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


OBJECTIVE
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.


METHODS
Thirty-four healthy, male ambulatory volunteers were studied in three consecutive, randomized, double blind, crossover studies.


METHODS
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.


CONCLUSIONS
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.
Beglinger
Svetlana
S
Division of Gastroenterology, University Hospital, CH-4031 Basel, Switzerland. beglinger@tmr.ch
Drewe
Juergen
J
Schirra
Joerg
J
Göke
Burkhard
B
D'Amato
Massimo
M
Beglinger
Christoph
C
D000328:Adult; D002766:Cholecystokinin / Q000378:metabolism; D018592:Cross-Over Studies; D004311:Double-Blind Method; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D008066:Lipolysis; D008297:Male; D019301:Oleic Acid / Q000494:pharmacology; D000077403:Orlistat; D010421:Pentanoic Acids / Q000494:pharmacology; D055815:Young Adult
D007783:Lactones; D010421:Pentanoic Acids; D019301:Oleic Acid; C013173:osteum; C103490:dexloxiglumide; D052216:Glucagon-Like Peptide 1; D002766:Cholecystokinin; D000077403:Orlistat