Abstract
Fusion proteins made up of glucagon-like peptide 1 (GLP-1) and exendin-4 (EX-4) fused to a nonglycosylated form of human transferrin (GLP-1-Tf or EX-4-Tf) were produced and characterized. GLP-1-Tf activated the GLP-1 receptor, was resistant to inactivation by peptidases, and had a half-life of approximately 2 days, compared with 1 to 2 min for native GLP-1. GLP-1-Tf retained the acute, glucose-dependent insulin-secretory properties of native GLP-1 in diabetic animals and had a profound effect on proliferation of pancreatic beta-cells. In addition, Tf and the fusion proteins did not cross the blood-brain-barrier but still reduced food intake after peripheral administration. EX-4-Tf proved to be as effective as EX-4 but had longer lived effects on blood glucose and food intake. This novel transferrin fusion technology could improve the pharmacology of various peptides.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Blood Glucose / metabolism
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CHO Cells
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Cell Proliferation / drug effects
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Cricetinae
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Cricetulus
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Diabetes Mellitus / drug therapy
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Diabetes Mellitus / genetics
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Diabetes Mellitus / metabolism
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Dipeptidyl Peptidase 4 / metabolism
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Eating / drug effects
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Enzyme-Linked Immunosorbent Assay
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Genes, fos / drug effects
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Glucagon-Like Peptide 1 / genetics
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Glucagon-Like Peptide-1 Receptor
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Half-Life
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Humans
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Hypoglycemic Agents / pharmacokinetics*
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In Vitro Techniques
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Insulin / metabolism*
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Insulin-Secreting Cells / drug effects
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Islets of Langerhans / drug effects
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Islets of Langerhans / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Protein Engineering*
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Rats
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Rats, Sprague-Dawley
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Receptors, Glucagon / agonists
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Recombinant Fusion Proteins
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Saccharomyces cerevisiae / metabolism
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Transferrin / genetics*
Substances
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Blood Glucose
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GLP1R protein, human
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Glp1r protein, mouse
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Glp1r protein, rat
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Glucagon-Like Peptide-1 Receptor
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Hypoglycemic Agents
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Insulin
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Receptors, Glucagon
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Recombinant Fusion Proteins
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Transferrin
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Glucagon-Like Peptide 1
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Dipeptidyl Peptidase 4