CONTEXT: Bile acids have been suggested to mediate glucagon-like peptide-1 (GLP-1) secretion via activation of the bile acid receptor TGR5 on enteroendocrine L cells. 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-8 (CCK)-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 (aged 22 (range 20-32) years; body mass index 21.7 (19.3-24.2) kg/m(2); fasting plasma glucose 4.9 (4.7-5.3) mM; and HbA1c 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 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 (GIP) 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.