Type 2 Diabetes
Conditions
Brief summary
Accumulating evidence suggests that bile acids and bacteria in our intestines may constitute essential components in the complex mechanisms regulating gut hormone secretion and glucose homeostasis. At the same time, bile acids and gut bacteria are interdependent. Thus, it is likely that modification of the enterohepatic circulation of bile acids can lead to changes in gut hormone secretion or gut bacteria composition and consequently affect glucose homeostasis. The current study is a human interventional study with 7-day ingestion of a bile acid sequestrant or placebo, preceded and followed by meal tests and faecal sampling. The aim is to examine how (and if) bile acid sequestration can influence postprandial glucagon-like peptide-1 (GLP-1) secretion, gut microbiota and glucose homeostasis in patients with type 2 diabetes and healthy individuals. 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 was recently shown to improve glycaemic control in patients with chronic kidney disease and type 2 diabetes. The investigators hypothesize that higher luminal concentrations of bile acids in the distal gut will elicit changes in the postprandial gut hormone secretion and gut bacteria composition. 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, gut bacteria and glucose metabolism.
Interventions
DRUGSevelamer 1600 mg TID for 7 days
DRUGPlacebo 1600 mg TID for 7 days
Sponsors
Sanofi
University Hospital, Gentofte, Copenhagen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
35 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
Both groups * Caucasian ethnicity * Normal haemoglobin * Age above 35 years and below 80 years * Informed and written consent * BMI \> 23 kg/m2 and \<35 kg/m2 Patients with type 2 diabetes * Type 2 diabetes for at least 3 months * Diagnosed according to the criteria of the World Health Organization (WHO) Healthy Subjects * Normal fasting plasma glucose (FPG) \<6.5 mM and * Normal glycated haemoglobin (HbA1c) \<6.0 %
Exclusion criteria
Both groups * 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 * Hypo- or hyperphosphataemia * Nephropathy (serum creatinine \>150 µM and/or albuminuria * Treatment with medicine that cannot be paused for 12 hours * Intake of antibiotics six months prior to study * Hypo- or hypercalcaemia * Hypo- and hyperthyroidism * Treatment with oral anticoagulants * Active or recent malignant disease * Any treatment or condition requiring acute or sub-acute medical or surgical intervention * Lack of effective birth control in premenopausal women * Positive pregnancy test on study days in premenopausal women * Tobacco smoking * Any condition considered incompatible with participation by the investigators Patients with type 2 diabetes * Treatment with insulin * Treatment with incretin-based therapy Healthy Subjects * Diabetes or * prediabetes (fasting plasma glucose levels \>6.5 mM or HbA1c \>6.0%) * First-degree relatives with diabetes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 and 7 (meal tests start at 0 min) | Postprandial responses of glucagon-like peptide-1 (GLP-1) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 and 7 (meal tests start at 0 min) | Postprandial responses of various other gut hormones |
Other
| Measure | Time frame | Description |
|---|---|---|
| Blood analysis of paracetamol | -30 min to 240 min (ingestion of meal at 0 min) on study days 1 and 7 | Assessment of gastric emptying |
| Bodyweight | Fasting state on study days 1 and 7 | — |
| Blood analysis | Fasting status on study days 1 and 7 | Lipids |
| Ultrasound measurements | -30 min to 240 min (ingestion of meal at 0 min) on study days 1 and 7 | Gall bladder volume |
| Visual analog scale score | -30 min to 240 min (ingestion of meal at 0 min) on study days 1 and 7 | Appetite |
| Indirect calorimetry | -30 min to 240 min (ingestion of meal at 0 min) on study days 1 and 7 | Basal metabolic rate |
| Faecal samples | Prior to study days 1 and 7 | Gut microbiota composition |
Countries
Denmark
Outcome results
None listed