1. Overview the function of dietary carbohydrate in the diet, its role as a macronutrient, and its connection to the metabolic syndrome.

2. Compare and contrast very low carbohydrate and low fat diets on metabolic syndrome markers and cardiovascular risk factors.

3. Provide evidence that the collection of metabolic syndrome markers responds in concert to carbohydrate restriction.

4. Provide evidence that dietary fat, even saturated fat, is not deleterious in the presence of low carbohydrate.

KEY RECOMMENDATIONSConsume <10% of calories from saturated fatty acids and less than 300 mg/day of cholesterol, and keep trans fatty acid consumption as low as possible. Keep total fat intake between 20 to 35% of calories, with most fats coming from sources of polyunsaturated and monounsaturated fatty acids, such as fish, nuts, and vegetable oils. When selecting and preparing meat, poultry, dry beans, and milk or milk products, make choices that are lean, low-fat, or fat-free. Limit intake of fats and oils high in saturated and/or trans fatty acids, and choose products low in such fats and oils.

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.

Bethesda, we have a problem.

Mensink et al. AJCN. 77:1146-55, 2003.

Jakobsen et al. AJCN Feb 11 (Epub)

Replacing 5%en of SFA with

carbohydrate increased coronary events (HR 1.07)

Replacing 5%en of SFA with

carbohydrate increased coronary events (HR 1.07)

Glucose

Carbohydrate

Insulin Sensitive

Insulin Resistant

Lipogenesis

Hypertriglyceridemia

Petersen et al. PNAS 104(31):12587-94, 2007

Weight

Fat

TG

HDL

Glu

Insulin

BP

Features of MetSyn

Weight

Fat

TG

HDL

Glu

Insulin

BP

Improved by CHO Restriction

↑Insulin

↑Carbs

Essential Structural and

Functional Roles

Fuel (Energy)

Roadblock to Burning

Fat

Does carbohydrate have to be a macronutrient?

100% Carbs (RQ 1.0)

100% Fat(RQ 0.7)

Fuel Mix

↓ Metabolic Syndrome &CVD Risk

↓ Metabolic Syndrome &CVD Risk

50:50(RQ 0.85)

+ Insulin- Insulin

Improvement of Metabolic Syndrome Markers

↓ Hyperinsulinemia/Insulin Resistance

↓ Glucose↓ Insulin↓ RBP-4

Dyslipidemia↓ Fasting TG↓ Postprandial TG↑ HDL-C↓ Small LDL

Adiposity↓ % body fat↓ Abdominal fat

Inflammation↓ Cytokines

Vascular Function

↑ Flow-mediated dilation↑ NO bioavailability

Fatty AcidMetabolism/Composition↓ SFA↑ Fat Oxidation↓ Lipogenesis

↓ Carbohydrate

Consistent with the idea that intolerance to carbohydrate is a fundamental feature of metabolic syndrome, we proposed that dietary restriction of carbohydrate would improve traditional and emerging aspects of the syndrome compared to a low fat diet.

Lipids. 2008 Jan;43(1):65-77. Epub 2007 Nov 29.

Lipids. 2008 Dec 12. [Epub ahead of print]

-50

-40

-30

-20

-10

0

10

Glucose Insulin RBP-4 TG HDL-C ApoB/ApoA-1

CRD LFD

Perc

ent

Chan

ge

**

******

******

Percent changes in glucose, insulin, RBP-4, and markers of atherogenic dyslipidemia after 12 wk of a CRD or low fat diet (LFD) (***P<0.001, **P<0.01, *P<0.05).

Low Fat

R2 = 0.08

Low Carbohydrate

R2 = 0.29

-40

-30

-20

-10

0

10

20

30

40

-350 -300 -250 -200 -150 -100 -50 0 50

Change in Dietary Carbohydrate (g)

Ch

ang

e in

RB

P4

(mg

/mL

)

Carbohydrate Restriction But Not Fat Restriction Reduces Retinol-Binding Protein 4 and Features of Metabolic Syndrome. T.E. GRAHAM, J.S. VOLEK, M.L FERNANDEZ, W.J. KRAEMER, R.J. WOOD, C.E. FORSYTHE, E.E. QUANN, B.B. KAHN.

VLCKD LFD-20

-15

-10

-5

5

0

%C

hang

e R

BP

4

Most reliable response to carbohydrate restriction

Carbohydrate induced triglyceridemia

-250

-200

-150

-100

-50

0

50

D T

rig

lyce

rid

es (

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)

Trig

lyce

rides

(mg/

dL)

Postprandial lipemic responses to a high fat meal (908 kcal, 84% fat) before and after a CRD and LFD. Mean total AUC was significantly different between the CRD and LFD (P < 0.000).

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

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 (m

g/d

L)

B CRD

-5

0

5

10

15LFD

13% 1%

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

CRD CRD LFD LFDLarger

ParticlesSmallerParticles

Representative gels showing an abundance of larger LDL particles after a CRD and a predominance of smaller LDL particles after a LFD.

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

-22

-20

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

2

4

6

8

10

D S

mal

l LD

L3+

(%

)

D CRD

-22

-20

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

2

4

6

8

10LFD

Volek et al. Lipids. 2009 Apr;44(4):297-309. Epub 2008 Dec 12Krauss RM. Annu Rev Nutr. 21:283-95, 2001

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4LFD

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

D ap

oB

/ap

oA

1 (

mg

/dL

)

CRD

-15% 8%

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

-12

-10

-8

-6

-4

-2

0

0 1 2 3 4 5 6 7 8 9 10 11 12Week

Wei

gh

t L

oss

(kg

)

VLCKDLow Fat

A

-25

-20

-15

-10

-5

0

LFD

Wk 0 Wk 12

-25

-20

-15

-10

-5

0

Wei

gh

t L

oss

(kg

)

VLCKD

Wk 0 Wk 12

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

-6

-5

-4

-3

-2

-1

0

Whole Body Fat Loss (kg)

*Low-CHO

Low-Fat

-4

-3

-2

-1

0

Pre Mid Post

Trunk Fat Loss (kg)

Low-Fat

Low-CHO

*

Volek et al. Nutr Metab. 2004 Nov 8;1(1):13.

-2.0

-3.4

-6

-5

-4

-3

-2

-1

0

Ch

an

ge P

erc

en

t Fa

t (%

)

LF

-3.5

-5.3

LF+RE LC+RELC

(A) Longitudinal image of the brachial artery before and after 5 min of arm cuff occlusion to induce reactive hyperemia. (B) Postprandial vascular responses to a high fat meal before and after 12 wk in subjects who consumed a CRD or LFD. Values represent the absolute difference (Wk 12 – Baseline) in peak %FMD of the brachial artery. Peak FMD = [(post occlusion diameter – pre occlusion diameter) / pre occlusion diameter]. **P < 0.01, *P < 0.05.

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

Pre 1.5 3 4.5

CRD LFD

Abso

lute

Cha

nge

in P

eak

%FM

D

*

**

Time (hours)

A Pre Occlusion Diameter Post Occlusion Diameter

B

Volek et al. Metabolism. In Press

Blood Saturated Fat Levels

High Fat Diet 36 g SFA/d

Low Fat Diet 12 g SFA/d

Saturated Fat

Saturated Fat

208 CHO/d

45 CHO/d

Saturated Fat

Saturated Fat

Blood Saturated Fat Levels

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)

-4

-3

-2

-1

0

1

TG CE

CRD (36 g SFA/d)LFD (12 g SFA/d)

Chan

ge in

Ser

um S

FA (%

)

* *

-4

-3

-2

-1

0

1

TG CE

CRD (36 g SFA/d)LFD (12 g SFA/d)

Chan

ge in

Ser

um 1

6:1n

-7 (%

)

*** ***

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

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

-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

CRP

EGF

E-sel

I-CAM

IL-6

IL-8

L-sel

MCP-1

PAI-1

P-sel

V-CAM

VEGF

TNF-

IFN-

-0.6 -0.4 -0.2 0 0.2 0.4 0.6

Change CE 20:4n-6/20:5n-3

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

0

5

10

15

20

25

30

35

Serum TG Fraction

LFD (40 g SFA/d)CRD (86 g SFA/d)CRD (47 g SFA/d)

Plas

ma

SFA

(%) *

0

50

100

150

200

250

300

Serum TG Fraction

LFD (40 g SFA/d)CRD (86 g SFA/d)CRD (47 g SFA/d)

Plas

ma

SFA

(mg/

mL)

**

0

1

2

3

4

Serum TG Fraction

LFD (40 g SFA/d)CRD (86 g SFA/d)CRD (47 g SFA/d)

Plas

ma

16:1

n-7

(%)

* *

0

200

400

600

800

1000

1200

1400

0 1 2 3 4 5 6 7 8

8-is

o PG

F2α

pg/

mg

crea

tinin

e

Subjects

Baseline

CRD-SFA

CRD-UFA

Low Fat

Low Carbohydrate

LDL Concentration

Small LDL (Pattern B)

Fasting & Postprandial TG

HDL (concentration and size)

TC/HDL or apoB/apoA-1

Fasting & Postprandial Glucose

Fasting & Postprandial Insulin

Insulin Sensitivity (HOMA, Clamp, TG/HDL, RBP-4)

CRP (Inflammation)

Vascular Function

Serum SFA (Fatty Acid Composition)

Oxidative Stress

1. Carbohydrate intake is intimately linked to metabolic syndrome

2. Properly implemented very low carbohydrate diets favorably impact a broad spectrum of metabolic syndrome markers and cardiovascular risk factors

3. Carbohydrate restriction targets all the markers of metabolic syndrome, whereas drugs target individual markers and have well known side effects

Metabolically Compromised/obese

Athletes

Naturally lean

Overweight/obese

Biomarkers: Weight lossTG16:1n-7