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

Study Overview
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Brief Summary
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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.

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Isotonic saline
* Drug: Metformin placebo
* Drug: Cholecystokinin
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo+Placebo<br>Oral ingestion of metformin placebo combined with intravenous infusion of isotonic saline. | Drug: Isotonic saline<br> <br> Drug: Metformin placebo<br> <br> |
| Active Comparator: Placebo+Cholecystokinin<br>Oral ingestion of metformin placebo combined with intravenous infusion of cholecystokinin. | Drug: Metformin placebo<br> <br> Drug: Cholecystokinin<br> <br> |
| Active Comparator: Metformin+Placebo<br>Oral ingestion of metformin combined with intravenous infusion of isotonic saline. | Drug: Isotonic saline<br> <br> Drug: Metformin<br> <br> |
| Active Comparator: Metformin+Cholecystokinin<br>Oral ingestion of metformin combined with intravenous infusion of cholecystokinin. | Drug: Cholecystokinin<br> <br> Drug: Metformin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucagon-like peptide-1 (GLP-1): Incremental and total area under the Concentration-Time Curve | Incremental and total area under the Concentration-Time Curve (AUC 0-240 min) | -30, -15, 0, 10, 20, 30, 45, 60, 90, 120, 180, 240 min on study days 1-4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responses of various other gut hormones: Incremental and total area under the Concentration-Time Curve | Incremental and total area under the Concentration-Time Curve (AUC 0-240 min) | -30, -15, 0, 10, 20, 30, 45, 60, 90, 120, 180, 240 min on study days 1-4 | 
| Blood analysis of paracetamol as an assessment of gastric emptying | Assessment of gastric emptying | -30, -15, 0, 10, 20, 30, 45, 60, 90, 120, 180, 240 min on study days 1-4 | 
| Indirect calorimetry: Basal metabolic rate | Basal metabolic rate | -30 min to 240 min | 
| Gallbladder volume as assessed by Ultrasound measurements | Gallbladder volume | -30 min to 240 min | 
| Appetite as assessed by Visual analog scale score | Appetite | -30 min to 240 min |