Lack of effect of exendin-4 and glucagon-like peptide-1-(7,36)-amide on insulin action in non-diabetic humans

Diabetologia. 2002 Oct;45(10):1410-5. doi: 10.1007/s00125-002-0924-4. Epub 2002 Sep 5.


Aims/hypothesis: 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, exendin-4 (0.12, 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.

Conclusion/interpretation: 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Animals
  • Biotransformation
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism*
  • Body Mass Index
  • C-Peptide / blood
  • Dipeptidyl Peptidase 4 / metabolism
  • Exenatide
  • Glucagon / blood
  • Glucagon-Like Peptide 1
  • Glucagon-Like Peptides
  • Human Growth Hormone / blood
  • Humans
  • Hydrocortisone / blood
  • Infusions, Intravenous
  • Insulin / blood*
  • Kinetics
  • Lizards
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / pharmacology*
  • Peptides / administration & dosage
  • Peptides / pharmacokinetics
  • Peptides / pharmacology*
  • Reference Values
  • Venoms / pharmacology*


  • Blood Glucose
  • C-Peptide
  • Insulin
  • Peptide Fragments
  • Peptides
  • Venoms
  • glucagon-like peptide 1 (7-36)
  • Human Growth Hormone
  • Glucagon-Like Peptides
  • Glucagon-Like Peptide 1
  • Glucagon
  • Exenatide
  • Dipeptidyl Peptidase 4
  • Hydrocortisone