Role of fat hydrolysis in regulating glucagon-like Peptide-1 secretion

J Clin Endocrinol Metab. 2010 Feb;95(2):879-86. doi: 10.1210/jc.2009-1062. Epub 2009 Oct 16.


Context: Glucagon-like peptide-1 (GLP-1) is produced by specialized cells in the gut and secreted in response to carbohydrates and lipids. The mechanisms regulating fat-stimulated GLP-1 release have, however, not been clarified in detail.

Aim: We aimed to investigate the effect of intraduodenal (ID) fat hydrolysis on GLP-1 release and test whether the signal is mediated through cholecystokinin (CCK)-1 receptors.

Design and setting: Thirty-four healthy, male ambulatory volunteers were studied in three consecutive, randomized, double blind, crossover studies.

Intervention: There were three interventions: 1) 12 subjects received an ID fat infusion with or without orlistat, an irreversible inhibitor of gastrointestinal lipases, in comparison with vehicle; 2) 12 subjects received ID sodium oleate (C18:1), ID sodium caprylate (C8:0), or ID vehicle; and 3) 10 subjects received ID sodium oleate with and without the CCK-1 receptor antagonist dexloxiglumide or ID vehicle plus iv saline (placebo). The effect of these treatments on GLP-1 concentrations and CCK release was quantified.

Results: The following results were reached: 1) ID fat induced significant increase in GLP-1 concentrations (P < 0.004), and inhibition of fat hydrolysis by orlistat abolished this effect; 2) sodium oleate significantly stimulated GLP-1 release (P < 0.008), whereas sodium caprylate was ineffective compared with controls; and 3) dexloxiglumide administration abolished the effect of sodium oleate on GLP-1. ID fat or sodium oleate significantly stimulated plasma CCK (P < 0.006 and P < 0.004) compared with saline, whereas sodium caprylate did not.

Conclusion: Generation of long-chain fatty acids through hydrolysis of fat is a critical step for fat-induced stimulation of GLP-1 in humans; the signal is mediated via CCK release and CCK-1 receptors.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cholecystokinin / metabolism
  • Cross-Over Studies
  • Double-Blind Method
  • Glucagon-Like Peptide 1 / metabolism*
  • Humans
  • Lactones / pharmacology
  • Lipolysis*
  • Male
  • Oleic Acid / pharmacology
  • Orlistat
  • Pentanoic Acids / pharmacology
  • Young Adult


  • Lactones
  • Pentanoic Acids
  • Oleic Acid
  • osteum
  • dexloxiglumide
  • Glucagon-Like Peptide 1
  • Cholecystokinin
  • Orlistat