Atkins Nutritionals Scientific Advisory Board Meeting, July 9, 2010

Human Studies 1.Al-Sarraj T, Saadi H, Volek JS, Fernandez ML. Metabolic syndrome prevalence, dietary intake, and cardiovascular risk profile among overweight

and obese adults 18-50 years old from the United Arab Emirates. Metab Syndr Relat Disord. 2010 Feb;8(1):39-46.

2.Al-Sarraj T, Saadi H, Volek JS, Fernandez ML. Carbohydrate restriction favorably alters lipoprotein metabolism in Emirati subjects classified with

the metabolic syndrome. Nutr Metab Cardiovasc Dis. 2009 Sep 11.

3.Volek JS, Ballard KD, Silvestre R, Judelson DA, Quann EE, Forsythe CE, Fernandez ML, Kraemer WJ. Effects of dietary carbohydrate

restriction versus low-fat diet on flow-mediated dilation. Metabolism. 2009 Dec;58(12):1769-77.

4.Mutungi G, Waters D, Ratliff J, Puglisi M, Clark RM, Volek JS, Fernandez ML.Eggs distinctly modulate plasma carotenoid and lipoprotein

subclasses in adult men following a carbohydrate-restricted diet. J Nutr Biochem. 2010 Apr;21(4):261-7.

5.Volek JS, Phinney SD, Forsythe CE, Quann EE, Wood RJ, Puglisi MJ, Kraemer WJ, Bibus DM, Fernandez ML, Feinman RD. Carbohydrate

restriction has a more favorable impact on the metabolic syndrome than a low fat diet. Lipids. 2009 Apr;44(4):297-309.

6.Ratliff J, Mutungi G, Puglisi MJ, Volek JS, Fernandez ML. Carbohydrate restriction (with or without additional dietary choles terol provided by

eggs) reduces insulin resistance and plasma leptin without modifying appetite hormones in adult men. Nutr Res. 2009 Apr;29(4):262-8.

7.Ratliff JC, Mutungi G, Puglisi MJ, Volek JS, Fernandez ML. Eggs modulate the inflammatory response to carbohydrate restricted diets in

overweight men. Nutr Metab (Lond). 2008 Feb 20;5:6.

8.Seip RL, Volek JS, Windemuth A, Kocherla M, Fernandez ML, Kraemer WJ, Ruaño G. Physiogenomic comparison of human fat loss in

response to diets restrictive of carbohydrate or fat. Nutr Metab (Lond). 2008 Feb 6;5:4.

9.Mutungi G, Ratliff J, Puglisi M, Torres-Gonzalez M, Vaishnav U, Leite JO, Quann E, Volek JS, Fernandez ML. Dietary cholesterol f rom eggs

increases plasma HDL cholesterol in overweight men consuming a carbohydrate-restricted diet. J Nutr. 2008 Feb;138(2):272-6.

10.Forsythe CE, Phinney SD, Fernandez ML, Quann EE, Wood RJ, Bibus DM, Kraemer WJ, Feinman RD, Volek JS. Comparison of low fat and

low carbohydrate diets on circulating fatty acid composition and markers of inflammation. Lipids. 2008 Jan;43(1):65-77.

11.Mutungi G, Torres-Gonzalez M, McGrane MM, Volek JS, Fernandez ML. Carbohydrate restriction and dietary cholesterol modulate the

expression of HMG-CoA reductase and the LDL receptor in mononuclear cells from adult men. Lipids Health Dis. 2007 Nov 28;6:34.

12.Torres-Gonzalez M, Shrestha S, Sharman M, Freake HC, Volek JS, Fernandez ML. Carbohydrate restriction alters hepatic cholesterol

metabolism in guinea pigs fed a hypercholesterolemic diet. J Nutr. 2007 Oct;137(10):2219-23.

13.Wood RJ, Fernandez ML, Sharman MJ, Silvestre R, Greene CM, Zern TL, Shrestha S, Judelson DA, Gomez AL, Kraemer WJ, Volek JS.

Effects of a carbohydrate-restricted diet with and without supplemental soluble fiber on plasma low-density lipoprotein cholesterol and other clinical

markers of cardiovascular risk. Metabolism. 2007 Jan;56(1):58-67.

14.Ruaño G, Windemuth A, Kocherla M, Holford T, Fernandez ML, Forsythe CE, Wood RJ, Kraemer WJ, Volek JS. Physiogenomic analysis of

weight loss induced by dietary carbohydrate restriction. Nutr Metab (Lond). 2006 May 15;3:20.

15.Wood RJ, Volek JS, Davis SR, Dell'Ova C, Fernandez ML. Effects of a carbohydrate-restricted diet on emerging plasma markers for

cardiovascular disease. Nutr Metab (Lond). 2006 May 4;3:19.

16.Wood RJ, Volek JS, Liu Y, Shachter NS, Contois JH, Fernandez ML. Carbohydrate restriction alters lipoprotein metabolism by modifying

VLDL, LDL, and HDL subfraction distribution and size in overweight men. J Nutr. 2006 Feb;136(2):384-9.

17.Volek J, Sharman M, Gómez A, Judelson D, Rubin M, Watson G, Sokmen B, Silvestre R, French D, Kraemer W. Comparison of energy-

restricted very low-carbohydrate and low-fat diets on weight loss and body composition in overweight men and women. Nutr Metab (Lond). 2004

Nov 8;1(1):13

18.Sharman MJ, Volek JS. Weight loss leads to reductions in inflammatory biomarkers after a very-low-carbohydrate diet and a low-fat diet in

overweight men. Clin Sci (Lond). 2004 Oct;107(4):365-9.

19.Sharman MJ, Gómez AL, Kraemer WJ, Volek JS. Very low-carbohydrate and low-fat diets affect fasting lipids and postprandial lipemia

differently in overweight men. J Nutr. 2004 Apr;134(4):880-5.

20.Volek JS, Sharman MJ, Gómez AL, DiPasquale C, Roti M, Pumerantz A, Kraemer WJ. Comparison of a very low-carbohydrate and low-fat diet

on fasting lipids, LDL subclasses, insulin resistance, and postprandial lipemic responses in overweight women. J Am Coll Nut r. 2004

Apr;23(2):177-84.

21.Volek JS, Sharman MJ, Gómez AL, Scheett TP, Kraemer WJ. An isoenergetic very low carbohydrate diet improves serum HDL cholesterol

and triacylglycerol concentrations, the total cholesterol to HDL cholesterol ratio and postprandial pipemic responses compared with a low fat diet in

normal weight, normolipidemic women. J Nutr. 2003 Sep;133(9):2756-61.

22.Sharman MJ, Kraemer WJ, Love DM, Avery NG, Gómez AL, Scheett TP, Volek JS. A ketogenic diet favorably affects serum biomarkers for

cardiovascular disease in normal-weight men. J Nutr. 2002 Jul;132(7):1879-85.

23.Volek JS, Gómez AL, Kraemer WJ. Fasting lipoprotein and postprandial triacylglycerol responses to a low-carbohydrate diet supplemented with

n-3 fatty acids. J Am Coll Nutr. 2000 Jun;19(3):383-91.

Animal Studies 1.Leite JO, DeOgburn R, Ratliff J, Su R, Smyth JA, Volek JS, McGrane MM, Dardik A, Fernandez ML. Low-carbohydrate

diets reduce lipid accumulation and arterial inflammation in guinea pigs fed a high-cholesterol diet. Atherosclerosis. 2010

Apr;209(2):442-8.

2.Fine EJ, Miao W, Koba W, Volek JS, Blaufox MD. Chronic effects of dietary carbohydrate variation on [18F]-2-fluoro-2-

deoxyglucose uptake in rodent heart. Nucl Med Commun. 2009 Sep;30(9):675-80.

3.Leite JO, DeOgburn R, Ratliff JC, Su R, Volek JS, McGrane MM, Dardik A, Fernandez ML. Low-carbohydrate diet

disrupts the association between insulin resistance and weight gain. Metabolism. 2009 Aug;58(8):1116-22.

4.Sharman MJ, Fernandez ML, Zern TL, Torres-Gonzalez M, Kraemer WJ, Volek JS. Replacing dietary carbohydrate with

protein and fat decreases the concentrations of small LDL and the inflammatory response induced by atherogenic diets in

the guinea pig. J Nutr Biochem. 2008 Nov;19(11):732-8

5.Torres-Gonzalez M, Volek JS, Leite JO, Fraser H, Luz Fernandez M. Carbohydrate restriction reduces lipids and

inflammation and prevents atherosclerosis in Guinea pigs. J Atheroscler Thromb. 2008 Oct;15(5):235-43.

6.Torres-Gonzalez M, Leite JO, Volek JS, Contois JH, Fernandez ML. Carbohydrate restriction and dietary cholesterol

distinctly affect plasma lipids and lipoprotein subfractions in adult guinea pigs. J Nutr Biochem. 2008 Dec;19(12):856-63.

7.Torres-Gonzalez M, Volek JS, Sharman M, Contois JH, Fernandez ML. Dietary carbohydrate and cholesterol influence

the number of particles and distributions of lipoprotein subfractions in guinea pigs. J Nutr Biochem. 2006 Nov;17(11):773-

9.

Reviews 1.Feinman RD, Volek JS. Carbohydrate restriction as the default treatment for type 2 diabetes and metabolic syndrome.

Scand Cardiovasc J. 2008 Aug;42(4):256-63.

2.Accurso A, Bernstein RK, Dahlqvist A, Draznin B, Feinman RD, Fine EJ, Gleed A, Jacobs DB, Larson G, Lustig RH,

Manninen AH, McFarlane SI, Morrison K, Nielsen JV, Ravnskov U, Roth KS, Silvestre R, Sowers JR, Sundberg R, Volek

JS, Westman EC, Wood RJ, Wortman J, Vernon MC. Dietary carbohydrate restriction in type 2 diabetes mellitus and

metabolic syndrome: time for a critical appraisal. Nutr Metab (Lond). 2008 Apr 8;5:9.

3.Volek JS, Fernandez ML, Feinman RD, Phinney SD. Dietary carbohydrate restriction induces a unique metabolic state

positively affecting atherogenic dyslipidemia, fatty acid partitioning, and metabolic syndrome. Prog Lipid Res. 2008

Sep;47(5):307-18.

4.Westman EC, Yancy WS, Haub MD, Volek JS. Insulin resistance from a low carbohydrate, high fat diet perspective.

Metab Syndr Relat Disord. 2005;3(1):14-8.

5.Westman EC, Feinman RD, Mavropoulos JC, Vernon MC, Volek JS, Wortman JA, Yancy WS, Phinney SD. Low-

carbohydrate nutrition and metabolism. Am J Clin Nutr. 2007 Aug;86(2):276-84.

6.Feinman RD, Volek JS. Low carbohydrate diets improve atherogenic dyslipidemia even in the absence of weight loss.

Nutr Metab (Lond). 2006 Jun 21;3:24.

7.Fernandez ML, Volek JS. Guinea pigs: a suitable animal model to study lipoprotein metabolism, atherosclerosis and

inflammation. Nutr Metab (Lond). 2006 Mar 27;3:17.

8.Volek JS, Feinman RD. Carbohydrate restriction improves the features of Metabolic Syndrome. Metabolic Syndrome may

be defined by the response to carbohydrate restriction. Nutr Metab (Lond). 2005 Nov 16;2:31.

9.Volek JS, Forsythe CE. The case for not restricting saturated fat on a low carbohydrate diet. Nutr Metab (Lond). 2005

Aug 31;2:21.

10.Volek JS, Sharman MJ, Forsythe CE. Modification of lipoproteins by very low-carbohydrate diets. J Nutr. 2005

Jun;135(6):1339-42.

11.Volek JS, Vanheest JL, Forsythe CE. Diet and exercise for weight loss: a review of current issues. Sports Med.

2005;35(1):1-9.

12.Volek JS, Sharman MJ. Cardiovascular and hormonal aspects of very-low-carbohydrate ketogenic diets. Obes Res.

2004 Nov;12 Suppl 2:115S-23S.

13.Westman EC, Mavropoulos J, Yancy WS, Volek JS. A review of low-carbohydrate ketogenic diets. Curr Atheroscler

Rep. 2003 Nov;5(6):476-83.

14.Volek JS, Westman EC. Very-low-carbohydrate weight-loss diets revisited. Cleve Clin J Med. 2002 Nov;69(11):849,

853, 856-8 passim.

13.3 14.6 15.1

23.3

30.9 32.233.9

44.847.7 47.4

56

64.566.3

68.3

0

10

20

30

40

50

60

70

1960 1972 1978 1991 2000 2004 2008

Pre

vale

nce

(%)

OverweightBMI ≥ 25

ObeseBMI ≥ 30

That only a relatively small subset

of adults has maintained a healthy

weight in the context of current low

fat guidelines implies that a majority

of Americans may be metabolically

and genetically programmed to

benefit from alternative approaches

CARBOHYDRATE

FAT

PROTEIN

The increase in calories

during the obesity epidemic

was due largely to

carbohydrate intake

Lipogenesis (fat synthesis)

Ingest Carbohydrate

Blood Sugar (20 g)

Road to

Metabolic Syndrome

Road to

Health

Glycogen

(300-400 g)

Oxidation

Glycogen (100 g)

Am J Physiol. 262:E631-36, 1992

84 hr of fasting or lipid infusion to meet REE

Changes in plasma glucose, fatty acids, glycerol, ketones, insulin, epinephrine, as well as rates of lipolysis were similar

“Carbohydrate restriction, not

the presence of a negative

energy balance, is responsible

for initiating the metabolic

response to fasting.”

Low High

Insulin Concentration

Fat Breakdown Maximum

Minimum

High

Carbohydrate

Diet

Decreases in insulin that

occur on the Atkins diet

result in large increases in

fat breakdown and

oxidation

Impaired

Glucose

Tolerance

Insulin

Resistance

Late

Diabetes

Hyperinsulinemia

b-Cell Defect

(↓ insulin secretion)

Early

Diabetes b -Cell Failure

Obesity

↑ Carbs

Obesity (BMI ≥30) 2006 to 2008:

24% Non-Hispanic white

36% Non-Hispanic blacks

29% Black

Diabetes (2007):

23.5 million (10.7%) adults

Estimated Costs = $174 billion

Pre-Diabetes (2003 to 2006):

IFG = 100 to 125 mg/dL

25.9% of adults ≥20 yr

35.4% of adults ≥60 yr

Excessive carb intake is a

slippery slope to diabetes

Progression from Insulin

Resistance to Diabetes is

not inevitable

Insulin Signaling

Insulin Function Lipolysis

Glucose Secretion

VLDL Secretion

Nitric Oxide

Glucose Uptake Glucose Uptake

Lipolysis

Glucose Secretion

VLDL Secretion

Nitric Oxide

Metabolic syndrome, insulin resistance,

diabetes, and even many forms of

obesity are all manifestations of

carbohydrate intolerance

How do we management other food intolerances (lactose,

gluten)?

Weight

Fat

TG

HDL

Glu

Insulin

BP

Features of MetS

Weight

Fat

TG

HDL

Glu

Insulin

BP

Improved by CHO Restriction

Low carbohydrate

diets are more likely

than low fat diets to

effect global

improvement in

markers associated

with insulin

resistance

Most reliable response to carbohydrate restriction

-250

-200

-150

-100

-50

0

50

D T

rig

lyc

eri

de

s (

mg

/dL

)

A CRD

-250

-200

-150

-100

-50

0

50LFD

-51% -19%

Volek et al. Lipids. 2009 Apr;44(4):297-309. Epub 2008 Dec 12

0.0

50.0

100.0

150.0

200.0

250.0

300.0

350.0

400.0

Pre IP 1 2 3 4 5 6

Low Fat Diet Wk 0

Low Fat Diet Wk 12

Time (hours)

0

50

100

150

200

250

300

350

400

Pre IP 1 2 3 4 5 6

CRD Wk 0

CRD Wk 12

Time (hours)

Tri

glyc

eri

de

s (m

g/d

L)

Volek et al. Lipids. 44:297-309, 2009

Pre Occlusion Diameter Post Occlusion Diameter

Volek et al. Metabolism. 2009 July 24

More effective than other lifestyle changes (exercise, smoking cessation, weight loss, n-3 PUFA) Not dependent on starting levels Stronger effect in women Dependent on the cholesterol content of diet

-5

0

5

10

15

D H

DL

-C (

mg

/dL

)

B CRD

-5

0

5

10

15LFD

13% 1%

Volek et al. Lipids. 2009 Apr;44(4):297-309. Epub 2008 Dec 12

Volek et al. Lipids. 2009 Apr;44(4):297-309. Epub 2008 Dec 12

CRD LFD Larger

Particles Smaller

Particles

High Carbohydrate/Low-Fat

Low Carbohydrate/High-Fat

Volek et al. Lipids. 2009 Apr;44(4):297-

309. Epub 2008 Dec 12 Krauss RM. Annu Rev Nutr. 21:283-95, 2001

-22

-20

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

2

4

6

8

10

D S

mall L

DL

3+

(%

)

D CRD

-22

-20

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

2

4

6

8

10LFD

-40

-35

-30

-25

-20

-15

-10

-5

0

5

10

IL-6 IL-8 TNF-a MCP-1 I-CAM E-

Selectin

PAI-1

Pe

rce

nt

Ch

an

ge

VLCKD LFD

Forsythe et al. Lipids. 43(1):65-77, 2008

Treating any of the

individual MetSyn markers w/

carbohydrate restriction holds

promise to benefit the others.

Low carbohydrate diets

preferred primary intervention

when >1 sign of insulin

resistance is observed.

“Limit your intake of

saturated fat to <7%

of energy.”

Renowned science writer Gary Taubes

“What if It’s All Been a Big Fat Lie?” - 2002

“Good Calories, Bad Calories” - 2007

Provocative articles exposing the lack of quality science

behind low-fat diets.

SFA

Intake Plasma LDL

Heart

Disease

?

Conclusions Over a mean of 8.1 years, a dietary intervention that reduced total fat intake and increased

intakes of vegetables, fruits, and grains did not significantly reduce the risk of CHD, stroke, or CVD in

postmenopausal women and achieved only modest effects on CVD risk factors, suggesting that more

focused diet and lifestyle interventions may be needed to improve risk factors and reduce CVD risk.

Jakobsen et al. AJCN

Feb 11 (Epub)

Replacing 5%en

of SFA w/ carbs

↑ coronary events

(HR 1.07)

CHOPRO

FAT

Low Fat Diet

~1500 kcal/day

CHOPRO

FAT

Low Carb Diet

~1500 kcal/day

Saturated Fat = 12 g Saturated Fat = 36 g

Low Carbohydrate Diet

12 wk

Low Fat Low SFA

Forsythe et al. Lipids. 43(1):65-77, 2008

-4

-3

-2

-1

0

-1.5

-4.0

Low Fat Low Carb

Change Plasma SFA (%wt) in TAG

-40

-30

-20

-10

0

-13.7

-40.2

Low Fat Low Carb

Change Plasma SFA (mg/dL) in TAG

Despite eating 3

times more SFA

compared to low-fat,

subjects showed

significantly greater

reductions in plasma

SFA on a low

carbohydrate diet

Saturated Fat

Saturated Fat

Metabolic Processing of Saturated Fat

Saturated Fat Burned as

Fuel

Saturated Fat Burned as

Fuel

Low Carbohydrate

Diet (45 g CHO/d)

Low Fat Diet

(208 g CHO/d)

Saturated Fat Synthesis

Saturated Fat Intake (12 g/d)

Saturated Fat Synthesis

Saturated Fat Intake (36 g/d)

Processing of

dietary SFA is

more efficient

when carbohydrate

intake is low

CRD-SFA

CRD-UFA

Habitual

PRO (%) 25 29 30

CHO (%) 34 13 12 Fat (%) 41 58 58 Fat (g) 94 164 161

SFA (g) 40 86 47 MUFA (g) 37 58 69 PUFA (g) 16 12 41 n-3 (%) 0.7 0.6 2.9 n-6 (%) 6.6 3.8 10.8

Chol (mg) 426 854 820

0

5

10

15

20

25

30

35

Baseline CRD-SFA CRD-UFA

29.231.3

25.8

Plasma SFA (%wt) in TAG

0

5

10

15

20

25

30

Baseline CRD-SFA CRD-UFA

26.8

14.713.0

Plasma SFA (mg/dL) in TAG

Low carbohydrate

is a profound

stimulus impacting

the metabolic

processing of

ingested SFA

A CRD decreases fat

synthesis regardless of

fat quality

0

1

2

3

4

Baseline CRD-SFA CRD-UFA

3.5

2.5 2.4

Plasma 16:1 (%wt) in TAG

…or you are

what you do

with what you

eat!

SFA

Dietary

Matrix

Plasma SFA

Insulin Resistance

Dyslipidema

Plasma SFA

Insulin Sensitivity

Normolipidemia

Carbs

Path Dependence on Ambient Carbohydrate

Metabolic Health Continuum

Dietary Carbohydrate Carbohydrate Carbohydrate

Saturated fat has a

totally different

metabolic behavior

when consumed in

the context of a low

carbohydrate diet

Recent research showing rapid

clearing of saturated fats,

reduced inflammation and

improvements in other

biomarkers when consuming

well-formulated low

carbohydrate diets (Atkins

Diet) should encourage us to

re-examine their therapeutic

value

Immediate opportunity is to

harness these benefits in the

management of insulin

resistance