Gene - Diet Interactions (Genediet)

Gene-diet Interactions

Interactions between genes and environment, i.e. our inherited responses to environmental changes, may be crucial in the development of the common diseases. The investigators were the first to identify PPARG gene as risk gene for type 2 diabetes. The role of the Pro12Ala polymorphism in diabetes risk has also been verified in meta-analysis. However, this effect on seems to depend on intervention and age. In this study the effects of diets high with saturated fatty acids (SAFA) and polyunsaturated fatty acids (PUFA) are compared in subjects carrying either Pro12Pro or Ala12Ala genotype of the PPARG gene.

Aim of the study:

To test if subjects with Pro12Pro and Ala12Ala genotypes respond differentially to a diet supplemented with high saturated (SAFA) or polyunsaturated fat (PUFA).

Hypotheses:

1. Specific: Subjects with the Ala12Ala genotype will be more sensitive to dietary modification, and therefore respond more favorably to PUFA diet
2. More general: Dietary instructions individually tailored according to the genotype would allow better treatment of obesity and diabetes

Study Overview

• Status: Completed
• Conditions: Insulin Sensitivity
• Intervention / Treatment: Other: PUFA-diet; Other: SAFA-diet

Detailed Description

Obesity and type 2 diabetes are increasing in all western countries, including Finland. Recent genome wide analyses have found > 30 genes that contribute to either condition.. However, none of these genes explain >5% of the disease risk and altogether they explain < 10% of the total disease risk in cross-sectional studies. Therefore, diet and physical activity are still the major determinants of the risk, as demonstrated by our earlier intervention studies in order to find out the effect of different dietary modifications on glucose and lipid metabolism. More importantly, interactions between genes and environment, i.e. our inherited responses to environmental changes, may be crucial in the development of the common diseases. Unfortunately, gene-environment interaction can only be effectively investigated in intervention studies that are more expensive than cross-sectional population screenings. This leads to a lower sample size and reduced power to detect effects of minor alleles. Despite these limitations the investigators have been able to demonstrate gene-intervention interactions for several genes, including PPARG, in the Finnish Diabetes Prevention study. There is an urgent need for studies investigating effects of tailored diets in individuals selected based on their genotype. This will be the next essential step leading to improved dietary treatments guided by genetic information.

The investigators were the first to identify PPARG gene as risk gene for type 2 diabetes. The role of the Pro12Ala polymorphism in diabetes risk has also been verified in meta-analysis. However, this effect on seems to depend on intervention and age. Based on these findings the investigators created in collaboration with Johan Auwerx an Pro12Ala animal model that demonstrated a differential effect of dietary fat composition depending on the genotype. However, an important conclusive proof that subjects selected based on their Pro12Ala genotype would respond differently to specifically tailored diet modification is still needed.

In this study the effects of diets high with saturated fatty acids (SAFA) and polyunsaturated fatty acids (PUFA) are compared in subjects carrying either Pro12Pro or Ala12Ala genotype of the PPARG gene. As a primary endpoint the investigators expect insulin sensitivity to alter differently depending on the genotype. Additionally, a detailed characterization of energy, glucose and lipid metabolism will be performed. Because PPARG gene plays a central role in adipogenesis one of the aims of this study is to find new pathways, genes and gene clusters that are regulated by PPARG in humans.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Finland
  • Kuopio, Finland, FIN-70211
    • University of Eastern Finland

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• BMI >20kg/m2 <29kg/m2
• Pro12Pro and Ala12Ala genotypes of PPARG Pro12Ala polymorphism
• participation to METSIM-study (METabolic Syndrome in Men, currently >10000 men included from the population living in Kuopio, principal investigator Markku Laakso)
• normoglycemia

Exclusion Criteria:

• type 2 diabetes
• other chronic diseases

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: P/S-ratio 1.0; Diets will contain 30% of energy as fat, 18% as protein and 52% as carbohydrates: polyunsaturated fatty acid diet (PUFA) will have P/S ratio 1.0.	Other: PUFA-diet; Diets will contain 30% of energy as fat, 18% as protein and 52% as carbohydrates: polyunsaturated fatty acid diet (PUFA) will have P/S ratio 1.0.
Experimental: P/S-ration 0.3; Diets will contain 30% of energy as fat, 18% as protein and 52% as carbohydrates:. Saturated fatty acid diet (SAFA) will polyunsaturated/saturated (P/S) ratio of 0.3.	Other: SAFA-diet; Diets will contain 30% of energy as fat, 18% as protein and 52% as carbohydrates: Saturated fatty acid diet (SAFA) will polyunsaturated/saturated (P/S) ratio of 0.3.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
insulin sensitivity	insulin sensitivity measured by oral glucose tolerance test at the beginning of the first, randomised diet	week 0
insulin sensitivity	insulin sensitivty measured by oral glucose tolerance test after the first diet	week 8
insulin sensitivity	Insulin sensitivity measured by oral glucose tolerance test in the beginning of the second, randomised diet	week 10
insulin sensitivity	insulin sensitivity measured by oral glucose tolerance test after the second diet	week 18

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
peripheral blood mononuclear cell gene expression		week 8
peripheral blood mononuclear cell gene expression		week 18
serum lipids	serum lipids, including serum lipidomics and fatty acid composition	week 8
serum lipids	serum lipids, including serum lipidomics and fatty acid composition	week 18
inflammation	inflammation measured as serum cytokines and adipose tissue inflammation	week 8
inflammation	inflammation measured as serum cytokines and adipose tissue inflammation	week 18
energy expenditure	energy expenditure and the rates of substrate oxidation	week 8
energy expenditure	energy expenditure and the rates of substrate oxidation	week 18
insulin secretion		week 8
insulin secretion		week 18
adipose tissue gene expression		week 8
adipose tissue gene expression		week 18

Collaborators and Investigators

• Sponsor: Marjukka Kolehmainen
• Collaborators: Kuopio University Hospital
• Investigators: Principal Investigator: Jussi Pihlajamäki, Professor, University of Eastern Finland, Kuopio University Hospital; Study Director: Ursula S Schwab, Clinical Lect, adjunct prof, University of Eastern Finland; Study Chair: Matti Uusitupa, Professor, Professor

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: January 10, 2011
• First Submitted That Met QC Criteria: January 10, 2011
• First Posted (Estimate): January 11, 2011

Study Record Updates

• Last Update Posted (Estimate): April 17, 2012
• Last Update Submitted That Met QC Criteria: April 16, 2012
• Last Verified: April 1, 2012

More Information

Terms related to this study

• Keywords: Insulin sensitivity; Fatty acids; Glucose metabolism; Gene-diet interaction; PPARgamma gene; Pro12Ala; Dietary modification
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Hyperinsulinism; Hypersensitivity; Insulin Resistance
• Other Study ID Numbers: 28//2010