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The TCF7L2 Gene: Dietary Prevention of T2DM

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ClinicalTrials.gov Identifier: NCT03458494
Recruitment Status : Active, not recruiting
First Posted : March 8, 2018
Last Update Posted : April 19, 2021
Sponsor:
Collaborator:
Allen Foundation Inc.
Information provided by (Responsible Party):
Jose Ordovas, Tufts University

Tracking Information
First Submitted Date  ICMJE February 24, 2018
First Posted Date  ICMJE March 8, 2018
Last Update Posted Date April 19, 2021
Actual Study Start Date  ICMJE February 15, 2018
Actual Primary Completion Date April 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 1, 2018)
Glucose [ Time Frame: 1 week per intervention arm ]
Plasma glucose levels (mg/dl) will be measured in the fasting state during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 1, 2018)
  • Insulin [ Time Frame: 1 week per intervention arm ]
    Fasting plasma insulin levels (pmol/l) will be measured in the fasting state during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP
  • Metabolomics [ Time Frame: 1 week per intervention arm ]
    The response of plasma metabolites to the Mediterranean and low-fat diets diet) will be measured using ultra high-performance liquid chromatography/tandem accurate mass spectrometry (UHPLC/MS/MS) during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP
  • Very low density lipoproteins (VLDL) [ Time Frame: 1 week per intervention arm ]
    Fasting plasma concentrations of VLDL in mg/dl, assessed by proton nuclear magnetic resonance (NMR) spectroscopy will be measured during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP
  • Low-density lipoproteins (LDL) [ Time Frame: 1 week per intervention arm ]
    Fasting plasma concentrations of LDL in mg/dl, assessed by proton nuclear magnetic resonance (NMR) spectroscopy will be measured during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP
  • High-density lipoproteins (HDL) [ Time Frame: 1 week per intervention arm ]
    Fasting plasma concentrations of HDL in mg/dl, assessed by proton nuclear magnetic resonance (NMR) spectroscopy will be measured during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP
  • CRP [ Time Frame: 1 week per intervention arm ]
    Plasma C-reactive protein (mg/dl) will be measured in the fasting state during each one of the intervention phases (the Mediterranean and low-fat diets) in participants with the TT and CC genotypes at the TCF7L2 rs7903146 SNP
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The TCF7L2 Gene: Dietary Prevention of T2DM
Official Title  ICMJE The TCF7L2 Gene: Nutrigenomics and Dietary Prevention of Type 2 Diabetes
Brief Summary Nutrients and chemicals in food are able to regulate expression of genetic elements. Gene-nutrient interaction in response specific diets can increase an individual's risk, shifting the individual from health toward the development of chronic disease. The Transcription Factor 7 Like 2 (TCF7L2) gene may either put individuals at risk for or protect from Type 2 diabetes mellitus in the presence of certain foods. The main purpose of this four-week study is to examine diet-induced gene-nutrient interaction, with a focus on glucose, insulin, inflammation (CRP) and the plasma metabolome in individuals who have either the CC or the TT form of the rs7903146 single nucleotide polymorphism (SNP) (C/T) within the TCF7L2 gene. The (2) one-week study diets, one Mediterranean diet (MedDiet) based and the other low-fat based will be separated by a (1) week return to a regular habitual diet.
Detailed Description

Type 2 diabetes (T2DM) is associated with increased morbidity and mortality, and its growing prevalence represents a major public health concern. T2D results from a combination of genetics and the exposure to external factors (i.e., diet, exercise, and stress). Multiple T2D-related genes have been identified, but they explain only ~10% of the estimated T2D heritability. Therefore, it has been proposed that interactions between genetic and environmental factors contribute to the missing heritability. The identification of these gene-environment interactions could provide a breakthrough in the prevention of T2D and its complications through the implementation of novel nutrigenomics approaches.

The rs7903146 single nucleotide polymorphism (SNP) (C/T) within the TCF7L2 gene is the most replicated T2D-associated SNP. However, the mechanism associating TCF7L2 with T2D remains unknown. Moreover, there is little knowledge of how diet modulates this association. A better understanding is crucial for improving existing, or designing new interventions for T2D prevention.

The current knowledge supports the notion that subjects homozygous for the deleterious allele (TT) have a higher risk of T2D than subjects homozygous for the common allele (CC). Furthermore, there is a gene-diet interaction between this SNP and Mediterranean diet (MedDiet) on fasting glucose and lipids. Thus, a higher MedDiet adherence neutralizes the effects of the deleterious TT genotype. Moreover, after ~5 years, TT subjects consuming a low-fat diet have higher incidence of stroke than CC subjects, whereas this association is annulled in TT subjects consuming a MedDiet. the objective of this study is to validate these findings under practical conditions similar to those encountered in clinical practice and to identify biological mechanisms involved in such interactions.

For this purpose, a four-week study will be conducted to examine diet-induced gene-nutrient interaction, with a focus on glucose, insulin, and inflammation (CRP) in individuals who have either the CC or the TT form of the rs7903146 single nucleotide polymorphism (SNP) (C/T) within the TCF7L2 gene. The (2) one-week study diets, one Mediterranean diet (MedDiet) based and the other low-fat based will be separated by a (1) week return to a regular habitual diet.

The specific aims include:

  1. To investigate whether the TCF7L2-by-diet interaction in relation to T2D and cardiovascular disease (CVD) risk factors can be validated in the context of a more realistic scenario of personalized dietary advice based on genetic information (nutrigenomics).
  2. To elucidate the molecular mechanisms responsible for these gene-by-diet interactions using deep phenotyping (i.e., metabolomics).

The hypothesis is that genetics can offer precise information about which healthy diet (low-fat or Mediterranean) can deliver real benefits on an individual basis.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
randomized crossover dietary intervention
Masking: Single (Investigator)
Primary Purpose: Prevention
Condition  ICMJE
  • Type2 Diabetes
  • Glucose, High Blood
Intervention  ICMJE
  • Other: Mediterranean Diet
    Participants will receive meals traditionally consumed in Mediterranean countries
  • Other: Low-fat diet
    Participants will receive meals with a low content of total fat.
Study Arms  ICMJE
  • Experimental: Mediterranean Diet
    during one week participants will receive food products common in the diet of Mediterranean populations
    Intervention: Other: Mediterranean Diet
  • Experimental: Low-fat diet
    during one week participants will receive food products low in fat content
    Intervention: Other: Low-fat diet
Publications * Corella D, Carrasco P, Sorlí JV, Estruch R, Rico-Sanz J, Martínez-González MÁ, Salas-Salvadó J, Covas MI, Coltell O, Arós F, Lapetra J, Serra-Majem L, Ruiz-Gutiérrez V, Warnberg J, Fiol M, Pintó X, Ortega-Azorín C, Muñoz MÁ, Martínez JA, Gómez-Gracia E, González JI, Ros E, Ordovás JM. Mediterranean diet reduces the adverse effect of the TCF7L2-rs7903146 polymorphism on cardiovascular risk factors and stroke incidence: a randomized controlled trial in a high-cardiovascular-risk population. Diabetes Care. 2013 Nov;36(11):3803-11. doi: 10.2337/dc13-0955. Epub 2013 Aug 13.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: April 15, 2021)
37
Original Estimated Enrollment  ICMJE
 (submitted: March 1, 2018)
40
Estimated Study Completion Date  ICMJE December 15, 2021
Actual Primary Completion Date April 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Men and women.
  • 18 years or older.
  • Women who are not pregnant.
  • A BMI ranging between 27 and 34

Exclusion Criteria:

  • Unexplained elevation in serum transaminases (i.e. >1.5 times the upper limit of normal) or with evidence of active liver disease, including primary biliary cirrhosis or pre-existing gallbladder disease.
  • Severe renal dysfunction (serum creatinine >2.0mg/dL).
  • Excessive alcohol consumption (>2 drinks/day).
  • Preexisting CVD.
  • Stable exertional angina pectoris requiring sublingual nitroglycerin within the prior 3 months.
  • Uncontrolled T2D (fasting glucose >126 mg/dl) or other significant endocrine disease.
  • Uncontrolled hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure >100 mmHg).
  • History of pancreatitis within 1 yr. prior to screening.
  • Subjects on lipid-lowering or diabetes medications.
  • Smoking.
  • Pregnancy.
  • Body mass index (BMI) below 27 or greater than 34 kg/m2
  • Participants will also be excluded for drug abuse, extreme dietary habits, multiple food allergies, extreme levels of physical or athletic activity, or by changes in body weight >20 lbs. during the last 6 months.
  • Inability to follow any of the experimental diets or to perform the sampling required for this study.
  • Thyroid diseases.
  • Use of omega-3 supplements (unless it is discontinued one month prior to the beginning of the study).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03458494
Other Study ID Numbers  ICMJE TCF7L2_2965
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: No plans are in place to share individual participant data (IPD) with other researchers others than those involved in the study. However, the study investigators are open to collaborations that do not include sharing IPD
Responsible Party Jose Ordovas, Tufts University
Study Sponsor  ICMJE Tufts University
Collaborators  ICMJE Allen Foundation Inc.
Investigators  ICMJE
Principal Investigator: Jose M Ordovas, PHD Tufts University
PRS Account Tufts University
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP