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Department of Medical Physiology, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark
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 · l
1 · min) than after
GLP-1-(9-36) amide (73 ± 19 mmol · l1 · min; P < 0.05), GLP-1-(7-36) amide (62 ± 13 mmol · l1 · min; P < 0.02) or GLP-1-(7-36) amide + GLP-1-(9-36) amide
(50 ± 13 mmol · l1 · 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.
glucagon-like peptide-1 receptor; glucose homeostasis; dipeptidyl peptidase IV; inhibitor; valine-pyrrolidide
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