Dual-acting peptide with prolonged glucagon-like peptide-1 receptor agonist and glucagon receptor antagonist activity for the treatment of type 2 diabetes.
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.
Claus
Thomas H
TH
Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, CA 94701, USA.
Pan
Clark Q
CQ
Buxton
Joanne M
JM
Yang
Ling
L
Reynolds
Jennifer C
JC
Barucci
Nicole
N
Burns
Michael
M
Ortiz
Astrid A
AA
Roczniak
Steve
S
Livingston
James N
JN
Clairmont
Kevin B
KB
Whelan
James P
JP
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
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