An increased ratio of islet amyloid polypeptide (IAPP) to insulin for mRNA and peptide content in pancreatic extracts and for secretion has been observed in experimental diabetes, suggesting a differentially regulated IAPP and insulin expression. Therefore, we investigated the islet expression of IAPP and insulin in streptozotocin and alloxan diabetic rats and mice, using in situ hybridization and immunocytochemistry. A low dose of streptozotocin equivalently reduced IAPP and insulin mRNA levels to approximately 45% of controls. In contrast, a high dose of streptozotocin or alloxan reduced IAPP mRNA levels significantly less than those of insulin mRNA (streptozotocin: 24 vs. 15%, P = 0.011; alloxan: 15 vs. 6%, P < 0.0001). In situ hybridization and immunocytochemistry revealed expression of IAPP in experimental diabetes to occur predominantly in insulin cells. Thus, IAPP and insulin gene expression are differentially regulated in experimental diabetes in rodents and IAPP is predominantly expressed in insulin cells.