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Articles in PresS, published online ahead of print December 4, 2001
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00452.2001
Submitted on October 10, 2001
Accepted on November 28, 2001
1 Department of Medical Physiology, Panum Institute, University of Copenhagen, Copenhagen, Denmark
* To whom correspondence should be addressed. E-mail: deacon{at}mfi.ku.dk.
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 iv 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 co-infused 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/l x min) than after GLP-1 (9-36)amide (73 ± 19 mmol/l x min; P < 0.05), GLP-1 (7-36)amide (62 ± 13 mmol/l x min; P < 0.02) or GLP-1 (7-36)amide + (9-36)amide (50 ± 13 mmol/l 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.
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