Molecular forms of glucagon-like peptide-1 in human pancreas and glucagonomas.
The structure of human preproglucagon, as deduced from nucleotide sequencing of the preproglucagon gene, contains two glucagon-like peptides (GLP-1 and GLP-2) in the portion C-terminal to glucagon. A rabbit antiserum was raised against synthetic GLP-1-(1-19) which had 20% cross-reactivity with synthetic GLP-1 and des-Gly37-GLP-1 amide, two possible forms of the GLP-1 whole molecule, but no significant cross-reactivity with glucagon or other pancreatic peptides. Immunocytochemistry revealed that the distribution of GLP-1-(1-19) immunoreactivity followed that of glucagon-like immunoreactivity in the normal human pancreas and in two human glucagon-secreting pancreatic tumors. Chromatography of human pancreas extracts on Sephadex G-50 gave peaks of cross-reactivity at Kav values of 0.06-0.16, 0.34-0.39, 0.54-0.58 (the elution position of synthetic GLP-1), and 0.64-0.70. The concentration of immunoreactivity in the Kav 0.54-0.58 peak measured by RIA using GLP-1 or des-Gly37-GLP-1 amide as standard was 94 +/- 7 pmol/g (mean +/- SEM), while the total pancreatic glucagon content was 4.8 +/- 0.8 nmol/g. One extract of a human glucagon-secreting pancreatic tumor contained a prominent peak of GLP-1-(1-19) peptide cross-reactivity with properties identical to those of GLP-1 or des-Gly37-GLP-1 amide on gel filtration and reverse phase high pressure liquid chromatography, but another tumor contained a preponderance of cross-reactive forms of greater molecular size. Pretreatment plasma from three patients with radiological and biochemical evidence of glucagon-secreting tumors contained a peak of cross-reactivity with the chromatographic properties of intact GLP-1. The low concentrations of intact GLP-1 in normal pancreas compared with pancreatic glucagon concentrations suggest that the majority of the proglucagon is cleaved in a manner that does not produce GLP-1, as defined by its delimiting pairs of basic amino acid residues.
Uttenthal
L O
LO
Ghiglione
M
M
George
S K
SK
Bishop
A E
AE
Polak
J M
JM
Bloom
S R
SR
D007516:Adenoma, Islet Cell / Q000378:metabolism*; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D052216:Glucagon-Like Peptide 1; D053767:Glucagon-Like Peptide 2; D005935:Glucagonoma / Q000097:blood / Q000378:metabolism*; D006651:Histocytochemistry; D006801:Humans; D007124:Immunoenzyme Techniques; D010179:Pancreas / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000097:blood / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000097:blood / Q000378:metabolism*; D011863:Radioimmunoassay
D053767:Glucagon-Like Peptide 2; D010446:Peptide Fragments; D010455:Peptides; D052216:Glucagon-Like Peptide 1