Insulin Receptor Substrate 1 (IRS1) Gene Variation Modifies Insulin Resistance Response to Weight-loss Diets in A Two-year Randomized Trial

Transcription

1 Nutrition, Physical Activity and Metabolism Conference 2011 Insulin Receptor Substrate 1 (IRS1) Gene Variation Modifies Insulin Resistance Response to Weight-loss Diets in A Two-year Randomized Trial Qibin Qi, Frank M. Sacks, Frank B. Hu, Lu Qi Department of Nutrition Harvard School of Public Health March 23, 2011

2 Presenter Disclosure Information Financial Disclosure: No relevant financial relationship exists Funding/Support: This study was supported by grants from the National Heart, Lung, and Blood Institute (HL071981), the General Clinical Research Center (RR-02635) and the Boston Obesity Nutrition Research Center (DK46200). Dr. Lu Qi was a recipient of the American Heart Association Scientist Development Award ( N)

3 Gene-Environment Interactions Dietary Intervention Reduced-calorie diets Weight Loss Insulin resistance Improvement Genetic Background

4 Insulin Receptor Substrate 1 (IRS1) Muscle Liver Insulin receptor substrate 1 (IRS1) in insulin signaling Adapt from Samuel et al.the Lancet. 2010;375: Rung et al. Nat Genet. 2009;41(10): A 4-week intervention study reported that IRS1 gene variation (G972R) might modulate the effect of a low-fat and high-carbohydrate diet on insulin sensitivity (n=59) Marín et al. Molecular Nutrition & Food Research :

5 Objective To examine whether the IRS1 genetic variant rs (the best-associated SNP) modifies the long-term changes in insulin resistance and body weight in response to four weight-loss diets in a two-year randomized trial (the Pounds Lost Trial)

6 The Pounds Lost Trial A 2-year randomized clinical trial 811 overweight adults Four diets varying in macronutrients To compare the effects of macronutrients Four Reduced-calorie Diets Resulted in Similar Weight Loss on weight-loss Trial Registration No.: NCT Nutrient goals for the 4 diet groups (percentages of energy) Diet Group Fat (%) Protein (%) Carbohydrate (%) The diets consisted of similar foods and met guidelines for cardiovascular health, and carbohydrate-rich foods were used having a lower glycemic index Sacks et al, NEJM, 360 (9): , 2009

7 Methods Participants 738 subjects with DNA sample available were included 91% of the entire Pounds Lost trial 61% were women 80% were white, 15% were African American, 5% were other ethnic groups Genotyping IRS1 SNP rs Endpoints Changes in body weight, fasting insulin and insulin resistance (estimated by HOMA-IR) at 6 months and 2 years Statistical analysis Generalized linear models: Genotype-intervention interactions at 6 months and 2 years Genotype effects in each of 4 diet groups at 6 months and 2 years Linear mixed models Genotype effect on the trajectory of changes in each of 4 diet groups over the 2-year intervention

8 Characteristics of Participants Results Table 1. Baseline characteristics according to the IRS1 rs genotype IRS1 rs CC (risk) CT TT N (%) 331 (44.9) 312 (42.3) 95 (12.8) P* Age, yr 51 ± 9 51 ± 9 50 ± Sex, n (%) 0.19 Female 213 (64.4) 179 (57.4) 59 (62.1) Male 118 (35.6) 133 (42.6) 36 (37.9) Diet groups (fat/ protein/ carbohydrate), n (%) 0.63 Group 1 (20/15/65%) 83 (44.4) 82 (43.8) 22 (11.8) Group 2 (20/25/55%) 91 (50.0) 69 (37.9) 22 (12.1) Group 3 (40/15/45%) 74 (39.8) 86 (46.2) 26 (14.0) Group 4 (40/25/35%) 83 (45.4) 75 (41.0) 25 (13.7) Weight, kg 94 ± ± ± BMI, kg/m 2 33 ± 4 32 ± 4 33 ± Insulin, µu/ml 10.8 ( ) 10.4 ( ) 9.3 ( ) HOMA-IR 2.4 ( ) 2.3 ( ) 2.0 ( ) * P-values were calculated by χ 2 test for categorical variables, and F test for continuous variables

9 Genotype Effect on weight Loss at 6 months Results Highest-carbohydrate diet Lowest-carbohydrate diet 0 Diet 1 (20/15/65%) Diet 2 (20/25/55%) Diet 3 (40/15/45%) Diet 4 (40/25/35%) Weight Loss (%) IRS1 rs P=0.01 P=0.22 P=0.33 P=0.22 P for interaction =0.03 CC CT+TT

10 Improvement in Insulin Resistance at 6 months Results 0 Diet 1 (20/15/65%) Diet 2 (20/25/55%) Diet 3 (40/15/45%) Diet 4 (40/25/35%) Change in Log-insulin P=0.009 P=0.15 P=0.56 P=0.05 P for interaction =0.01 IRS1 rs CC CT+TT 0 Change in Log-HOMA-IR P=0.01 P=0.18 P=0.56 P=0.05 P for interaction =0.01

11 Genotype Effect on Weight Loss at 2 Years Results 0 Diet 1 (20/15/65%) Diet 2 (20/25/55%) Diet 3 (40/15/45%) Diet 4 (40/25/35%) Weight Loss (%) IRS1 rs P=0.32 P=0.71 P=0.81 P=0.17 P for interaction =0.23 CC CT+TT

12 Improvement in Insulin Resistance at 2 Years Results 0 Diet 1 (20/15/65%) Diet 2 (20/25/55%) Diet 3 (40/15/45%) Diet 4 (40/25/35%) Change in Log-insulin P=0.02 P=0.79 P=0.86 P=0.11 P for interaction =0.07 IRS1 rs CC CT+TT Change in Log-HOMA-IR P=0.02 P=0.83 P=0.97 P=0.09 P for interaction =0.07

13 The Trajectory of Changes over Intervention Results Genotype*time interaction in the highest-carbohydrate diet group

14 Significance and Limitation Assessed the gene-diet interactions on improvement of insulin resistance with weight-loss in a large and long-term randomized trial Provide novel information to the development of effective strategies for dietary interventions based on genetic background Insulin resistance was assessed by HOMA-IR rather than by using euglycemic glucose clamp technique Adherence to various diets declined after 6 months Most of the participants are whites (80%) Potential mechanisms are unclear

15 Summary Subjects with the CC genotype had greater weight loss and improvement in insulin resistance in the highest carbohydrate diet group at 6 months Genotype effect on changes in insulin resistance remained significant in subjects assigned to the highest carbohydrate diet group at 2 years Individuals with the IRS1 rs CC genotype might obtain more benefits in weight loss and improvement of insulin resistance than those without this genotype by choosing a high-carbohydrate and low-fat diet

16 Acknowledgements Harvard School of Public Health: Drs Frank M. Sacks, Frank B. Hu, Lu Qi and colleagues in our group Pennington Biomedical Research Center of the Louisiana State University System: Drs George A. Bray and Steven R. Smith We thank the participants in the trial for their dedication and contribution to the research! Thank You for Your Attention!