Effect of Bile Acid Secretion and Sequestration on GLP-1 Secretion

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. As a tool to sequester bile acids we will use sevelamer, a phosphate binding resin used in the treatment of hyperphosphataemia in adult patients with chronic kidney disease. Surprisingly, sevelamer has been shown to improve glycaemic control in patients with chronic kidney disease and type 2 diabetes. Intravenous infusion of cholecystokinin will be used to elicit gallbladder contraction and emptying. The aim is to examine how (and if) bile acid sequestration 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 Age above 40 years and below 70 years 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