In insulin-dependent diabetes mellitus aberrant expression of major histocompatibility complex (MHC) class II antigens might induce autoimmune destruction of insulin-producing pancreatic beta cells. Here we demonstrate that already the expression of single MHC class II chains (E alpha k and E beta b) is sufficient to cause diabetes without affecting beta cell morphology and cell numbers. Our transgenes interfere at least in two points of insulin production leading to a severely diabetic phenotype. In one case E beta b expression led to a 10-30-fold decrease of mouse insulin mRNA. In another case E alpha k expression reduced insulin secretion to background levels. In addition, we also found a patchy distribution of both insulin and E alpha k expression, indicating heterogeneity of the beta cell population, without the concomitant development of diabetes. Although the transgenic E alpha k E beta b MHC class II molecules were expressed on the surface of pancreatic beta cells, the transgenic mice did not prove to be tolerant for I-E antigen. Autoimmune reactions remained absent showing that aberrant MHC class II expression on pancreatic beta cells alone is not sufficient for the development of autoimmune diabetes in mice.