GLP-1 (9-36) amide, cleavage product of GLP-1 (7-36) amide, is a glucoregulatory peptide.
OBJECTIVE
Glucagon-like peptide-1 (GLP-1) (7-36) amide is a glucoregulatory hormone with insulinotropic and insulinomimetic actions. We determined whether the insulinomimetic effects of GLP-1 are mediated through its principal metabolite, GLP-1 (9-36) amide (GLP-1m).


METHODS
Glucose turnover during two, 2-h, euglycemic clamps was measured in 12 lean and 12 obese (BMI <25 or >30 kg/m(2)) male and female subject volunteers with normal oral glucose tolerance test. Saline or GLP-1m were infused from 0 to 60 min in each study. Additionally, seven lean and six obese subjects underwent a third clamp in which the GLP-1 receptor (GLP-1R) antagonist, exendin (9-39) amide was infused from -60 to 60 min with GLP-1m from 0 to 60 min.


RESULTS
No glucose infusion was required in lean subjects to sustain euglycemia (glucose clamp) during saline or GLP-1m infusions. However, in obese subjects glucose infusion was necessary during GLP-1m infusion alone in order to compensate for a marked (>50%) inhibition of hepatic glucose production (HGP). Plasma insulin levels remained constant in lean subjects but rose significantly in obese subjects after termination of the peptide infusions. During GLP-1R blockade, infusion of glucose was immediately required upon starting GLP-1m infusions in all subjects due to a more dramatic reduction in HGP, as well as a delayed and modest insulinotropic response.


CONCLUSIONS
We conclude that GLP-1m potently inhibits HGP and is a weak insulinotropic agent. These properties are particularly apparent and pronounced in obese but only become apparent in lean subjects during GLP-1 (7-36) receptor blockade. These previously unrecognized antidiabetogenic actions of GLP-1m may have therapeutic usefulness.
Elahi
Dariush
D
Department of Surgery, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA. delahi1@jhmi.edu
Egan
Josephine M
JM
Shannon
Richard P
RP
Meneilly
Graydon S
GS
Khatri
Ashok
A
Habener
Joel F
JF
Andersen
Dana K
DK
D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000378:metabolism*; D007263:Infusions, Parenteral; D007328:Insulin / Q000097:blood*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D010455:Peptides / Q000008:administration & dosage / Q000378:metabolism*; D018027:Receptors, Glucagon / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
D001786:Blood Glucose; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D018027:Receptors, Glucagon; C114437:glucagon-like peptide-1 (9-36)-amide; C055453:glucagon-like peptide 1 (7-36)amide; C083773:exendin (9-39); D052216:Glucagon-Like Peptide 1