GLP-1 treatment reduces endogenous insulin resistance via activation of central GLP-1 receptors in mice fed a high-fat diet

Am J Physiol Endocrinol Metab. 2010 Aug;299(2):E318-24. doi: 10.1152/ajpendo.00191.2010. Epub 2010 Jun 8.


Glucagon-like peptide-1 (GLP-1) improves insulin sensitivity in humans and rodents. It is currently unknown to what extent the (metabolic) effects of GLP-1 treatment are mediated by central GLP-1 receptors. We studied the impact of central GLP-1 receptor (GLP-1R) antagonism on the metabolic effects of peripheral GLP-1 administration in mice. High-fat-fed insulin-resistant C57Bl/6 mice were treated with continuous subcutaneous infusion of GLP-1 or saline (PBS) for 2 wk, whereas the GLP-1R antagonist exendin-9 (EX-9) and cerebrospinal fluid (CSF) were simultaneously infused in the left lateral cerebral ventricle (icv). Glucose and glycerol turnover were determined during a hyperinsulinemic euglycemic clamp. VLDL-triglyceride (VLDL-TG) production was determined in hyperinsulinemic conditions. Our data show that the rate of glucose infusion necessary to maintain euglycemia was significantly increased by GLP-1. Simultaneous icv infusion of EX-9 diminished this effect by 62%. The capacities of insulin to stimulate glucose disposal and inhibit glucose production were reinforced by GLP-1. Simultaneous icv infusion of EX-9 significantly diminished the latter effect. Central GLP-1R antagonism alone did not affect glucose metabolism. Also, GLP-1 treatment reinforced the inhibitory action of insulin on VLDL-TG production. In conclusion, peripheral administration of GLP-1 reinforces the ability of insulin to suppress endogenous glucose and VLDL-TG production (but not lipolysis) and boosts its capacity to stimulate glucose disposal in high-fat-fed C57Bl/6 mice. Activation of central GLP-1Rs contributes substantially to the inhibition of endogenous glucose production by GLP-1 treatment in this animal model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Body Weight / drug effects
  • Body Weight / physiology
  • Cerebral Ventricle Neoplasms
  • Dietary Fats / pharmacology*
  • Fatty Acids, Nonesterified / blood
  • Glucagon-Like Peptide 1 / pharmacology*
  • Glucagon-Like Peptide-1 Receptor
  • Glucose / metabolism
  • Glucose Clamp Technique
  • Hyperinsulinism / metabolism
  • Insulin / blood
  • Insulin Resistance / physiology*
  • Lipoproteins, VLDL / biosynthesis
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Glucagon / antagonists & inhibitors
  • Receptors, Glucagon / drug effects*
  • Triglycerides / biosynthesis


  • Blood Glucose
  • Dietary Fats
  • Fatty Acids, Nonesterified
  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Insulin
  • Lipoproteins, VLDL
  • Receptors, Glucagon
  • Triglycerides
  • Glucagon-Like Peptide 1
  • Glucose