GLP-1-mediated Gluco-metabolic Effects of Bile Acid Sequestration (SeveX)

The objective of this study is to investigate the potential GLP-1-mediated contribution to the well-established glucose-lowering effect of sevelamer-induced bile acid sequestration . Exendin9-39 has been demonstrated to act as a potent and specific GLP-1 receptor antagonist with no partial agonistic potential and is considered a useful tool in the assessment of GLP-1 physiology. The aim is to evaluate any contribution of sevelamer-induced GLP-1 secretion to the reduced plasma glucose concentrations observed after treatment with sevelamer. A randomised placebo-controlled cross-over study involving two 17-day treatment periods with sevelamer and placebo, respectively, in metformin-treated patients with type 2 diabetes, will be conducted. The impact of bile acid sequestration on GLP-1 secretion and effect will be examined during two randomised experimental days after 15 and 17 days of treatment with sevelamer (1,600 mg three times a day) and placebo, respectively. During each of these two experimental days, a meal test with concomitant exendin9-39 infusion or placebo will be performed (for evaluation of any GLP-1-mediated effects). Postprandial plasma glucose excursion is the primary endpoint, and secondary endpoints include postprandial plasma/serum excursions of insulin, C-peptide, GLP-1, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), peptide YY (PYY), oxyntomodulin, ghrelin, fibroblast growth factor (FGF)-19, FGF-21, C4 (an intermediate in the de novo synthesis of bile acids), cholecystokinin (CCK), bile acids and plasma lipids. Furthermore, gastric emptying, gallbladder emptying, liver fat content, appetite and ad libitum food intake will be examined.

Gastric emptying measured by paracetamol absorption test. Paracetamol is ingested along with meal, the appearance in blood will be calculated as a measure of gastric emptying.

Gall bladder volumen measured by ultrasound over time after a meal (see time frame below). The rate of gall bladder emptying will be calculated

We assessed appetite parameters (hunger, satiety, fullness, prospective food consumption) and well-being, nausea, and thirst by visual analogue scales. Overall appetite score (OAS) will be calculated as (satiety + fullness + (100 - hunger) + (100 - prospective food consumption)

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 glucose-lowering drug Caucasian ethnicity Normal haemoglobin Age above 40 years and below 75 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- or hyperthyroidism Hypo- or hypercalcaemia Hypo- or 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