Identical mRNA for preproglucagon in pancreas and gut

Abstract

The structure of the human glucagon gene and the sequence around the putative promoter region and transcriptional start site are shown. Cloning and sequencing of the cDNAs, coding for preproglucagon from human pancreas and colon, as well as primer extension analysis of RNA from pancreas, ileum and colon point' to an identical transcriptional start site in all tissues, about 3 x lo3 base pairs upstream from the first coding exon as defined by Bell et al. [I].Glucagon is a peptide hormone of 29 amino acids [2], which is produced and stored in granules in the A cells of the islets of Langerhans in the pancreas [3]. It controls the blood glucose levels by stimulating glycogenolysis and gluconeogenesis, counteracting the effects of insulin [4].Glicentin, the major form of the family of enteroglucagons [S], is a 69-amino-acid peptide hormone which contains the entire glucagon sequence in addition to 32 N-terminal and 8 C-terminal amino acids. Both glicentin and glucagon are cleavage products of an identical 180 amino acid precursor, which undergoes differential processing in the pancreas and the gut [l]. The precursor consists of a signal sequence, followed by glicentin and the major proglucagon fragment, which contains two glucagon-like peptide sequences, GLPI and GLPII. Glicentin is stored in granules in L cells in the intestinal mucosa [6]. The functions of enteroglucagon are not known with certainty, however, there is circumstantial evidence that it may be trophic for the intestinal mucosa as it is expressed at elevated levels during gut adaptation after gut resection and during lactation [7]. Low serum glucose levels, shortage of intracellular ATP as well as vasoactive intestinal peptide, which is supplied by peptidergic innervation of the pancreas and j-adrenergic agonists, increase glucagon release whereas insulin and somatostatin decrease glucagon release.Glicentin release seems to be regulated by luminal factors. It is increased mainly by food, intraluminal glucose and triglycerides [8] and possibly by neuroendocrine or paracrine effects of bombesin, but not by hypoglycemia, intravenous arginine or other factors, stimulating the release of glucagon (for review see [9]). The glucagon/enteroglucagon release thus seems to be regulated by different extracellular factors in the pancreas and the intestines and this may reflect differential expression of the gene.Differential gene expression can be achieved by a variety of mechanisms. The metallothionein gene, for example, retains the capacity to be activated by both glucocorticoids and heavy-metal ions by utilising control sequences specific for As a first step towards exploring the nature of the tissuespecific regulation of the human glucagon/enteroglucagon gene we have characterised the gene [l] at its 5' boundary and defined the transcriptional start sites in both pancreas and colon. MATERIALS AND METHODS Isolation of nucleic acidsHuman pancreas or intestinal mucosa were homogenised in the presence of 10 volumes of buffer containing 4 M guanidine thiocyanate buf...

Human colon produces fully processed glucagon‐like peptide‐1 (7–36) amide

“…In the pancreas, the major products are glicentin-related pancreatic polypeptide (GRPP; corresponding to PG 1-30), glucagon (PG 33-61) and the major proglucagon fragment (PG 72-158) [4], whilst in the small intestine, glicentin (PG 1-69), GRPP, oxyntomodulin (PG 33-69), glucagon-like peptide-1 (GLP-1; PG 78-107amide) and GLP-2 (PG 126-158) are the main molecular forms [reviewed in 5]. Many L-cells are also found in the large intestine, where the preproglucagon gene is also known to be expressed [1,6] in enteroglucagon producing cells [7,8]. GLP-1 and GLP-2 immunostaining is co-localised with glicentin/enteroglucagon staining in open-type endocrine cells in the ileum of all mammals studied so far [6,[9][10][11], and GLP-1 immunostaining has been shown in both the colon [12] and the rectum [10].…”

The Physiology of Glucagon-like Peptide 1

“…Also the murine and bovine genes were cloned (105,171). Apparently, only a single gene encodes proglucagon in mammalian species, and identical mRNAs are produced in the pancreas and the intestines (189,221). The differences in the proglucagon products in these tissues are, therefore, due to tissue-specific, differential, posttranslational processing of proglucagon (189,227).…”

The influence of the colon on postprandial glucagon-like peptide 1 (7-36) amide concentration in man

“…Expression occurs in both the pancreatic islets and the endocrine cells of the gastrointestinal mucosa (Novak et al 1987). In the pancreas, glucagon is the major biologically active hormone cleaved from proglucagon but in the small intestine cleavage sites differ and the glucagon sequence is contained within a larger molecule called glicentin which corresponds to PG 1-69 (Thim & Moody 1981).…”