The synthesis and secretion of proglucagon-derived peptides are regulated in a tissue-specific manner in pancreas, intestine, and brain. We have examined the plasma and tissue levels of these peptides during the first 3 weeks of streptozotocin (STZ)-induced diabetes in the rat. Plasma glucose levels were markedly elevated (P less than 0.0001) within 24 h of STZ administration. The plasma levels of glucagon-like immunoreactive (GLI) peptides were significantly elevated on days 8-22 of diabetes (P less than 0.05-0.001). Ileal GLI peptide concentrations rose in parallel with the plasma levels (r = 0.39; P less than 0.006) to 250% of control levels (P less than 0.001); however, pancreatic GLI peptide content increased only transiently on day 1 (P less than 0.05). No significant differences in the posttranslational processing of proglucagon in normal or diabetic rats could be detected. The increment in ileal GLI peptide content was not associated with increases in intestinal proglucagon mRNA transcripts. In contrast, pancreatic, but not intestinal, somatostatin mRNA levels were increased on day 22 of diabetes. Diabetic rats were found to have small but significant changes in GLI and immunoreactive glucagon peptide content of the hypothalamus and medulla oblongata (P less than 0.05). These observations suggest that STZ-induced diabetes may produce tissue-specific perturbations in the biosynthesis and secretion of the proglucagon-derived peptides.