Effect of Metformin and Cholecystokinin-mediated Gallbladder Emptying on GLP-1 Secretion in Type 2 Diabetes

Effect of Metformin and Cholecystokinin-mediated Gallbladder Emptying on GLP-1 Secretion in Type 2 Diabetes

Accumulating evidence suggests that bile acids in our intestines may constitute essential components in the complex mechanisms regulating gut hormone secretion and glucose homeostasis. Thus, it is likely that modification of the enterohepatic circulation of bile acids can lead to changes in gut hormone secretion and consequently affect glucose homeostasis. The current study is a human interventional randomized controlled cross-over study including four study days for each participant. Metformin will be applied as a tool to reduce bile acid reuptake in the small intestine; thereby increasing bile acid concentration in the more distal parts of the gut where GLP-1-secreting L cell are abundant. Interestingly, metformin has been shown to reduce the active reabsorption of bile acids in the ileum and cause increased faecal elimination of bile acids. Clinical data has suggested that metformin causes an increase in the postprandial secretion of GLP-1 in humans including patients with type 2 diabetes. Intravenous infusion of cholecystokinin will be used to elicit gallbladder contraction and emptying. The aim is to examine how (and if) modification of bile acid reabsorption can influence postprandial glucagon-like peptide-1 (GLP-1) secretion and glucose homeostasis in patients with type 2 diabetes. The investigators hypothesize that higher luminal concentrations of bile acids in the distal gut will elicit changes in gut hormone secretion. The current study will help to clarify this hypothesis and improve our general understanding of the association between bile acid circulation and signalling, gut hormone secretion and glucose metabolism.

Responses of various other gut hormones: Incremental and total area under the Concentration-Time Curve

Inclusion Criteria: Type 2 diabetes for at least 3 months (diagnosed according to the criteria of the World Health Organization (WHO)) Men and postmenopausal women Metformin applied as the only anti-diabetic drug Caucasian ethnicity Normal haemoglobin BMI >23 kg/m2 and <35 kg/m2 Informed and written consent Exclusion Criteria: Liver disease (alanine aminotransferase (ALAT) and/or serum aspartate aminotransferase (ASAT) >2 times normal values) or history of hepatobiliary disorder Gastrointestinal disease, previous intestinal resection, cholecystectomy or any major intra-abdominal surgery Nephropathy (serum creatinine >150 µM and/or albuminuria) Hypo- and hyperthyroidism Hypo- and hypercalcaemia Hypo- and hyperphosphataemia Active or recent malignant disease Treatment with medicine that cannot be paused for 12 hours Treatment with oral anticoagulants Any treatment or condition requiring acute or sub-acute medical or surgical intervention Any condition considered incompatible with participation by the investigators

Bronden A, Alber A, Rohde U, Rehfeld JF, Holst JJ, Vilsboll T, Knop FK. Single-Dose Metformin Enhances Bile Acid-Induced Glucagon-Like Peptide-1 Secretion in Patients With Type 2 Diabetes. J Clin Endocrinol Metab. 2017 Nov 1;102(11):4153-4162. doi: 10.1210/jc.2017-01091.