Islet amyloid polypeptide (IAPP) is a novel amyloid-forming beta-cell hormone with putative roles in glucose metabolism and non-insulin-dependent diabetes mellitus (NIDDM) pathogenesis. To study how IAPP and insulin expression are regulated by glucose, rats were fasted for 48h followed by administration of glucose at repeated 4-h intervals; IAPP and insulin mRNA levels were determined by quantitative in situ hybridization. Fasting markedly reduced IAPP and insulin mRNA levels. Two (6 h) and four (14 h) glucose injections dose dependently increased both mRNA levels; the effects were matched by similar changes in plasma glucose levels. Actinomycin D blocked the glucose-induced increase in IAPP expression. IAPP and insulin mRNA levels were significantly correlated over the range of glucose levels. The parallel regulation of IAPP and insulin gene expression by glucose is consistent with a role for IAPP in glucose homeostasis. Thus, under hyperglycemic conditions such as NIDDM, IAPP gene expression is likely to increase. Hence, IAPP could, by elevated local concentrations, contribute to amyloid formation and/or affect metabolism unfavorably by inhibition of insulin release and action.