Increased major histocompatibility complex (MHC) class I gene expression in target tissues may be relevant to the pathogenesis of autoimmune diseases. In this study, we questioned whether high glucose levels might increase MHC class I levels and thereby contribute to autoimmune complications. We used thyrocytes in continuous culture, because there is an increased incidence of autoimmune thyroiditis in type 2 diabetics and because transcriptional regulation of MHC class I is well studied in these cells. Northern analysis and flow cytometry showed that 20 and 30 mM D-glucose up-regulated MHC class I expression and that the glucose effect was additive to and independent of interferon-gamma. The effect was specific, because L-glucose did not modify class I expression. The glucose acted transcriptionally, requiring both enhancer A and a cAMP-response element-like element located in the hormone-sensitive region of the MHC class I 5'flanking region. These elements are different from those activated by interferon-gamma. High glucose levels increase formation of the MOD-1 complex with enhancer A; MOD-1 is a heterodimer of fra-2 and the p50 subunit of NF-kappaB. Both TSH and insulin are required for full expression of the glucose activity in thyrocytes. The glucose effect is partially blocked by wortmannin, suggesting involvement of the PI3K signal system. The data support the possibility that high serum glucose levels in type 2 diabetic patients may increase MHC class I levels in target tissues and contribute to autoimmune complications of the disease.