Nutrient-independent increases in proglucagon and ornithine decarboxylase messenger RNAs after jejunoileal resection.

To assess potential mediators of adaptive bowel growth, ileal proglucagon messenger RNA (mRNA) ornithine decarboxylase (ODC) mRNA, plasma enteroglucagons, and plasma glucagonlike peptide I (GLP-I) were analyzed in rats soon after jejunoileal resection or control transection. Analyses were performed before and after refeeding to establish whether responses are nutrient dependent. The elevation of ileal proglucagon and ODC mRNAs within 12 hours after resection and before refeeding shows a nutrient-independent component of the adaptive response. The onset of adaptive growth of the ileum required luminal nutrient but occurred very rapidly, within 4 hours of refeeding. The onset of adaptive growth was accompanied by transient elevation of ileal ODC mRNAs. Ileal proglucagon mRNA and plasma GLP-I levels were also elevated, and these increases were sustained up to 8 days after resection. These early and sustained increases in proglucagon mRNA and plasma GLP-I indicate that in addition to the enteroglucagons, other intestinal proglucagon-derived peptides must be considered as potential mediators of adaptive growth after jejunoileal resection.

Molecular biology of gastrointestinal peptides and growth factors: relevance to intestinal adaptation.

New approaches towards understanding regulation of growth and adaptation of the small intestine are made possible by the isolation and characterization of genes and complementary DNAs (cDNAs) encoding gastrointestinal peptides, growth factors and their receptors. Nucleotide sequencing provides prerequisite structural information. Analyses of gene expression by quantitation and localization of mRNAs provide information about correlations between local alterations in peptide or receptor synthesis and intestinal growth. Analyses of intestinal growth in transgenic animals that overexpress or underexpress growth factor or receptor genes provides direct information about peptide effects on growth. Our recent studies with genes and cDNAs encoding proglucagon and the growth hormone dependent insulin-like growth factor 1 (IGF-I) represent examples of these approaches. Sequences of proglucagon and IGF-I cDNAs provide the primary structures of the peptide precursors. Analyses of proglucagon mRNA during adaptive growth after small bowel resection indicate that increases in proglucagon gene transcription or mRNA stability underly previously observed increases in serum enteroglucagons during adaptive growth. Analyses of IGF-I mRNAs in intestine indicate that small intestine expresses only a subset of the IGF-I mRNAs expressed in liver due to utilization of specific promotors and/or exon splicing mechanisms. Oligomers derived from the 3' end of the rat IGF-I gene detect a novel intestinal specific IGF-I related mRNA that shows an aboral decline in abundance from duodenum to colon and is upregulated in a number of situations of adaptive growth. Transgenic mice that overexpress growth hormone or IGF-I are under analysis to establish the effects of growth hormone and IGF-I on intestinal growth.