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ID
Source
Brief title
Health condition
Type 2 diabetes
Sponsors and support
Intervention
Outcome measures
Primary outcome
Evaluate ImP, urocanate, glutamate and histamine plasma level excursions upon 4 grams of histidine supplementation before, during and after a short course of oral antibiotics in T2D and healthy controls of Caucasian and Surinamese ethnicity.
Secondary outcome
Imidazole propionate
- ImP excursion before ATB challenge in both T2D and healthy controls (evaluation criteria = compare the AUC in both metabolic groups from
- ImP excursion immediately after the ATB challenge in both T2D and healthy controls (evaluation criteria = compare the AUC in both metabolic groups between before and after the ATB course)
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- Imp excursion during ATB washout in both metabolic groups (evaluation criteria = compare the AUC in both groups).
Insulin resistance and glucose metabolism
- Evaluate the effect of oral histidine challenge on insulin resistance (evaluation criteria = changes in MMT in both groups and HOMA) in T2D vs healthy controls before short term antibiotics course
- Evaluate the effect of oral histidine challenge on insulin resistance (evaluation criteria = changes in HOMA) in T2D vs healthy controls before, during and after short term antibiotics course
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- At baseline (V2) and after histidine supplementation (V4), subjects receive a 4-hour mixed meal test with 250cc Nutridrink (Fortimel® Compact 2x125ml, Nutricia) consisting of 96kcal protein, 294kcal carbohydrates and 210kcal fat, total energy content 600 kcal) after an overnight fast. Postprandial plasma samples will be taken at T0min, T30min, T60min and , T 120minvia an intravenous cannula (venflon) and glucose/insulin levels will be determined.
Effect of oral histidine challenge on continuous glucose levels (2 weeks Freestyle libre) in T2D vs healthy controls before, during and after short term antibiotics course. Subjects will learn how to implant the Freestyle Libre monitor (http://abbottnextfrontier.com/freestyle-libre) subcutaneously prior to the start of the study Their glucose levels will then be continuously monitored during three-time windows of 2 weeks during the study. Subjects are not required to perform finger pricks in order to calibrate the monitor and can perform all normal activities whilst wearing a monitor
Inflammation
- Evaluate the effect of oral histidine challenge on the gut microbiome of T2D and healthy controls before, during and after short term antibiotics course on plasma inflammatory markers and FACS (evaluation criteria = changes in PBMC phenotype)
Gut microbiome composition
- Change in relative abundance of bacteria taxa and bacterial gene richness by 16s rRNA profiling during several timepoints.
Background summary
Background:
In-vivo and in-vitro studies have suggested that histidine could drive metabolic alterations in obese type 2 DM (T2D) humans via the production of imidazole proprionate (ImP), the production of which might be driven via an altered gut microbiota composition. Since there are currently no data on direct oral histidine supplementation on several markers of cardiometabolism in obese T2D humans nor on its related metabolite production ImP by the gut microbiota in humans, we therefore propopose the following study.
Objective:
Evaluate pharmacokinetic levels of imidazole propionate as a result of orally administrated histidine and assess the role of the gut microbiome in this respect, T2D as compared to healthy controls.
Rationale:
The gut microbiota plays a pivotal role in the pathophysiology of cardio-metabolic diseases (CMD), such as T2D, obesity and atherosclerosis. The diet shapes the gut microbiota, which can further transform dietary food items into circulating metabolites, which acts on the host. Among them, ImP has recently been discovered. In- vitro and animal experiments demonstrated that ImP originate from histidine metabolization by the gut microbiota. Furthermore, ImP is increased in T2D individuals as compared to healthy controls and can induce glucose intolerance in mice. In this study we aim to confirm in humans that ImP indeed derive from gut microbiota processing of oral histidine intake. Furthermore, we aim to evaluate ImP concentrations after an oral challenge and demonstrate that it differs between T2D and controls. We also aim to see if these processes differ by ethnicity, as the gut micorbiota has been shown to also differ per ethnic group.
Study design:
Interventional controlled single centre study
Study Population:
44 subjects: 22 healthy controls, 22 type 2 diabetes mellitus (T2D) on stable metformin use. 11/22 subjects of both groups will be of Caucasian descent and the other 11 of Surinamese descent.
Intervention:
We will orally administrate 4g of the food supplement histidine (Vital Cell Life L-Histidine 500 MG Capsules 100CP) once a day for 7 weeks, after the first 2 weeks, one week of antibiotics will be added to suppress the gut microbiome followed by a four weeks recovery period. Plasma and urinary ImP, histidine, urocanate and glutamate levels will be measured as well as, peripheral blood monocyte cells (PBMC) for inflammatory status will be measured at specific time points.
Outcome measures:
Primary objective will be determination of ImP levels after histidine intake and other degradation products such as urocanate and glutamate before and after oral antibiotics. Secondary objectives will be differences in histidine uptake effect upon oral histidine supplementation on PBMC inflammatory status, influence of gut microbiome on ImP production, continuous (freestyle libre) as well as postprandial (after a mixed meal test) glucose levels between healthy and T2D subjects on stable dose of oral metformin.
Sample Size: 44
Study objective
Histidine supplementation will lead to higher plasma ImP levels in T2D patients, but not in healthy controls and this effect is mediated by the gut microbiota.
Study design
total intervention will be 2 months per subject and the subjects will visit the center for 7 times in total during the 2 months
Intervention
Histidine supplemenation 4g/day for 7 weeks.
Inclusion criteria
Healthy controls:
- 22 healthy controls 40-70 years, BMI <30kg/m2
- 11 controls of Caucasian descent and 11 of Surinamese descent
Type 2 Diabetes (T2D) subjects:
- 22 T2D patients (11 of Caucasian descent and 11 of Surinamese descent)
- 40-70 years
- BMI 25-35
- Stable anti diabetic drugs for 3 months (metformin is obligatory)
- All on statin
- Stable medication uses past 3 months
- Able to give informed consent
Exclusion criteria
- Previous major cardiovascular event (e.g. AMI/stroke/TIA)
- PPI
- GLP1 nor insulin
- antibiotic use in the past 3 months
- Probiotic or symbiotic usage
- Pregnant women,
- Chronic illness (including a known history of heart failure, renal failure (eGFR <30 ml/min), pulmonary disease, gastrointestinal disorders, or hematologic diseases), or other inflammatory diseases
- Active infection,
- Previous intestinal (e.g., bowel resection/reconstruction) surgery
- Smoking (can also influence microbiota)
- Vegetarian diet (since they have different microbiota)
- >6 alcohol units per day or >14 alcohol units per week
- Active malignancy
- HbA1c >9% (75mmol/mol)
- The subject is already involved in a clinical trial
Design
Recruitment
IPD sharing statement
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In other registers
| Register | ID |
|---|---|
| NTR-new | NL8372 |
| Other | METC AMC : METC 2019_261 |