDM has, presumably, an autoimmune origin (1–4). This offered new clues to the etiology and elicited hopes of immunoprevention, which is still the ultimate goal of research in the immunology of IDDM.

This review will attempt to cover the major pending questions on the origin of the autoimmune process that leads to IDDM and will discuss in some depth genetic predisposition and environmental factors, the interaction of which creates the conditions required for disease onset. This will be followed by a characterization of the anti-β-cell immune response and the mechanisms by which the β-cell lesion is induced.