Animal Studies 1.Leite JO, DeOgburn R, Ratliff J, Su R, Smyth JA, - - PowerPoint PPT Presentation

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 cholesterol 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

• verweight 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 from 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

• verweight 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

• n fasting lipids, LDL subclasses, insulin resistance, and postprandial lipemic responses in overweight women. J Am Coll Nutr. 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 32.2 33.9 44.8 47.7 47.4 56 64.5 66.3 68.3

10 20 30 40 50 60 70 1960 1972 1978 1991 2000 2004 2008

Prevalence (%) Overweight BMI ≥ 25 Obese BMI ≥ 30

That only a relatively small subset

• f adults has maintained a healthy

weight in the context of current low fat guidelines implies that a majority

• f 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

• ccur on the Atkins diet

result in large increases in fat breakdown and

• xidation

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

• besity are all manifestations of

carbohydrate intolerance

How do we management other food intolerances (lactose, gluten)?

  Weight   Fat   TG   HDL   Glu   Insulin   BP Features

• f 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

50

D Triglycerides (mg/dL)

A

CRD

• 250
• 200
• 150
• 100
• 50

50

LFD

• 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)

50 100 150 200 250 300 350 400 Pre IP 1 2 3 4 5 6 CRD Wk 0 CRD Wk 12

Time (hours) Triglycerides (mg/dL)

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

5 10 15

D HDL-C (mg/dL)

B

CRD

• 5

5 10 15

LFD

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

2 4 6 8 10

D Small LDL3+ (%)

D

CRD

• 22
• 20
• 18
• 16
• 14
• 12
• 10
• 8
• 6
• 4
• 2

2 4 6 8 10

LFD

• 40
• 35
• 30
• 25
• 20
• 15
• 10
• 5

5 10 IL-6 IL-8 TNF-a MCP-1 I-CAM E- Selectin PAI-1

Percent Change

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%

• f 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

• f SFA w/ carbs

↑ coronary events (HR 1.07)

CHO PRO FAT

Low Fat Diet ~1500 kcal/day

CHO PRO 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
• 1.5
• 4.0

Low Fat Low Carb

Change Plasma SFA (%wt) in TAG

• 40
• 30
• 20
• 10
• 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

5 10 15 20 25 30 35

Baseline CRD-SFA CRD-UFA 29.2 31.3 25.8

Plasma SFA (%wt) in TAG

5 10 15 20 25 30

Baseline CRD-SFA CRD-UFA 26.8 14.7 13.0

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

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

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