OVEREXPRESSION OF BETA-2-MICROGLOBULIN IN TRANSGENIC MOUSE ISLET BETA-CELLS RESULTS IN DEFECTIVE INSULIN-SECRETION

Overexpression of heavy chains of the class I major histocompatibility complex in islet beta-cells of transgenic mice is known to induce nonimmune diabetes. We have now overexpressed the secretory protein beta-2-microglobulin in beta-cells. Transgenic mice of one lineage had normal islets. Mice of another lineage did not become overtly diabetic but showed significant depletion of beta-cell insulin. When mice were made homozygous for the transgene locus, they developed diabetes. Introduction of the beta-2-microglobulin chain into class I heavy chain transgenic mice resulted in a significant improvement in their islet morphology and insulin content, and the female mice remained normoglycemic. These results suggest that different transgene molecules overexpressed in beta-cells can cause islet dysfunction, though not necessarily overt diabetes, and that this effect is mediated by the level of transgene expression. Evidence is provided to show that beta-cell disruption by transgene overexpression occurs at the level of protein and involves a defect in insulin secretion.