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.