A. Prof Catherine Itsiopoulos - UniSA · PREvencion con Dieta MEDiterranea (PREDIMED) trial 5y multi‐centre 1o prevention trial, 7500 participants Subjects @ high risk of CVD, aged

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‘The anti‐oxidant and anti‐inflammatory potential of the Cretan Mediterranean Diet: challenges and opportunities’

A. Prof Catherine ItsiopoulosHead of Department of Dietetics and Human Nutrition

UniSA Symposium 28 October 2014: Nutrition, chronic diseaseand the role of inflammation and the microbiome

No slides may be reproduced without the express permission of Catherine Itsiopoulos

2La Trobe University

The Obesity/Diabetes/CVD Pandemic Continues….

Around the World• >382 million people (8.3% of world population) have diabetes and ~500

million people are obese• The number of people with diabetes is increasing in every country and

worldwide obesity has doubled since 1980• Diabetes is the major cause of death for people under 60 years

In Australia• Diabetes ‐ 6th leading cause of death, ~60% is preventable• D&O costs the economy ~34.6 billion and $58.2 billion, resp.• ~275 Australians develop diabetes everyday; nearly 30% of them are obese• 1.7 million cases have been diagnosed but probably same number

undiagnosed• If trends continue, each Australian aged 20‐74 years who dies from

overweight/obesity in 2011 to 2050 will lose, on average, 12 years of life.



We live in an Obesogenic Environment!

Urbanisation

sedentary occupations

computerisation and mechanisation

improved transportation

Nutrition transitions

exponential growth in fast food industry (highly processed, high fat, sugar, salt)

livestock revolution (intensively reared animals with a high n6/n3 fatty acid profile – 20:1 vs 2:1 – not enough omega 3!)

highly processed grains (poor in fibre, micronutrients, and phytochemicals)



Do Saturated Fats Cause Heart Disease?


5La Trobe University No slides may be reproduced without the express permission of Catherine Itsiopoulos


Associations between Fatty Acid Intake and Coronary Risk: Systematic Review and Meta‐Analysis

(Chowdhury et al, 2014)

Data from 72 published observational studies and randomised controlled trials of 659,258 people from 18 countries was analysed to evaluate associations between:

• dietary fatty acid intake • fatty acid biomarkers • fatty acid supplementation And Coronary Disease* Risk

*fatal and non‐fatal myocardial infarction, coronary heart disease, coronary insufficiency, coronary death, angina, angiographic coronary stenosis, Or sudden cardiac death.

No effect in reducing CHD risk except for:Trans FatsLCN3 supps.



“Adopting a Mediterranean diet after a heart attack is almostthree times as powerful in reducing mortality as taking a statin”.


Maybe it is not so much about what we ARE eating but rather

what we are NOT eating?



O’Neil and Itsiopoulos (Ann. Int. Med, 2014)

Current CVD guidelines are based on the putative cause of CVD being lipid accumulation, to which dietary intake is a significant contributor. Powerfulevidence identifies autoimmune inflammation and oxidative stress as key initiators of atherosclerosis. Western diet is increasingly characterized by proinflammatory properties: insufficient consumption of nutrient- and fiber-dense foods and overconsumption of ultraprocessed food products (energy-dense sugars and hydrogenated plant-based oils). We should target whole-diet as a key modulator of this inflammatory process.


Major causes of chronic disease – inflammation, oxidation, glycation



http://www.genesmart.com/pages/a_perfect_storm/68.phpNo slides may be reproduced without the express permission of Catherine Itsiopoulos


Ref: Simopoulos and Sidosis. What is so special about the Greek diet?World Rev Nutr Diet 2000

•Vit C•Vit E

•Carotenoids•Phytoestrogens

•Phenolics•Allylthiosulfinates

•Flavonoids•Selenium

•N3 fatty acids: ALA and EPA DHA

Greek “Cretan” Mediterranean Diet: Anti‐inflammatory and antioxidant rich, low in AGEs!



The Greek Migrant Paradox:Persistent Low Mortality in Greek‐Born Migrants despite 60 years since migration (ABS, 2010)

Greek Australians Aust‐bornSMR 0.67 Colorectal Cancer vs 1.0SMR 0.76 CHD vs 1.0SMR 0.69 Stroke vs 1.0

Total M

ortality

25-35% lowermortality



Are Greek Migrants Emulating the Long Living “Blue Zones” Populations?

Populations around the world living beyond 100 yrs:

Okinawa (Japan)

Sardinia (Italy)

Nicoya (Costa Rica)

Lima Loma (California)

Ikaria (Greece)

Key lifestyle features:

family coherence

no smoking

active social life

very low levels of stress

physical active

a plant‐based diet. www.bluezones.comNo slides may be reproduced without the express permission of Catherine Itsiopoulos

Evidence for Health Benefits of Mediterranean Diet from Cohort

Studies



First Score to Assess Compliance with the Mediterranean Diet: Trichopoulou, Kouris‐Blazos, Wahlqvist et al (BMJ, 1995)

9 point food group based score: 1 point increase = 17% reduction in overall mortality.



Meta‐Analysis of Mediterranean Diet Studies and Health Outcomes.

Systematic review of 18 international studies between 1966‐2010 involving 2 Million people.

Greater adherence to Mediterranean diet was associated with:

9% reduction in overall death;

9% reduction in cardiovascular death;

6% reduction in cancer death;

13% reduction in Parkinson’s & Alzheimer’s;Sofi et al, Adherence to Mediterranean diet and health status: meta‐analysis.

BMJ 2008:337:1344. AND Sofi et al, AJCN 2010.



Relationship between CVD and IHD mortality and dietary patterns evaluated at the 10 yr follow‐up of the MCCS ‐A multi‐ethnic cohort of 40,653 volunteers.

Adherence to a Mediterranean diet pattern associated with50% reduction in risk of IHD and CVD deaths (adjusted forCVD risk factors and ethnicity).

(Harriss et al, AJCN; 2007)



Evidence for Health Benefits of the Mediterranean Diet from

Large Clinical Trials



PREvencion con DietaMEDiterranea (PREDIMED) trial

5y multi‐centre 1o prevention trial, 7500 participants

Subjects @ high risk of CVD, aged 55‐80yrs:

2 MED diets (olive oil 1L/wk or nuts 30g/d) vs low fat diet, ad libitum

Med diets down‐regulated inflammatory biomarkers (CRP, IL‐6, endothelial adhesion molecules) in addition to lowering BP, IR and dyslipidaemia.

Refs: Estruch, R. Proceedings Nutr Soc 2010;69:333‐340.Salas‐Salvado, J et al. Diabetes Care 2011;34(1):14‐9.



PREDIMED Cumulative diabetes free-survival: Med diets (a,b) vs control (c )

Salas-Salvadó J et al. Dia Care 2011;34:14-19

Copyright © 2014 American Diabetes Association, Inc.

50% RiskReduction DiabetesIncidence



PREDIMED Final Outcomes

Figure 1. Incidence of Primary End‐Point (a combination of acute myocardial infarction, stroke and all‐cause death) following use of the Mediterranean Diet for the primary prevention of cardiovascular disease.EVOO = Extra Virgin Olive Oil

(Estruch et al, 2013)

Med diet, EVOO: hazard ratio, 0.70(95% CI, 0.53–0.91); P=0.009Med diet, nuts: hazard ratio, 0.70(95% CI, 0.53–0.94); P=0.02

Incide

nce of cardiac events (%

)30% Reduction inCVD Mortality


Data from The Greek Migrant Paradox: Low CVD Mortality Despite

High CVD and T2DM Risk!



Conclusions:Prevalence of Diabetic Retinopathy was lower in Greek‐born vs Australian‐born men with diabetes (22% vs 37%) ‐ not explained by established risk factors.

Protective effect of ethnicity may be attributed to consumption of Mediterranean diet (Brazionis et al, BJN 2009).

Mediterranean‐style Diet May AmeliorateDiabetes Complications!



Diabetic Retinopathy Lower in Greek Migrants with T2DM

Advanced RetinopathyNormal Retina

Brazionis et al., Br J Nutr 2009 Brazionis et al., Diab Med 2010No slides may be reproduced without the express permission of Catherine Itsiopoulos

0

20

40

60

80

100

120

140

Greek-born non-diabetic

Greek-borndiabetic

Australian-bornnon-diabetic

Australian-borndiabetic

Tot

al p

lasm

a ca

rote

noid

s (m

g/dl

0

0.5

1

1.5

2

2.5

3

3.5

4

Die

tary

car

oten

oid

inta

ke (g

/MJ)

Total Plasma Carotenoids mg/dlTotal Dietary Carotenoids (g/MJ)

Ethnicity‐Diabetes Gradient for Carotenoid Status

Pethnicity = 0.005Pdiabetes = 0.030


Differences in Lycopene Intakes

0

2000

4000

6000

8000

10000

12000

10 20 30 40 50 60 70 80 90

Cummulative Frequency (percentiles)

Lyc

open

e In

take

( g/

day)

Greek WomenGreek MenAustralian WomenAustralian Men

Lycopene intake vs plasma R2 0.213; p=0.003

Greeks

Australians



Ethnic Differences in Sources of Carotenoids – bioavailability?



Greeks Consume Greater F&V variety AND Portion ‐> phytonutrient dose!

Typical Diet of Australian‐born

Typical Diet of Greek‐born

23g 106g

162g 466g

149g 45g

6g 65g

Plant: Animal Food Ratio 2:1 4:1

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Edible Wild Greens Rich in Carotenoids vsCommercial Varieties


31La Trobe University Q Su et al, Eur J Clin Nutr 2002

Wild Greens have 70% Higher Lutein and

‐carotene

Compared with commercial varieties



Wild species outshine cultivated varieties

http://www.nytimes.com/interactive/2013/05/26/sunday‐review/26corn‐ch.html?ref=sundayNo slides may be reproduced without the express permission of Catherine Itsiopoulos


Wild species outshine cultivated varieties

http://www.nytimes.com/interactive/2013/05/26/sunday‐review/26corn‐ch.html?ref=sundayNo slides may be reproduced without the express permission of Catherine Itsiopoulos

True potential of food is largely unknown

• We have limited knowledge about food

products

• We can identify only 100s out of

500,000+ metabolites in plants and

animals

• With systems biology techniques we can

begin to identify unique properties of

foods



•12 week RCT of Greek-style Med diet “ad libitum” vs Usual Diet in T2DM

•Clinically sign. change in HbA1c (of the order found in many OH drug trials)

•Change of - 0.3 HbA1c% = 10% reduction in CHD Mortality in T2 diabetesNo slides may be reproduced without the express permission of Catherine Itsiopoulos


Plasma Carotenoids – biomarkers of diet

0

5

10

15

20

25

30

35

40

Baseline Control Med Diet

b-carotenelycopeneLutz

P=0.05

P=0.001

P<0.001

Plasma Caroteno

ids (g/dl)



A myriad of peaks – what are we not measuring?



Plasma Fatty Acid Changes – biomarkers of diet

0

5

10

15

20

25

30

35

40

45

50

Baseline Control Med Diet

SaturatesMonounsaturatesTotal n6Total n3

ns

ns

%ph

osph

olipids

P=0.032

P<0.001


Our Food Supply is Low in N3 Fatty Acids!



Omega 3 sources in the Mediterranean diet

Offal – !

Wild edible leafy greens

Walnuts

Greek village eggs“free range”

fotobank.ru/image/FC01‐8880.html

Free range goat‐milk and cheese

Snails (Crete)

www.dreamthymefarm.com/goat_meat.html

Pumpkin seeds‘’

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Mediterranean Diet Reverses Fatty Liver and Improves IR Independent of Weight Loss.

Reduction in hepatic steatosis after the Med Diet compared with HCLF:39 ± 4% versus 7 ± 3% (p = 0.012).

Insulin sensitivity improved on Med diet but no change on HCLF (p = 0.03 between diets).

NEW Multi‐Centre Trial = MEDINA 2014 ‐> (Tierney et al)


Impact of Diet Derived Advanced Glycation End‐Products



Effect of Advanced Glycation End‐Products?

AGEs are classically formed by the Maillard Reaction (c1912) a non‐enzymatic reaction between reducing sugars and proteins and fats endogenously OR exogenously;

Endogenous AGEs:

Early glycation of proteins e.g. HbA1c

Early lipoxydation of lipids e.g. oxLDL

Later glycation of long lived proteins e.g. collagen, cataract in lens

AGE formation accelerated with ageing and oxidative stress and diabetes (hyperglycaemia)

Exogenous AGEs:

Formed in foods by Maillard reaction e.g. browning of foods through toasting/ BBQ/ grilling at high temperatures in dry heat.



AGEs: Browning of tissues

Changes of colour of tooth root surfaceshttp://www.forsci.cz/podrobnosti/prehled.jpg

Cataract



http://i0.wp.com/fuelyourhealth.net/wp‐content/uploads/2013/04/geronaglq074f04_lw.jpg

Advanced Glycation End‐Products



AGE Formation

http://www.vrp.com/graphics/OCT04BENFOfig1.jpg

HbA1c

CML

Carboxyl methyl lysine



Why is the Mediterranean Diet Low in AGEs?

Low in saturated fat

Moderately low in protein

Focus on slow and moist method of cooking

Highly plant based



Low AGEs DIET High AGEs DIET

Dish Cooking Method Dish Cooking Method

Chicken casserole with broad beans/ onions/garlic/tomatoes/

olive oil/herbs1011 kU AGE/serve

Moist slow cooking (180oC) Charcoal chicken with potato chips

5418 kU AGE/serve

Chicken (grilled), potato chips (fried/reheated in oven)

Lamb risoni pasta bake Meat not braised, but simmered followed by moist

slow baking

Lamb chops with potato chips Lamb chop (fried/grilled), potato chips (fried/reheated in

oven)

Beef casserole with peas, carrots, onions, potatoes and tomatoes

Meat not braised but slowly simmered

Grilled/fried steak with potato chips

Beef steak (fried/grilled), potato chips (fried/baked)

Fish with potatoes827 kU AGE/serve

Slow baking (180oC) without browning

Fried fish with potato chips7897 kU AGE/serve

Fish (fried), potato chips (fried/reheated in oven)

Meatballs Slow moist cooking (180oC in oven) without browning

Meatballs Fried until strongly browned

Red pepper Raw Red peppers Skin scorched over a flame

Pita bread & cold cooked beef (or fresh cooked chicken)

Sliced Deli beef (no charring) or poached chicken

Souvlaki Meat charred on a revolving spit

Almonds Raw Almonds Roasted

Eggs182 kU AGE/serve

Boiled/poached/scrambled Eggs1287 kU AGE/serve

Fried

Itsiopoulos, Walker, Brazionis et al. No slides may be reproduced without the express permission of Catherine Itsiopoulos


Chicken and Broad Bean Casserole

Low AGE: 1011 kU/ serve



Charcoal Chicken and Chips

High AGE: 5418 kU / serve



Impact of High and Low AGE diets in Healthy Volunteers(Itsiopoulos, Walker, Brazionis et al, unpublished)

200220240260280300320340360380400

Before LowAGE

After LowAGE

Before HighAGE

After HighAGE

Serum AGEs (ng/ml)

Serum AGEs (ng/ml)

Pdiet <0.05

4 wk RCT n=16

Subjects felt unwell on High AGE diet “lethargy,Heavy feeling, lowEnergy”.



74 overweight women randomised to high or low AGE diet for 4 weeks.

Low AGE diet decreased urinary AGEs, fasting insulin, and insulin resistance.


Why is the Mediterranean Diet the Optimal Solution for

Prevention and Management of Chronic Disease?



Ref: Simopoulos and Sidosis. What is so special about the Greek diet?World Rev Nutr Diet 2000

•Vit C•Vit E

•Carotenoids•Phytoestrogens

•Phenolics•Allylthiosulfinates

•Flavonoids•Selenium

•N3 fatty acids: ALA and EPA DHA

A Highly Palatable Cuisine Rich in Bioactive Phytochemicals & Optimal Macronutrient Profile and n3:n6 fatty acid ratio!


55La Trobe University No slides may be reproduced without the express permission of Catherine Itsiopoulos

CONCLUSIONS

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1. Inflammation and oxidative stress are key mediators to chronic diseases.

2. Western diets are largely pro‐inflammatory pro‐oxidative.

3. Single nutrient therapy is ineffective and we should target whole‐diet as a key modulator of this inflammatory process.

The Mediterranean Diet:

A Palatable and Sustainable “anti‐inflammatory” Lifestyle Intervention that prevents chronic disease and premature mortality independent of weight loss!



• Professor Kerin O’Dea

• Prof Peter Brooks

• Dr Laima Brazionis

• Dr Andrew Wilson

• Dr Marno Ryan

• A/Prof Antigone Kouris

• Dr Audrey Tierney

• A/Prof Bill van Gaal

• Dr Janine Danks

• Dr Hassan Vally,

• Dr Colleen Thomas

• Dr Agus Salim

• A/Prof Michael Kingsley

• Natalie Simmance

• Tanya Gilliver

• A/Prof Catherine Itsiopoulos

PhD Students• Tania Thodis,

• Spero Tsindos

• Rachelle Opie

• Teagan Kucianski

• Elena Pappas

• Serpil Kucuktepe

The Researchers


Documents

A. Prof Catherine Itsiopoulos - UniSA · PREvencion con Dieta MEDiterranea (PREDIMED) trial 5y multi‐centre 1o prevention trial, 7500 participants Subjects @ high risk of CVD, aged