Bariatric Surgery Candidate, Bile Acid, Elevated Serum, Glucose Metabolism Disorders
Conditions
Brief summary
Non-randomized, open-label, parallel-group clinical study evaluating the effects of endogenous bile acids on changes in plasma fibroblast growth factor-19 (FGF-19) and glucose metabolism by extended depletion of circulating bile acids using colesevelam as an experimental tool in subjects operated with gastric by-pass (RYGB).
Detailed description
The study design consists of 4 study visits, two performed before (V1 at day -7 and V2 at day 0 relative to initiation colesevelam treatment) and two after approximately 8 weeks of colesevelam treatment (V3 at day 49 and V4 at day 56). Biometrics, fasting blood samples and a standard mixed meal test are performed at V2 and V4. 75Se-HCAT scintigraphy is carried out between V1 to V2 and V3 to V4, respectively. Between V2 and V3 the subjects will have two telephone calls and one visit at the Endocrine Research Unit for fasting blood samples to make sure they do not experience any adverse events and are compliant. The control groups will only participate in V1 and V2. The aim with the control groups is to have baseline values for unoperated subjects with and without diabetes to compare with the values in the intervention group after 8 weeks of depletion of endogenous bile acids.
Interventions
DRUGColesevelam
Colesevelam is an approved drug with well known adverse events. Gastrointestinal side effects (Obstipation, flatulence, abdominal pain, diarrhea, nausea, meteorism, vomiting, chanced faeces) are very common (\>10%) or common (1-10%), but are mild and tolerable in most cases. All participants will be monitored closely, and colesevelam will be discontinued if the subject experience unreserved adverse events. All effects of colesevelam are transient (17-19) as the compound is not absorbed to the systemic circulation, i.e. treatment effects cease when the drug is excreted from the intestine. Specifically, no permanent metabolic effects of colesevelam has been observed in crossover experiments (27). Therefore, 8 weeks of colesevelam treatment as planned in the current study will have no long lasting positive or negative effects on the participants.
Sponsors
Hvidovre University Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Intervention group * RYGB-operated ≥ 18 months prior to inclusion * History of diabetes prior to RYGB (HbA1c ≥48 mmol/mol or use of antidiabetic medication) * HbA1c \<58 mmol/mol on no antidiabetic medication or metformin alone * Weight change \< ±3 kg for \>3 months at time of inclusion Control group A * No history of diabetes * HbA1c \<48 mmol/mol at time of inclusion * Fasting plasma glucose \< 7.0 mmol/L at time of inclusion * Weight change \< ±3 kg for \>3 months at time of inclusion Control group B * Type 2 diabetes (HbA1c ≥48 mmol/mol or use of antidiabetic medication at time of inclusion) * Weight change \< ±3 kg for \>3 months at time of inclusion
Exclusion criteria
* Pregnancy or breastfeeding * Haemoglobin \< 6.5 mmol/L at time of inclusion * Fasting plasma glucose \> 10.0 mmol/L at time of inclusion * Prior cholecystectomy * Chronic or tendency to diarrhoea
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glucose | 8 weeks | Changes in total areal under the curve (AUC) of plasma glucose concentrations during the mixed meal test after 8 weeks of colesevelam-induced depletion of endogenous bile acids (V4) compared with baseline in the intervention group (V2). |
| FGF-19 | 8 weeks | Changes in total AUC of plasma FGF-19 concentrations during the mixed meal test after 8 weeks of colesevelam-induced depletion of endogenous bile acids (V4) compared with baseline in the intervention group (V2). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Explorative outcomes, FGF-19 | 8 weeks | after 8 weeks of colesevelam-induced depletion of endogenous bile acids (V4) compared with baseline in the intervention group (V2). |
| Explorative outcomes, cholecystokinin (CCK) | 8 weeks | after 8 weeks of colesevelam-induced depletion of endogenous bile acids (V4) compared with baseline in the intervention group (V2). |
| Explorative outcomes, glucagon-like peptide-1 (GLP-1) | 8 weeks | after 8 weeks of colesevelam-induced depletion of endogenous bile acids (V4) compared with baseline in the intervention group (V2). |
| Explorative outcomes, Neurotensin | 8 weeks | after 8 weeks of colesevelam-induced depletion of endogenous bile acids (V4) compared with baseline in the intervention group (V2). |
| Explorative outcomes, triglycerides | 8 weeks | after 8 weeks of colesevelam-induced depletion of endogenous bile acids (V4) compared with baseline in the intervention group (V2). |
| Explorative outcomes, glucose | 8 weeks | Plasma glucose concentration during the mixed meal test after 8 weeks of colesevelam-induced depletion of endogenous bile acids (V4) compared with baseline in the intervention group (V2). |
| Explorative outcomes, C4 concentrations | 8 weeks | after 8 weeks of colesevelam-induced depletion of endogenous bile acids (V4) compared with baseline in the intervention group (V2). |
| Explorative outcomes, insulin sensitivity | 8 weeks | Changes in Insulin sensitivity (HOMA-IR) after 8 weeks of colesevelam-induced depletion of endogenous bile acids (V4) compared with baseline in the intervention group (V2). |
| Explorative outcomes, betal-cell function | 8 weeks | Changes in Beta-cell function (disposition index) after 8 weeks of colesevelam-induced depletion of endogenous bile acids (V4) compared with baseline in the intervention group (V2). |
| Explorative outcomes, bile acid retention | 8 weeks | Changes in Insulin bile acid retention (75Se-HCAT) after 8 weeks of colesevelam-induced depletion of endogenous bile acids (V4) compared with baseline in the intervention group (V2). |
| Explorative outcomes, cholesterol | 8 weeks | after 8 weeks of colesevelam-induced depletion of endogenous bile acids (V4) compared with baseline in the intervention group (V2). |
| Explorative outcomes, Bile acids | 8 weeks | after 8 weeks of colesevelam-induced depletion of endogenous bile acids (V4) compared with baseline in the intervention group (V2). |
Countries
Denmark
Contacts
Primary ContactMarie-Louise Dichman
Backup ContactCarsten Dirksen
Outcome results
None listed