Lack of effect of exendin-4 and glucagon-like peptide-1-(7,36)-amide on insulin action in non-diabetic humans.
OBJECTIVE
The aim of this study was to determine whether rapid conversion to inactive and potentially antagonistic peptides could alter the response to GLP-1.


METHODS
We evaluated the ability of exendin-4, a GLP-1 analogue resistant to degradation by dipeptidyl peptidase IV, to modulate insulin-induced stimulation of glucose uptake and suppression of glucose production in eight healthy subjects during infusion of GLP-1 (1.2 pmol.kg(-1).min(-1)), exendin-4 (0.12 pmol.kg(-1).min(-1)), or saline. Glucose was clamped at 5.3 mmol/l and insulin was infused to progressively increase insulin concentrations to about 65, 190 and 700 pmol/l, respectively. Endogenous insulin secretion was inhibited with somatostatin to ensure comparable portal insulin concentrations while glucagon and growth hormone were maintained at basal concentrations.


RESULTS
Glucose, insulin, C-peptide, glucagon and growth hormone concentrations did not differ on the three occasions. In contrast, cortisol concentrations were greater during both exendin-4 (25.1+/-4.4 mmol/l per 7 h; p<0.01) and GLP-1, (17.0+/-2.0 mmol/l 7 h; p<0.05) than saline (13.5+/-1.5 mmol/l per 7 h). While insulin-induced stimulation of glucose disappearance at the highest insulin concentrations tended to be greater and insulin-induced suppression of glucose production lower in the presence of exendin-4 or GLP-1 than saline, the differences were not significant.


CONCLUSIONS
Exendin-4 and GLP-1 increase cortisol secretion in human subjects. However, neither alters insulin action in non-diabetic human subjects. These data also suggest that the lack of an effect of GLP-1 on insulin action is not likely to be explained by rapid degradation to inactive or antagonistic peptides.
Vella
A
A
Department of Internal Medicine, Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic and Foundation, 200 1st Street SW, Rochester, MN 55905, USA.
Shah
P
P
Reed
A S
AS
Adkins
A S
AS
Basu
R
R
Rizza
R A
RA
D000328:Adult; D000818:Animals; D001711:Biotransformation; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D015992:Body Mass Index; D002096:C-Peptide / Q000097:blood; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D000077270:Exenatide; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood*; D007700:Kinetics; D008116:Lizards; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D010455:Peptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D012016:Reference Values; D014688:Venoms / Q000494:pharmacology*
D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D014688:Venoms; C061970:glucagon-like peptide 1 (7-36); D019382:Human Growth Hormone; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide; D018819:Dipeptidyl Peptidase 4; D006854:Hydrocortisone