Foliensatz von Dr. Robert H. Lustig (University of California, San Francisco ) zum 2. Deutschen Zuckerreduktionsgipfel: Fat vs. Sugar 2.0

1. Fat vs. Sugar 2.0
AOK, Berlin, October 17, 2018
Robert H. Lustig, M.D., M.S.L.
Emeritus Professor, Pediatric Endocrinology, UCSF
Member, Institute for Health Policy Studies
Adjunct Professor, Touro University-California
Adjunct Professor UC Hastings College of the Law
Chief Science Officer, Eat REAL

2. Disclosures
BIOLUMEN
Technologies

3. Decrease in U.S. Deaths from Heart Disease 1980–2000
offset by Type 2 Diabetes — and they’re not dying!
Ford et al, NEJM 356:2388, 2007

4. T2DM increasing around the world
People with DM (in millions) for 2000, projection for 2010, and % increase
Zimmet et al. Nature 414: 782, 2001
PROJECTED
Projected annualized inflation rate 3.88%

5. People with DM (in millions) for 2000, projection for 2010, and % increase
285 MILLION IN 2010
Actual annualized inflation rate 6.55%
T2DM increasing around the world
Zimmet et al. Nature 414: 782, 2001

6. People with DM (in millions) for 2000, projection for 2010, and % increase
422 MILLION IN 2014
Actual annualized inflation rate 10.30%
T2DM increasing around the world
Zimmet et al. Nature 414: 782, 2001

7. People with DM (in millions) for 2000, projection for 2010, and % increase
Was Zum Teufel??
422 MILLION IN 2014
T2DM increasing around the world
Zimmet et al. Nature 414: 782, 2001

8. Diabetes in Germany
Brinks et al. Eur J Epidemiol 27:791, 2012Tamayo et al. Dtsch Arztebl Int 113:177, 2016
2010 data Number Prevalence

9. The money is not going to hospitals, physicians,
or Big Pharma

10. The money is not going to hospitals, physicians,
or Big Pharma
It’s going to chronic metabolic disease

11. Two inconvenient truths

12. Two inconvenient truths
• There is no medicalized prevention for chronic
metabolic disease
• There’s just long-term treatment

13. Haw et al. JAMA Int Med 177:1808, 2017
Lifestyle RR: 0.61
Med RR: 0.64
For Both: Number needed to treat (NNT): 25
Meta-analysis of T2DM Prevention Strategies:
Lifestyle and/or Medication

14. Two inconvenient truths
• There is no medicalized prevention for chronic
metabolic disease
• There’s just long-term treatment
• You can’t fix healthcare until you fix health
• You can’t fix health until you fix the diet
• And you can’t fix the diet until you know what is wrong

15. 1984

16. 2001

17. The Fiction
“Beating obesity will take action by all of us, based on
one simple common sense fact: All calories count, no
matter where they come from, including Coca-Cola and
everything else with calories…”
-The Coca Cola Company, “Coming Together”, 2013

18. History

19. 1955

20. The macronutrient wars 1970-1980
1972, 1986

21. The Original Case Against Fat
Ancel Keys “7-Country Study” in fact listed 6, studied 22
Started in 1958, continued for 15 yr

22. The Original Case Against Fat
Ancel Keys “7-Country Study” in fact listed 6, studied 22
Started in 1958, continued for 15 yr

23. Add in the Maasai, Inuit, Rendille, and
Tokelau indigenous tribes

24. Seven Countries
Correlation of CHD with dietary fat

25. Seven Countries
Correlation of CHD with dietary fat
Page 262:
Diet

26. The USDA, AMA, and AHA
call for dietary fat reduction
• Early 1970’s: discovery of LDL
• Mid 1970’s: Dietary fat raises LDL (A B)
• Late 1970’s: LDL correlated with CVD (B ≋ C)
If A B, and B ≋ C, then A C, therefore no A, no C

27. 1977

28. 1977
Nothing about fruit, vegetable, or fiber consumption

29. The content of low-fat home-cooked food can be controlled
But low-fat processed food means substitution with carbohydrate
Which carbohydrate?
Either
• High fructose corn syrup (55% fructose)
• Sucrose (50% fructose)
e.g. Nabisco Snackwells® Oreos
—2g fat, +13g CHO (+4g sugars)
The low-fat craze

30. The SFUSD School Milk Program
Courtesy of
M. Lustig

31. The SFUSD School Milk Program
Courtesy of
M. Lustig

32. Carbohydrate
Fat Obesity (BMI>30)
Protein
Based on NHANES data. Int J Obes 1998;22:39-47. JAMA 2002;288:1723. MMWR 2004;53:80-82.
Trends in macronutrient intake and obesity

33. Carbohydrate
Fat Diagnosed DM
Protein
Based on NHANES data. MMWR 2004;53:80-82. Diabetes Care 2004;27:2806.
Trends in macronutrient intake and diabetes

34. Prospective Urban and Rural Epidemiology
(PURE)
Dehghan et al. Lancet epub Aug 29, 2017

35. Dehghan et al. Lancet epub Aug 29, 2017
Prospective Urban and Rural Epidemiology
(PURE)

36. The animal-based food effect on T2DM goes
away after you control for iron/heme intake
Talaei et al. Am J Epidemiol DOI: 10.1093/aje/kwx156, 2017

38. Branched chain amino-acids or choline in red meat
may contribute to insulin resistance and inflammation
Newgard et al. Cell Metab 9:311, 2009 Zhu et al. Circulation 135:1671, 2017
Trimethylamine Oxide (TMAO), a bacterial
metabolite of dietary choline, appears to be
pro-inflammatory

39. Blood levels of dairy saturated fatty acids
correlate with protection from T2DM
Yakoob et al. Circulation 133:1645, 2016

40. Imamura et al. PLoS Med 15:e1002670, 2018
Dairy saturated fats 15:0, 17:0, and t16:1n-7
are protective against Type 2 diabetes

41. FULL FAT DAIRY TOTAL (FULL/LOW FAT) DAIRY
Dehghan et al. Lancet epub Sept 11, pii: S0140-6736(18)31812-9. doi: 10.1016/S0140-6736(18)31812-9. 2018
Association of full-fat dairy with cardiovascular protection

42. Surrogate markers

43. LDL correlates with CVD,
but not all that well
5/12/2014 0 (3000×3535)

44. Ravnskov et al. BMJ Open 6:e010401, 2016

45. In Meta-Analysis
(univariate risk)
46,413 Men (16 studies)
2445 Events
8.4 yr f/u
10,864 women (5 studies)
439 events
11.4 yr f/u
holds up in mutltivariate analysis
Austin et al, Am J Cardiol 81:7B, 1998
Hypertriglyceridemia is a better CVD risk factor

47. Atherogenic dyslipidemia—
It’s not about LDL cholesterol,
it’s about LDL particle number
Cromwell et al. J Clin Lipidol 1:583, 2007

48. The lipoprotein continuum
VLDL IDL LDLA large buoyant HDL
LDLA-B intermediate
LDLB small dense
“Total LDL” won’t tell you particle number -
There’s more LDLB than LDLA at the same total concentration
PATTERN “A”
PATTERN “B”

49. Rizzo and Berneis, Quart J Med 99:1, 2006
TG and HDL change with LDL sizing

50. Randomized Clinical Trials

51. Conclusions: A dietary intervention that reduced total fat intake and
increased intakes of vegetables, fruits, and grains did not significantly
reduce the risk of CHD or stroke.
Howard et al. JAMA 295:655, 2006

52. DuBroff, Evidence-Based Medicine.;22:15, 2017
Randomized controlled trials (RCTs) of drug (41)
or dietary (3) interventions
• No overall benefit on mortality
• Most of these trials did not reduce CVD events
• Some of the drug studies reported harm
LDL-C lowering as primary or secondary prevention
of CVD

54. A high intake of omega-6 fats (vegetable oils) has not been proven as
beneficial for our health and trans-fats have been shown to have
negative health effects. The higher intake of vegetable oils and the
increase in carbohydrate consumption in the last 30-40 years are the
two leading factors behind the high rates of obesity and metabolic
syndrome in the U.S. Saturated and monounsaturated fats are not.

55. Malhotra et al. Br J Sports Med April 26, 2017 doi: 10.1136/bjsports-2016-097285
AM National Health Trust, UK
RR Editor-in-Chief, JAMA Int Med
PM Editor-in-Chief, BMJ Open Heart

56. New York Times, April 17, 2011
Nature 487:27-29, Feb 1, 2012

57. Histology of (N)AFLD
Normal (N)AFLD

58. NAFLD is a worldwide problem,
even in normal weight people

59. Loomis et al. J Clin Endocrinol Metab. 101:945, 2016
Obese
Normal
Weight
Obese
Over
Weight
Normal
Weight
Over
Weight
NAFLD is associated with diabetes,
even in normal weight people

60. MRI Fat FracAon Maps
Obese
Low Liver Fat = 2.6%

61. MRI Fat FracAon Maps
Obese
Low Liver Fat = 2.6%

62. MRI Fat FracAon Maps
Obese
Low Liver Fat = 2.6%
Obese
High Liver Fat = 24%

63. MRI Fat FracAon Maps
Obese
Low Liver Fat = 2.6%
Obese
High Liver Fat = 24%

64. MRI Fat FracAon Maps
Obese
Low Liver Fat = 2.6%
Obese
High Liver Fat = 24%
Thin
High Liver Fat = 23%

65. MRI Fat FracAon Maps
Obese
Low Liver Fat = 2.6%
Obese
High Liver Fat = 24%
Thin
High Liver Fat = 23%

66. (20%)
(80%)

67. Can you name an energy source that is:

68. Can you name an energy source that is:
Not necessary for life

69. Can you name an energy source that is:
Not necessary for life
There is no biochemical reaction in the body that requires it

70. Can you name an energy source that is:
Not necessary for life
There is no biochemical reaction in the body that requires it
Is not nutrition

71. Can you name an energy source that is:
Not necessary for life
There is no biochemical reaction in the body that requires it
Is not nutrition
When consumed in excess it is toxic

72. Can you name an energy source that is:
Not necessary for life
There is no biochemical reaction in the body that requires it
Is not nutrition
When consumed in excess it is toxic
We love anyway, and it’s addictive

73. Can you name an energy source that is:
Not necessary for life
There is no biochemical reaction in the body that requires it
Is not nutrition
When consumed in excess it is toxic
We love anyway, and it’s addictive
Answer: Ethanol

74. Ethanol
Ethanol
Acetate Acetate
Acetyl-CoA
VLDL
ACL ACC FAS MTP
ApoB
SREBP1
O2
ATP+
CO2
TG
JNK1
PKC
Muscle
IR
FFA
Insulin
Inflammation
Lipid
droplet
TCA
cycle
Dys-
lipidemiaCitrate
Metabolism of Ethanol
Acetaldehyde
Alcohol
Dehydrogenase
1B
Aldehyde
Dehydrogenase 2
ACCS2
ROS
Acyl-CoAAcetyl-CoA Malonyl-CoACitrate
CPT-1X
(80%)

75. (100%)

76. Sugar and Diabetes
(Causation)

77. Sugar is toxic unrelated to calories
Lustig et al. Obesity 24:453, 2016
Schwarz et al. Gastroenterology 153:743, 2017
Gugliucci et al. Atherosclerosis 253:171, 2016

78. Strategy
• Isocaloric fructose restriction x 9 days in children who are
habitual sugar consumers
• No change in weight
• Substitute complex carbs for sugar
• Maintain baseline macronutrient composition of the the
diet
• Study in PCRC at Day 0 and Day 10
• Assess changes in organ fat, de novo lipogenesis, and
metabolic health

79. FasAng Labs
Day 0 Day 10 β-coefficient
(Adjusted Change)
[95% CI]
p value
Heart rate (bpm) 83.1 ± 10.7 80.1 ± 11.3 -2.8 [-6.5, +0.9] 0.13
Systolic BP (mmHg) 122.6 ± 10.5 121.1 ± 9.9 - 1.39 [-4.9, +2.1] 0.43
Diastolic BP 68.8 ± 8.9 63.7 ± 7.5 - 4.9 [-8.1, -1.8] 0.003
FasAng lactate (mmol/
L)
1.2 ± 0.4 0.9 ± 0.3 -0.3 [-0.5, -0.2] <0.001
Lactate AUC
(mM/120 min)
160.0 ± 34.5 129.0 ± 34.5 -31.2 [-41.9, -20.5] <0.001
HOMA-IR¥ 7.9 ± 4.8 5.2 ± 2.6 -2.7 [-3.8, -1.5] <0.001
AST (U/L) * 27.4 ± 14.1 23.8 ± 8.9 0.02
ALT (U/L) ¥ 28.9 ± 22.8 26.7 ± 19.6 -2.2 [-4.7, +0.3] 0.09
FasAng TG (mM) 1.4 ± 0.9 1.0 ± 0.5 -0.4 [-0.6, -0.2] 0.002
FasAng LDL-C (mM) 2.4 ± 0.6 2.1 ± 0.6 -0.3 [-0.4, -0.1] <0.001
FasAng HDL-C (mM) 1.2 ± 0.2 1.0 ± 0.2 -0.1 [-0.2, -0.1] <0.001
FasAng FFA (mM) 0.6 ± 0.2 0.7 ± 0.2 +0.1 [+0.1, +0.2] <0.001

80. DNL is the Conversion of Dietary
Carbohydrates into Lipids
Into Fat (lipids)
*)
*)
*) *)
*)
*) *)
*)
*)
*)
*)
*)
*
*)
*)
*) *)
*)
*)
*)
*
Sugar
Fructose
*)
Palmitate
* * *
Acetate
*)
New Tracer Method using MIDA: Hellerstein and Neese, AJP 1999

81. 0
20
40
60
80
100
120
140
160
Day 0 Day 10
DNL AUC Pre and Post Fructose Restriction)
DNL)(%)))))))))))))))))))))))))))))))))

82. Oral glucose tolerance test
before and after isocaloric fructose restriction

83. Changes in liver, visceral, and subcutaneous fat
(n = 37)

84. LDL subclasses
Day 0
Day 10
AUC %
AUC %
VLDL MID LDL1 LDL2 LDL3 (sd-LDL)
Day 0
Day 10
VLDL MID LDL1 LDL2 LDL3 (sd-LDL)
A B
Day 10
HDL subclasses
Day 0
AUC %
AUC %
Large Intermediate Small
C
Gugliucci et al. Atherosclerosis 253:171, 2016

85. n Day 0* Day 10*
Change
(adj. for weight) p value
LDL-1** (%) 37 30.1 ± 10.7 26.5 ± 9.3 - 26% 0.009
LDL-2† (%) 37 16.5 ± 13.5 11.8 ± 8.3 NS
sdLDL (3) (%) 10 1.9 ± 1.7 0.6 ± 0.7 -1.3 0.04
LDL Size (nm) 37 271.3 ± 3.1 272.2 ± 2.5 + 0.87 0.008
Small HDL (%) 37 14.6 ± 6.1 11.8 ± 5.5 - 2.73 0.001
Large HDL (%) 37 26.8 ± 7.9 29.3 ± 7.7 + 2.42 0.04
Apo-B** (mg/dl) 37 78 ± 24 66 ± 24 - 32% <0.001
ApoC-II** (mg/dl) 37 8.7 ± 3.7 8.3 ± 4.2 - 15% 0.19
ApoC-III** (mg/dl) 37 8.7 ± 3.5 6.5 ± 2.6 - 49% <0.001
TG / HDL ratio** 43 3.1 ± 2.5 2.4 ± 1.4 - 38% 0.02
Changes in Lipoprotein Subfractions
** not normally distributed, log transformed, percent change, † non-parametric, Kruskal-Wallis
Gugliucci et al. Atherosclerosis 253:171, 2016

86. Ac CoA*
Malonyl
CoA
Glycerol-P
Fatty
Acid*
TG*
De novo
Lipogenesis
DNL
VLDL*

87. Ac CoA*
Malonyl
CoA
Glycerol-P
Fatty
Acid*
TG*
De novo
Lipogenesis
DNL
VLDL*
9 days
fructose
restric2on

88. Ac CoA*
Malonyl
CoA
Glycerol-P
Fatty
Acid*
TG*
De novo
Lipogenesis
DNL
VLDL*
LIVER
FAT
DNL
VLDL*
9 days
fructose
restric2on
Visceral fat

89. Ac CoA*
Malonyl
CoA
Glycerol-P
Fatty
Acid*
TG*
De novo
Lipogenesis
DNL
VLDL*
Improved
Insulin
kineAcs
LIVER
FAT
DNL
VLDL*
9 days
fructose
restric2on
Visceral fat

90. Sugar and disease
• Causation
– Diabetes
– Heart Disease
– Fatty Liver Disease
– Tooth Decay
• Correlation
– Cancer
– Dementia

91. Kearns et al. JAMA Int Med 176:1680, 2016

95. Where’s the sugar?
1/3 in beverages
1/6 in desserts
½ hidden in foods that didn’t used to have sugar
e.g. salad dressings
yogurt
tomato sauce, ketchup, condiments
crackers, other carbohydrate products

96. Processed food is the culprit
Monteiro et al. Pub Health Nutr 21:18, 2017

97. Ten conglomerates 11/9/13 9:28 PMchoice.jpg 2,400×1,507 pixels

98. Lustig, JAMA Pediatrics 171:212, 2017

99. Chandalia et al. N Engl J Med 342:1392, 2000
Low-carb diet

100. Conclusions: Real food led to weight loss, in either a high-fat or
high-carb diet. Processed food did not.
Gardner et al. JAMA 319:667, 2018
High fat or high carb doesn’t mader; it’s processed food that maders (DIETFITS)

101. PROCESSED food is high-sugar, low fiber

102. PROCESSED food is high-sugar, low fiber
REAL food is low-sugar, high-fiber

103. PROCESSED food is high-sugar, low fiber
REAL food is low-sugar, high-fiber
All diets that work are REAL food

104. PROCESSED food is high-sugar, low fiber
REAL food is low-sugar, high-fiber
All diets that work are REAL food
PROCESSED FOOD IS TOXIC

105. An educational moment
Let’s rebrand “Type 2 diabetes”:

106. An educational moment
Let’s rebrand “Type 2 diabetes”:
PROCESSED FOOD DISEASE

107. Let food be thy medicine
–Hippocrates

108. Good food is medicine
Bad food needs medicine

109. REAL Certified
eatreal.org