Botanical Research Center

Pennington Biomedical

“Why an Apple a day

keeps the doctor away!”

“Why an Apple a day

keeps the doctor away!”

William T. Cefalu, M.D.

Pennington Biomedical Research Center

The “apple” Story!The “apple” Story!

Changing Nutrition/Health ParadigmChanging Nutrition/Health Paradigm

� What food is required for me?

� Nutritional deficiency:

� Iron - Anemia

� Iodine – Thyroid goiter

� Vitamin D - Rickets

� Identifying essential nutrients required for

promoting growth and sustaining life.

� Vitamins

� Essential minerals – Calcium

� Essential amino acids

1920s-1980s

Changing Nutrition/Health ParadigmChanging Nutrition/Health Paradigm

� What does food do to me?

� Nutritional excess and imbalances

� Calories - obesity

� Fiber – Colon cancer

� Identifying nutrients and components that

contribute to premature death

� Saturated fat

� Cholesterol

� Sodium

1950s-1990s

Seven Countries Study: CHD Events are

Correlated with Saturated Fat

Seven Countries Study: CHD Events are

Correlated with Saturated Fat

0 5 10 15 20

% Calories from Saturated Fat

0

1

2

3

4

5

CHD Deaths and MI/100 R = 0.84

V

MC

D

G

SW

B

Z

UN

E

K

Keys, 1970

Changing Nutrition/Health ParadigmChanging Nutrition/Health Paradigm

� What does food do for me?

� Nutritional optimization of quality of life

� Identification of physiological active

components to prevent or delay premature

onset of chronic disease

� Phytochemicals

� Pre/Probiotics

� Fiber

Functional Foods

1990s-Today!

Functional FoodsFunctional Foods

� Phytochemicals

� “Phyto” - Plant or “botanical” source

� Making a food “functional”

� Increase Phytochemicals

� Add Phytochemicals

� Replace phytochemicals

PolyphenolsPolyphenols

� Epicatechin

� Epigallocatechin

� Epigallocatechin gallate

� Source: Green tea; grapes, red wine

� Benefits: Anti-cancer; CHD protective

� Function: Inhibit chemical carcinogenesis and

tumor formation; inhibit cancer cell

growth; antioxidant; reduces free

radical/oxidative damage

CarotenoidsCarotenoids

� Lycopene

� β-carotene

� β-cryptoxanthin

� Lutein

� Source: Tomatoes, carrots, yams, cantaloupe,

spinach, sweet potatoes; citrus fruits

� Benefits: Anti-cancer; CHD protective

� Function: Antioxidant; free radical scavenger;

induction of cell-cell communication and

growth control; inhibit tumor growth

β-carotene

IsoflavonesIsoflavones

� Genistein

� Daidzein

� Source: Soybean, flaxseed

� Benefits: Relieves menopausal symptoms; prevents

osteoporosis; anti-cancer; CHD protective

� Function: Estrogen-like activity; inhibit growth of

breast cancer cells; stimulate Ca

absorption; lower cholesterol levels

Genistein

FlavonoidsFlavonoids

� Quercetin

� Apigenin

� Luteolin

� Myricetin

� Source: Citrus fruits; vegetables

� Benefits: Heart protection; Increase stamina

� Function: Antioxidant; inhibit platelet aggregation;

inhibit cancer cell growth and

proliferation; cytotoxic to cancer cells

Luteolin

The Promise of Functional FoodsThe Promise of Functional Foods

� Better health through improved nutrition

can:

� Increase quality of life

�Enhance productivity

�Reduce health-care costs

- by preventing or delaying the onset of

chronic disease, i.e diabetes

- or improving metabolic factors related to the

disease, i.e. glucose

Health claims need to

be verified

with carefully controlled studies

Botanical (Natural) Supplements

29,000 supplements available to American consumer

Diabetes: the growing global burden

IDF:2 %• Diabetes currently affects 246 million people worldwide• It is expected to affect 380 million by 2025

No data

< 2%

2–5%

5–8%

8–11%

11–14%

14–17%

> 17%

20002000Prevalence estimates of diabetes mellitusnts'Ffsmys2se:bu F:se2i %2abF(s:se2u sffb:ce 3&&"3&&"

No data

< 2%

2–5%

5–8%

8–11%

11–14%

14–17%

> 17%

Prevalence estimates of diabetes mellitus 2003200320032003

No data

< 2%

2–5%

5–8%

8–11%

11–14%

14–17%

> 17%

Prevalence estimates of diabetes mellitus 2025202520252025

No data

< 2%

2–5%

5–8%

8–11%

11–14%

14–17%

> 17%

BrainCerebrovascular disease

• Transient ischemic attack

• Cerebrovascular accident

• Cognitive impairment

Complications of Diabetes

HeartCoronary artery disease

• Coronary syndrome• Myocardial infarction• Congestive heart

failure

ExtremitiesPeripheral vascular disease• Ulceration• Gangrene• Amputation

Large Blood Vessel Small Blood Vessel

NervesNeuropathy

• Peripheral• Autonomic

KidneyNephropathy

• Microalbuminuria• Gross albuminuria• Kidney failure

EyeRetinopathyCataractsGlaucoma

Prevalence of Diagnosed Diabetes in Adults2003

Prevalence of Diagnosed Diabetes in Adults2003

Insulin receptor

“SWITCH”

Plasma

membrane

Glucose carriers move

to the surface

Blood

Sugar

Insulin

Chemical Signals

Insulin Action (“Sensitivity”) in Muscle and Fat Insulin Action (“Sensitivity”) in Muscle and Fat

Carriers insert into

cell surface

Blood Sugar enters body

Glucose

(“sugar”)

carriers

GLUT4=glucose transporter 4

Insulin “Efficiency”

“Pre-Diabetes” (Insulin “inefficiency)

“Pre-Diabetes”

Type 2 diabetes

Years from

diagnosis0 5-10 -5 10 15

Pre-diabetes

Onset Diagnosis

Insulin secretion

Insulin “inefficiency

Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789 Nathan DM. N Engl J Med. 2002;347:1342-1349

Post-Meal glucose

Fasting glucose

Pancreas function

Progressive β-Cell Failure

Natural History of Type 2 Diabetes

PLASMA GLUCOSE

Normal: 99 mg/dl or less

Pre-Diabetes: 100-125 mg/dl)

Diabetes > 126 mg/dl fasting);

> 200 mg/dl )(PostPrandial)

Re

lati

ve

Ris

k o

f M

I o

r S

tro

ke

0

1

2

3

4

5

6

7

Nondiabetic

Throughout

2.4

>15 Yr

Before Dx

10-14.9 Yr

Before Dx

3.64

<10 Yr

Before Dx

Diabetic

Throughout

5.02

3.19

1.0

Hu FB, et al. Diabetes Care. 2002;25:1129-1134.

Non-Diabetic Diabetes

Cardiovascular Risk in Pre-diabetes

Pre-Diabetes

Obesity

Insulin inefficiency (“resistance”)

Abnormal

Lipids

Elevated

Blood Pressure

Blood Vessel

Dysfunction

Heart Disease

Physical

Inactivity Aging

High Blood Sugar

“Metabolic” Syndrome

Modified from S. Grundy MD

High Waist/Hip

(≥0.95 in men)

(≥0.80 in women)

Low Waist/Hip

(<0.95 in men)

(<0.80 in women)

An Index of Abdominal vs Peripheral Obesity

Body Shape Matters!!!

“Central” obesity

Body Shape Matters!!!

“Central” obesity

Visceral Fat Distribution:

Normal vs Type 2 Diabetes

Visceral Fat Distribution:

Normal vs Type 2 Diabetes

Type 2 DiabetesNormal

Larsson. Acta Med Scand Suppl. 1988;723:45-51.

Risk of diabetes mellitus during 13 years in relation to WHR at baseline.

Comparison between these in upper and lower 10% of WHR distribution.

Waist Measurement and

Diabetes Risk

Waist Measurement and

Diabetes Risk

25

20

15

10

5

054

Age

Ris

k (

%)

Upper 10% Waist to hip ratio

Lower 10% Waist to hip ratio

55 56 57 58 59 60 61 62 63 64 65 66 67

Cumulative hazard (%)

Follow-up (y)

YES

Metabolic Syndrome

NO

Heart Disease Deaths

0 2 6 8 124 100

5

10

15

Death Increases with Metabolic Syndrome

“Pre-Diabetes”

Type 2 diabetes

Years from

diagnosis

0 5-10 -5 10 15

Pre-diabetes

Onset Diagnosis

Insulin

“Inefficiency”

Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789 Nathan DM. N Engl J Med. 2002;347:1342-1349

Post-Meal glucose

Fasting glucose

Natural History of Type 2 Diabetes

Nutrition and Exercise

Reduces progression to diabetes by 60%

Type 2 diabetes

Years from

diagnosis0 5-10 -5 10 15

Pre-diabetes

Onset Diagnosis

Insulin

“Inefficiency”

Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789 Nathan DM. N Engl J Med. 2002;347:1342-1349

Post-Meal glucose

Fasting glucose

Natural History of Type 2 Diabetes

“Nutraceutical /Phytochemical)

Strategies”

Increased Consumption of

“Functional Foods”

Nutrition and Exercise

Reduces progression to diabetes by 60%

Blueberries Improved

the Ability of Insulin to Work

Blueberries Improved

the Ability of Insulin to Work

22.2

4.9

0

5

10

15

20

25

Blueberry Placebo

%∆

In

suli

n S

ensi

tivit

y

∆ insulin Sensitivity = ability of insulin to work from week 0 to week 6

4-Fold

Louisiana Agriculture and Diabetes

Sugar Cane can fight Diabetes?

Wang ZQ, Zuberi AR, Zhang XH, Macgowan J, Qin J, Ye X, Son L, Wu Q, Lian K, Cefalu WT. Effects of dietary fibers on

weight gain, carbohydrate metabolism, and gastric ghrelin gene expression in mice fed a high-fat diet. Metabolism. 2007

Dec;56(12):1635-42.

Tarragon and DiabetesTarragon and Diabetes

� Extract of Artemisia

dracunculus with

antidiabetic properties

� Produced from

hydroponically grown

plants under controlled

conditions

Russian tarragon

Potential Lifetime Impact for Pre-Diabetes

Intervention

83%75%63%

% Developing Diabetes over Lifetime

Diabetes Onset

$1755$ 635

Aroda VR, Ratner R. JCEM 93(9):3259-65, 2008

Life Expectancy: Increase by

0.5 Years

Macrovascular Microvascular

Potential Lifetime Impact for Pre-Diabetes

Lifestyle Intervention

Aroda VR, Ratner R. JCEM 93(9):3259-65, 2008

Stroke

9%

Coronary Heart Disease

8%

Amputations

35%

Blindness

39%

End Stage Renal Disease

38%

Summing it all upSumming it all up

“Eat and Drink the Rainbow”