title: Dual-acting peptide with prolonged glucagon-like peptide-1 receptor agonist and glucagon receptor antagonist activity for the treatment of type 2 diabetes.
abstract: Type 2 diabetes is characterized by reduced insulin secretion from the pancreas and overproduction of glucose by the liver. Glucagon-like peptide-1 (GLP-1) promotes glucose-dependent insulin secretion from the pancreas, while glucagon promotes glucose output from the liver. Taking advantage of the homology between GLP-1 and glucagon, a GLP-1/glucagon hybrid peptide, dual-acting peptide for diabetes (DAPD), was identified with combined GLP-1 receptor agonist and glucagon receptor antagonist activity. To overcome its short plasma half-life DAPD was PEGylated, resulting in dramatically prolonged activity in vivo. PEGylated DAPD (PEG-DAPD) increases insulin and decreases glucose in a glucose tolerance test, evidence of GLP-1 receptor agonism. It also reduces blood glucose following a glucagon challenge and elevates fasting glucagon levels in mice, evidence of glucagon receptor antagonism. The PEG-DAPD effects on glucose tolerance are also observed in the presence of the GLP-1 antagonist peptide, exendin(9-39). An antidiabetic effect of PEG-DAPD is observed in db/db mice. Furthermore, PEGylation of DAPD eliminates the inhibition of gastrointestinal motility observed with GLP-1 and its analogues. Thus, PEG-DAPD has the potential to be developed as a novel dual-acting peptide to treat type 2 diabetes, with prolonged in vivo activity, and without the GI side-effects.
authors.affiliation: Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, CA 94701, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Claus
authors.forename: Clark Q
authors.initials: CQ
authors.lastname: Pan
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Buxton
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Reynolds
authors.forename: Nicole
authors.initials: N
authors.lastname: Barucci
authors.forename: Michael
authors.initials: M
authors.lastname: Burns
authors.forename: Astrid A
authors.initials: AA
authors.lastname: Ortiz
authors.forename: Steve
authors.initials: S
authors.lastname: Roczniak
authors.forename: James N
authors.initials: JN
authors.lastname: Livingston
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Clairmont
authors.forename: James P
authors.initials: JP
authors.lastname: Whelan
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects; D005934:Glucagon / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009765:Obesity / Q000097:blood / Q000188:drug therapy; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001786:Blood Glucose; C518717:DAPD peptide; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; C518718:PEG-DAPD peptide; D010446:Peptide Fragments; D010455:Peptides; D018027:Receptors, Glucagon; D011092:Polyethylene Glycols; C083773:exendin (9-39); D005934:Glucagon