Cholecystokinin-induced gallbladder emptying and metformin elicit additive glucagon-like peptide-1 responses

Abstract

Context: Bile acids have been suggested to mediate glucagon-like peptide-1 (GLP-1) secretion. Metformin, too, has been shown to increase GLP-1 levels. The effect of gallbladder emptying, metformin, or a combination has, however, never been studied. Objective: We hypothesized that cholecystokinin (CCK)-8-induced gallbladder emptying stimulates human GLP-1 secretion and that metformin would potentiate this effect. Design: A double-blinded, randomized study. Setting: The study was conducted at a specialized research unit. Participants: Ten healthy male subjects with no family history of diabetes (age, 22 [range, 20-32] years; body mass index, 21.7 [19.3-24.2] kg/m2; fasting plasma glucose, 4.9 [4.7-5.3] mM; and glycosylated hemoglobin A1c, 5.1 [4.4-5.8] %). Intervention: On 4 separate days, the subjects received metformin or placebo and a concomitant 60-minute intravenous infusion of saline or CCK. Blood was sampled for 4 hours, and gallbladder volume was measured by ultrasound. Main Outcome Measures: Plasma levels of GLP-1. Results: CCK-induced gallbladder emptying and metformin alone (no observed effect on gallbladder emptying) both elicited significant and additive GLP-1 responses. Metformin alone or combined with gallbladder emptying elicited a significant peptide YY response. CCK-induced gallbladder emptying resulted in a short-lasting glucose-dependent insulinotropic polypeptide response independent of metformin. No effects were seen on plasma glucose, insulin, C-peptide, or gastrin. Conclusions: CCK-induced gallbladder emptying in healthy subjects elicits significant GLP-1 secretion, which can be potentiated by metformin.