GLP-1-(9-36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion.
Glucagon-like peptide 1 (GLP-1) is a potent anti-hyperglycemic hormone currently under investigation for its therapeutic potential. However, due to rapid degradation by dipeptidyl peptidase IV (DPP IV), which limits its metabolic stability and eliminates its insulinotropic activity, it has been impossible to assess its true efficacy in vivo. In chloralose-anesthetized pigs given valine-pyrrolidide (to block endogenous DPP IV activity), the independent effects of GLP-1-(7-36) amide on glucose and insulin responses to intravenous glucose were assessed, and the metabolite generated by DPP IV, GLP-1-(9-36) amide, was investigated for any ability to influence these responses. GLP-1-(7-36) amide enhanced insulin secretion (P < 0.03 vs. vehicle), but GLP-1-(9-36) amide was without effect, either alone or when coinfused with GLP-1-(7-36) amide. In contrast, GLP-1-(9-36) amide did affect glucose responses (P < 0.03). Glucose excursions were greater after saline (121 +/- 17 mmol x l(-1) x min) than after GLP-1-(9-36) amide (73 +/- 19 mmol x l(-1) x min; P < 0.05), GLP-1-(7-36) amide (62 +/- 13 mmol x l(-1) x min; P < 0.02) or GLP-1-(7-36) amide + GLP-1-(9-36) amide (50 +/-13 mmol x l(-1) x min; P < 0.005). Glucose elimination rates were faster after GLP-1-(7-36) amide + (9-36) amide (10.3 +/- 1.2%/min) than after GLP-1-(7-36) amide (7.0 +/- 0.9%/min; P < 0.04), GLP-1-(9-36) amide (6.8 +/- 1.0%/min; P < 0.03), or saline (5.4 +/- 1.2%/min; P < 0.005). Glucagon concentrations were unaffected. These results demonstrate that GLP-1-(9-36) amide neither stimulates insulin secretion nor antagonizes the insulinotropic effect of GLP-1-(7-36) amide in vivo. Moreover, the metabolite itself possesses anti-hyperglycemic effects, supporting the hypothesis that selective DPP IV action is important in glucose homeostasis.
Deacon
Carolyn F
CF
Department of Medical Physiology, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark. deacon@mfi.ku.dk
Plamboeck
Astrid
A
Møller
Søren
S
Holst
Jens J
JJ
D000758:Anesthesia; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002698:Chloralose; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives; D004763:Glucagon-Like Peptides; D007262:Infusions, Intravenous; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007700:Kinetics; D008657:Metabolic Clearance Rate; D010446:Peptide Fragments / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D010455:Peptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D011498:Protein Precursors / Q000097:blood; D011758:Pyrroles / Q000494:pharmacology; D013552:Swine; D014633:Valine / Q000494:pharmacology
D001786:Blood Glucose; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D011480:Protease Inhibitors; D011498:Protein Precursors; D011758:Pyrroles; C114437:glucagon-like peptide-1 (9-36)-amide; C112092:valine-pyrrolidide; C055453:glucagon-like peptide 1 (7-36)amide; D002698:Chloralose; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D018819:Dipeptidyl Peptidase 4; D014633:Valine