Tackling the Metabolic Syndrome

Transcription

1 Diabet Med 998;5: The Metabolic Syndrome Tackling the Metabolic Syndrome WHO definition Metabolic syndrome and chronic disease Insulin resistance and metabolic syndrome Across Europe approx 0-25% of men and women are obese The Statistics Estimated total bill for EU 33 billion in 2002 Cardiovascular Type 2 diabetes disease 5-6 fold increase 2-3 fold increase Across Europe approx 0-20% of men and women are obese The Statistics Estimated total bill for EU 33 billion in 2002 By 200, 3m people in Europe,239m people Globally will require treatment for T2DM &related complications Prevention of new cases progression Reduce wherever possible Manage the existing cohort

2 Project Title: Lipgene Diet, genomics and the metabolic syndrome: an integrated nutrition, agro-food, social and economic analysis 2

3 Lipgene Lipgene Economic Science Consumer Science Economic Science Consumer Science Animal Nutrition Human Nutrition Plant Biotech Dissemination Management & Training Animal Nutrition Human Nutrition Plant Biotech Dissemination Management & Training Prospective case-control genetic study SuViMax cohort of 3,500 adults All healthy at baseline Followed for 7 years INSERM (Marseilles/Paris) University College Dublin Hitachi Dublin Laboratory Selecting candidate genes SuViMax cohort of 3,500 adults All healthy at baseline Followed for 7 years Used NCEP to ascertain those who at 7 years had developed the metabolic syndrome n = 322 new cases at year pairs created: case & age-sex matched control Extensive consultation 469 targets listed 82 genes chosen 806 SNPs 3

4 Low-grade inflammation plays a role in the pathogenesis of the MS and T2DM OR of the MS across C3 rs genotypes stratified by plasma fatty acids Investigated 6 inflammatory related genes (33 SNPs) Complement component C3 - C3 Interleukin 6 - IL6 Lymphotoxin alpha - LTA Signal transducer and activator of transcription factor 3 - STAT3 Tumor necrosis factors alpha - TNFa Transforming growth factor beta TGFb MUFA < 2 % > 2 % AA (n = 869) AG + GG (n = 83) P value for genotype effect OR of the MS across C3 rs genotypes stratified by plasma fatty acids OR of the MS across C3 rs genotypes stratified by plasma fatty acids MUFA < 2 % > 2 % AA (n = 869) AG + GG (n = 83) P value for genotype effect MUFA < 2 % > 2 % AA (n = 869).74 ( ) 3.03 (.3-8.5) AG + GG (n = 83) P value for genotype effect OR of the MS across C3 rs genotypes stratified by plasma fatty acids Human Dietary Intervention Study MUFA < 2 % > 2 % AA (n = 869).74 ( ) 3.03 (.3-8.5) AG + GG (n = 83) P value for genotype effect Can the level and composition of dietary fat influence the metabolic syndrome? Can that in itself be influenced by genetic variability? 4

5 Multi-centre dietary intervention study 480 free living subjects with the MS Eight intervention centres across EU Unilever supply fat sources Multi-centre dietary intervention study 480 free living subjects with the MS Eight intervention centres across EU Unilever supply fat sources Randomised to one of four 2 week dietary treatments. Control, high-fat, SFA-rich diet 2. High-fat, MUFA-rich diet 3. Isocaloric low-fat, high-complex CHO diet 4. Isocaloric low-fat, high-complex CHO diet +.2g/d LC n-3 PUFA Production & delivery of spreads, oils, fats & mayonnaise I5,593 approached I5,593 approached I5,058 rejected I5,593 rejected 535 met 3/5 MS symptoms 535 met 3/5 MS symptoms 49 dropped out 5

6 I5,593 approached I5,593 rejected Change Oleic Acid 535 met 3/5 MS symptoms 49 dropped out Diet : randomised Diet 2: 26 Diet 3: 9 Diet 4: 20 Change EPA Overall effects of dietary fat modification Improvements in insulin sensitivity Determined by habitual dietary fat intake Females respond better than males Overall effects of dietary fat modification Improvements in insulin sensitivity Determined by habitual dietary fat intake Females respond better than males Lipid metabolism Significant modification of TAG and NEFA metabolism Males respond better than females Overall effects of dietary fat modification Improvements in insulin sensitivity Determined by habitual dietary fat intake Females respond better than males Lipid metabolism Significant modification of TAG and NEFA metabolism Males respond better than females Inflammation & coagulation No significant effect overall Not determined effect of habitual dietary fat / gender 6

7 Adiponectin Gene and Fasting Insulin Lipgene WP PlasmaPreSFA (Banded) <= Today Metabolic engineering oil crops designed for the production of LC-PUFA Tomorrow Mean Fasting Insulin SNP rs is in the 5 near-gene region of ACDC CC n= 38 CG n= 56 GG n= p= p= p= p= CC CG GG rs Error bars: +/- SE Establish a sustainable and safe source for LC-PUFA for human nutrition. lower odour and sensory problems less environmental contamination by-product of plant LC-PUFA are healthy vegetable fatty acids sustainable and cheap source Today Lipgene WP2 Metabolic engineering oil crops designed for the production of LC-PUFA Establish a sustainable and safe source for LC-PUFA for human nutrition. lower odour and sensory problems less environmental contamination by-product of plant LC-PUFA are healthy vegetable fatty acids sustainable and cheap source Tomorrow Achievements to date Engineering of Brassicanapus resulted in an accumulation of up to: 5 % Arachidonic acid 3 % Eicosapentaenoic acid 3 % Docosahexaenoic acid GM versus conventional rapeseed crops: extent of genetic modification Compare 2-fold changes (+/-) in gene expression GM versus conventional rapeseed crops: extent of genetic modification Compare 2-fold changes (+/-) in gene expression GM v wildtype = 37 genes 7

8 GM versus conventional rapeseed crops: extent of genetic modification Compare 2-fold changes (+/-) in gene expression GM v wildtype = 37 genes Wildtype (Westar) v Wildtype (Stratos) = >000 genes For more information see: 8