The proglucagon-derived peptides (PGDPs) play key roles in the regulation of carbohydrate metabolism and insulin secretion, yet the factors important for the regulation of proglucagon gene expression remain poorly understood. Recent experiments demonstrated that nude mice carrying subcutaneous proglucagon-SV40 T antigen tumors contained markedly reduced levels of the pancreatic PGDPs. To determine if elevated circulating levels of the PGDPs are consistently associated with inhibition of endogenous pancreatic proglucagon gene expression, we have now studied islet hormone gene expression in mice bearing three different endocrine tumors (InR1-G9, RIN1056A, and STC-1) that express the proglucagon gene. All tumors synthesized large amounts of the PGDPs. Plasma levels of the PGDPs were elevated in all tumor-bearing mice (8- to 22-fold greater than controls, P < 0.001), and this was associated with marked inhibition of mouse pancreatic proglucagon gene expression. The levels of pancreatic PGDPs were also significantly lower in tumor-bearing mice compared with controls (71 +/- 4, 38 +/- 6, and 18 +/- 2% of controls for InR1-G9-, RIN1056A-, and STC-1-bearing mice, respectively, P < 0.05-0.001). This inhibition of proglucagon gene expression was highly specific, in that no consistent change in pancreatic insulin or somatostatin gene expression was detected. Examination of proglucagon posttranslational processing in the tumors demonstrated that proglucagon was processed differently in each tumor to yield a unique profile of PGDPs. These observations demonstrate that elevated circulating levels of the PGDPs are associated with reduction in islet size and inhibition of proglucagon gene expression and PGDP synthesis in the pancreatic A cell.