The Interaction Between Protein Intake, Gut Microbiota and Type 2 Diabetes in Subjects With Different Ethnic Backgrounds (MICRODIET)

September 9, 2021 updated by: Assistance Publique - Hôpitaux de Paris

Modulation of Protein Intake to Target Gut-microbiota Derived Metabolites of Amino Acids in Individuals With Type 2 Diabetes From Varying Ethnic Backgrounds

Context and justification:

There is growing evidence that the gut microbiota is a key element in the pathophysiology of cardio-metabolic diseases (CMD) such as Type 2 Diabetes (T2D). One hypothesis is that gut-derived metabolites (from diet) have an important role in the host metabolism. Preliminary results show that imidazole propionate (ImP), a degradation product of the essential amino acid histidine, is produced by the gut microbiota of T2D patients, but not healthy subjects. The gut microbiota itself is strongly influenced by diet and ethnicity. However, most dietary intervention studies have focused on the role of fiber intake and the effect of dietary protein on the gut microbiota composition and metabolite production is not well known. Our hypothesis is that, depending on the baseline gut microbiome composition, a diminution in protein intake could decrease the microbial production of metabolites such as ImP and improve the metabolism of the host. We also hypothesize that the effects of such an intervention could depend the ethnic background.

Objective:

To study the effects of a high protein (HP) vs a low protein (LP) diet on gut microbiota composition and production of pro-diabetic metabolites in type 2 diabetes (T2D) patients from Caucasian and Caribbean ethnicity depending on baseline metagenomics richness.

Study design:

Randomized controlled three months dietary intervention study

Study Population:

T2D patients from Caucasian (N=80) and Caribbean (N=40) background who are on a stable dose of metformin and do not use insulin or proton-pump inhibitors.

Intervention:

Subjects will be randomized to either a high protein (HP) or low protein (LP) diet for three months. Individuals of Caucasian ethnicity, will also be stratified according to either a high or low gut microbiota gene richness. All subjects will receive pre-cooked meals 6 days per week and daily food packages. Subjects are required to keep food diaries three days a week and will also have weekly contact with an Pitié-Salpêtrière dietician.

Outcome measures:

Primary endpoint is the change in glycemic excursion (area under the curve) after a mixed meal test between baseline and 12 weeks after the beginning of the intervention. Furthermore, we will study oral and fecal microbiota composition changes as well as serum levels of intestinal metabolites, such as ImP, body weight and body composition at baseline and after 12 weeks.

Sample Size:

It is calculated that a total of 20 patients per arm are needed so 120 patients in total.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Context and justification:

There is growing evidence that the gut microbiota is a key element in the pathophysiology of cardio-metabolic diseases (CMD) such as Type 2 Diabetes (T2D). One hypothesis is that gut-derived metabolites (from diet) have an important role in the host metabolism. Preliminary results show that imidazole propionate (ImP), a degradation product of the essential amino acid histidine, is produced by the gut microbiota of T2D patients, but not healthy subjects. The gut microbiota itself is strongly influenced by diet and ethnicity. However, most dietary intervention studies have focused on the role of fiber intake and the effect of dietary protein on the gut microbiota composition and metabolite production is not well known. Moreover, it has been shown that the response to a dietary intervention may depend on the baseline gut microbiome richness.

Main hypothesis: Depending on the baseline gut microbiome composition, a diminution in protein intake could decrease the microbial production of metabolites such as ImP and improve the metabolism of the host. We also hypothesize that the effects of such an intervention could depend the ethnic background.

Study population:

Individuals with type 2 diabetes (T2D), of Caucasian or Caribbean origin, 120 patients will be included in total

Intervention:

Assignment after randomization to one of the following 2 diets:

  • HP diet: high protein (High Protein, HP) diet with 30% protein, 40% carbohydrate and 30% fat (as% of total energy intake)
  • LP diet: low protein diet (Low Protein, LP) with 10% protein, 55% carbohydrate and 35% fat (as% of total energy intake) Food boxes adapted to each diet (HP or LP pre-cooked meals, HP or LP breads and snacks) will be provided to the participants throughout the study reaching 40-50% of their prescribed daily energy intake for 6 days per week.

Subjects are required to keep food diaries three days a week and will also have weekly contact with a dietician.

Visits:

- Inclusion visit V0 (maximum 1 month before V1): Participants will first be recruited from the diabetic population of the French cohort of the European project METACARDIS. Individuals eligible for the study are screened for inclusion.

Baseline phenotyping is performed (metabolic, inflammatory blood markers, stool and oral microbiota sampling, body composition by DXA, questionnaires)

- Randomization visit V1 (T0 - start of the intervention): Randomization into 2 parallel groups (High Protein or Low protein diet) will be stratified based on metagenomics richness (obtained from Metacardis results), age (< or ≥ 60), gender, ethnic background (Caribbean or Caucasian).

Meal tolerance test, anthropometric measures, resting energy expenditure measure, one week CGMS, 24h urinary urea measure are performed.

- Follow-up visit V2 (T42 +/- 7 days): Mid protocol visit with anthropometric measures, one week CGMS, 24h urinary urea measures, stool sampling.

- End of study visit V3 (T84 +/- 7 days): Phenotyping is performed (metabolic, inflammatory blood markers, stool and oral microbiota sampling, body composition by DXA, questionnaires, meal tolerance test, anthropometric measures, resting energy expenditure measure, one week CGMS, 24h urinary urea measure)

Statistical analysis:

There are no multiple hypotheses since our study has only one primary objective (AUC delta of the glycemic excursion after a mixed meal tolerance test (MMT) between the beginning of study and 3 months post intervention). Thus, the problem of the type 1 error will not arise.

The primary endpoint will be analyzed to compare changes in AUC for glycemic excursion versus diet (rich vs. low protein), based on initial metagenomic richness (high vs. low) and ethnicity (Caucasian vs. Caribbean). AUC changes after dietary intervention between the different groups will be tested using linear regression models for repeated measurements with adjustment for initial levels. The effect of diet composition within the groups will be tested using Bonferroni's post-hoc covariance analysis (ANCOVA) analyzes. For secondary endpoints, the same approaches will be used for analysis of postprandial metabolites (AUC, AUC, post-MMT variation). Differences in relative abundance of bacterial species and functional modules (generated by metagenomic sequencing) and quality of life questionnaires will also be analyzed by subgroups using uni / multivariate analyzes. Correlations will be sought between changes in bio-clinical variables and changes in measurements of different metabolites.

Funding:

  • European Program (Join Program Initiative, JPI HDHL / ERA-NET cofund HDHL-INTIMIC, -Edition 2017) through the National Agency for Research (ANR)
  • Leducq Foundation (Research Grant 17CVD01 titled "Gut Microbiome as a Target for the Treatment of Cardiometabolic Diseases").
  • K Santé Society providing meals for the study.
  • Nutrisens Society providing snacks for the study.

Study Type

Interventional

Enrollment (Actual)

65

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Paris, France, 75013
        • Hopital Pitié Salpetriere - APHP

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

38 years to 68 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Age ≥ 40 years and <70 years 2.
  2. Type 2 Diabetic Subjects (T2D)
  3. Treated with stable dose of metformin (no dose change in the last 3 months)
  4. BMI ≥ 25 kg / m2
  5. Caucasian or Caribbean origin
  6. Written and oral comprehension of the French language
  7. Patient affiliated to health care.
  8. Patient having been informed of the study and having given written consent to participation

Exclusion Criteria:

  1. Pregnancy or breastfeeding
  2. Insulin treatment
  3. HbA1c ≥ 9% (<3 months)
  4. Recent antibiotic treatment (<3 months)
  5. Recent treatment with proton pump inhibitor (<3 months)
  6. Food allergies or documented intolerances
  7. Patient not willing to eat the foods provided in the protocol
  8. Neuromuscular or neurological disease
  9. History of digestive cancer and / or abdominal radiotherapy
  10. History of gastrointestinal surgery with gastrointestinal resection
  11. Acute or chronic inflammatory or infectious disease (including HIV, HCV, HBV)
  12. Organ Transplantation, Immunosuppressive drugs
  13. Severe chronic renal insufficiency (creatinine> 150 μmol / l or eDFG <50 ml / min per 1.73 m2 body surface area)
  14. Patient currently included in an interventional clinical study (patients included in an observational study may be included)
  15. Patient who received an experimental treatment in a research involving the human person in the last 2 months
  16. Subject taking a dietary supplement (> 100kcal / d)
  17. Subject with severe eating disorders (anorexia, bulimia, binge eating disorders, etc.)
  18. History of bariatric surgery
  19. Subject practicing an intense sport activity (more than 10 hours of sport per week)
  20. Subject unwilling to maintain an alcohol consumption of less than 50g per week (eg 5 glasses of wine) and less than 10g per day (eg 1 glass of wine)
  21. Patient under tutorship or curatorship

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Diet High Protein (HP)
Diet High Protein (HP) : 30% protein, 40% carbohydrate and 30% fat

2000kcal for men 1800 kcal for women. Food boxes (HP pre-cooked meals and meat/chicken/fish portions, HP breads and snacks) will be provided to the participants throughout the study reaching 40-50% of their prescribed daily energy intake for 6 days per week. In total 932 kcal are provided through this food boxes (54g of carbohydrate, 101g of protein, 34,6g of fat). The rest of the daily food intake will be guided by a dietician with a list of recommended high protein foods.

Subjects are required to keep food diaries three days a week and will also have weekly contact with a dietician.

Other: Diet Low Protein (LP)
Diet Low Protein (LP) : 10% protein, 55% carbohydrate and 35% fat
2000kcal for men 1800 kcal for women. Food boxes (LP pre-cooked meals, LP breads and snacks) will be provided to the participants throughout the study

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Post meal tolerance test glycemic excursion (area under the curve)
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)

After overnight fasting: Ingestion of 2x125ml de Fortimel® Compact (Nutricia) 600 kcal with 74g carbohydrates (50% of energy), 24g protein (16% of energy) et 23,2g fat (34% of energy).

Blood glucose sampling à T0, 30, 60, 90, 120, 180, 240 min

Change between baseline (T0) and the end of the intervention (T12 weeks)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Post meal tolerance test insulin excursion (area under the curve)
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)

After overnight fasting: Ingestion of 2x125ml de Fortimel® Compact (Nutricia) 600 kcal with 74g carbohydrates (50% of energy), 24g protein (16% of energy) et 23,2g fat (34% of energy).

Blood glucose sampling à T0, 30, 60, 90, 120, 180, 240 min

Change between baseline (T0) and the end of the intervention (T12 weeks)
Matsuda index (from post meal tolerance test glucose and insulin levels)
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)

After overnight fasting: Ingestion of 2x125ml de Fortimel® Compact (Nutricia) 600 kcal with 74g carbohydrates (50% of energy), 24g protein (16% of energy) et 23,2g fat (34% of energy).

Blood glucose sampling à T0, 30, 60, 90, 120, 180, 240 min

Change between baseline (T0) and the end of the intervention (T12 weeks)
Insulinogenic index (from post meal tolerance test glucose and insulin levels)
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)

After overnight fasting: Ingestion of 2x125ml de Fortimel® Compact (Nutricia) 600 kcal with 74g carbohydrates (50% of energy), 24g protein (16% of energy) et 23,2g fat (34% of energy).

Blood glucose sampling à T0, 30, 60, 90, 120, 180, 240 min

Change between baseline (T0) and the end of the intervention (T12 weeks)
Disposition index (kahn) (from post meal tolerance test glucose and insulin levels)
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)

After overnight fasting: Ingestion of 2x125ml de Fortimel® Compact (Nutricia) 600 kcal with 74g carbohydrates (50% of energy), 24g protein (16% of energy) et 23,2g fat (34% of energy).

Blood glucose sampling à T0, 30, 60, 90, 120, 180, 240 min

Change between baseline (T0) and the end of the intervention (T12 weeks)
Serum concentration of glycated hemoglobin (HbA1c)
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
After overnight fasting
Change between baseline (T0) and the end of the intervention (T12 weeks)
Fasting concentration of glucose
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
After overnight fasting
Change between baseline (T0) and the end of the intervention (T12 weeks)
Insulin resistance index : HOMA 2 IR (based on fasting glucose and insulin concentration)
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
Fasting
Change between baseline (T0) and the end of the intervention (T12 weeks)
Insulin secretion index: HOMA 2 B (based on fasting glucose and insulin concentration)
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
Fasting
Change between baseline (T0) and the end of the intervention (T12 weeks)
One week postprandial glucose excursions measured by continuous glucose monitoring sensors (CGMS)
Time Frame: Evolution between T0 (baseline) T6 weeks and T12 weeks of intervention
Freestyle libre (Abbott) sensors placed for one week with continuous glucose monitoring
Evolution between T0 (baseline) T6 weeks and T12 weeks of intervention
Weight (kg)
Time Frame: Evolution between T0 (baseline) T6 weeks and T12 weeks of intervention
Measured with same scale
Evolution between T0 (baseline) T6 weeks and T12 weeks of intervention
Waist circumference (cm)
Time Frame: Evolution between T0 (baseline) T6 weeks and T12 weeks of intervention
Measured standing with a GULICK meter
Evolution between T0 (baseline) T6 weeks and T12 weeks of intervention
Sagittal diameter (cm)
Time Frame: Evolution between T0 (baseline) T6 weeks and T12 weeks of intervention
Measured lying down with measuring rod
Evolution between T0 (baseline) T6 weeks and T12 weeks of intervention
Fat mass (DXA)
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
Measured by Dual-energy X-ray absorptiometry (DXA)
Change between baseline (T0) and the end of the intervention (T12 weeks)
Fat free mass (DXA)
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
Measured by Dual-energy X-ray absorptiometry (DXA)
Change between baseline (T0) and the end of the intervention (T12 weeks)
Visceral fat mass (DXA)
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
Measured by Dual-energy X-ray absorptiometry (DXA)
Change between baseline (T0) and the end of the intervention (T12 weeks)
Fat mass (BIA)
Time Frame: Evolution between T0 (baseline) T6 weeks and T12 weeks of intervention
Measured by Body impedance analysis (Tanita scale)
Evolution between T0 (baseline) T6 weeks and T12 weeks of intervention
Fat free mass (BIA)
Time Frame: Evolution between T0 (baseline) T6 weeks and T12 weeks of intervention
Measured by Body impedance analysis (Tanita scale)aspiration on a subgroup of patients
Evolution between T0 (baseline) T6 weeks and T12 weeks of intervention
Fasting concentration of Alanine transaminase (ALT)
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
After overnight fast
Change between baseline (T0) and the end of the intervention (T12 weeks)
Fasting concentration of Aspartate transaminase (AST)
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
After overnight fast
Change between baseline (T0) and the end of the intervention (T12 weeks)
Concentration of total cholesterol
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
After overnight fast
Change between baseline (T0) and the end of the intervention (T12 weeks)
Concentration of LDL cholesterol
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
After overnight fast
Change between baseline (T0) and the end of the intervention (T12 weeks)
Concentration of HDL cholesterol
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
After overnight fast
Change between baseline (T0) and the end of the intervention (T12 weeks)
Concentration of triglycerides
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
After overnight fast
Change between baseline (T0) and the end of the intervention (T12 weeks)
Gut microbiota changes
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
Shotgun metagenomic sequencing of DNA extracted from stool and saliva samples.
Change between baseline (T0) and the end of the intervention (T12 weeks)
Oral microbiota changes
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
Shotgun metagenomic sequencing of DNA extracted from stool and saliva samples.
Change between baseline (T0) and the end of the intervention (T12 weeks)
Concentration of Imidazole propionate
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
Targeted metabolomics
Change between baseline (T0) and the end of the intervention (T12 weeks)
Concentration of Trimethyl amine oxide (TMAO)
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
Targeted metabolomics
Change between baseline (T0) and the end of the intervention (T12 weeks)
Concentration of p cresol
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
Targeted metabolomics
Change between baseline (T0) and the end of the intervention (T12 weeks)
Concentration of indoxyl sulfate
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
Targeted metabolomics
Change between baseline (T0) and the end of the intervention (T12 weeks)
Concentration of C reactive protein (CRP)
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
Fasting serum levels measures
Change between baseline (T0) and the end of the intervention (T12 weeks)
Urinary urea excretion
Time Frame: Evolution between T0 (baseline) T6 weeks and T12 weeks of intervention
24h urinary sample measure
Evolution between T0 (baseline) T6 weeks and T12 weeks of intervention
SF 36 score (short form 36 quality of life questionnaire)
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
SF-36 questionnaire
Change between baseline (T0) and the end of the intervention (T12 weeks)
General self efficacy scale score (GSES questionnaire)
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
GSES questionnaire
Change between baseline (T0) and the end of the intervention (T12 weeks)
Patient health questionnaire 9 score (PHQ-9 questionnaire)
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
PHQ-9 questionnaire
Change between baseline (T0) and the end of the intervention (T12 weeks)
Gastro-intestinal discomfort changes
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
Rome IV criteria
Change between baseline (T0) and the end of the intervention (T12 weeks)
Resting energy expenditure changes
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
Indirect calorimetry (Cosmed Quark RMR)
Change between baseline (T0) and the end of the intervention (T12 weeks)
Epigenetic modifications
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
On serum isolated monocytes for a subgroup of patients
Change between baseline (T0) and the end of the intervention (T12 weeks)
Adipose tissue gene expression modifications
Time Frame: Change between baseline (T0) and the end of the intervention (T12 weeks)
RNA sequencing of RNA extracted from adipose tissue obtained from adipose tissue aspiration on a subgroup of patients
Change between baseline (T0) and the end of the intervention (T12 weeks)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Karine CLEMENT, Hopital Pitié Salpetriere - APHP

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 5, 2018

Primary Completion (Actual)

April 14, 2021

Study Completion (Actual)

April 14, 2021

Study Registration Dates

First Submitted

October 22, 2018

First Submitted That Met QC Criteria

November 2, 2018

First Posted (Actual)

November 7, 2018

Study Record Updates

Last Update Posted (Actual)

September 10, 2021

Last Update Submitted That Met QC Criteria

September 9, 2021

Last Verified

September 1, 2021

More Information

Terms related to this study

Other Study ID Numbers

  • P180402J
  • 2018-A01606-49 (Other Identifier: ANSM)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Type 2 Diabetes

Clinical Trials on Diet HP

3
Subscribe