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Sugar: the newest and bitterest truth
Plantrician Project, Anaheim, Sept. 25, 2017
Robert H. Lustig, M.D., M.S.L.
Emeritus Professor
Division of Endocrinology, Department of Pediatrics
Institute for Health Policy Studies
University of California, San Francisco
Adjunct Faculty, UC Hastings College of the Law
Chief Science Officer, EatREAL
Chief Medical Officer, Slendine
Disclosures
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
T2DM increasing around the world
People with DM (in millions) for 2000, projection for 2010, and % increase
Zimmet et al. Nature 414: 782, 2001
T2DM increasing around the world
People with DM (in millions) for 2000, projection for 2010, and % increase
Zimmet et al. Nature 414: 782, 2001 285 MILLION IN 2010, up 8.9% per yr
T2DM increasing around the world
People with DM (in millions) for 2000, projection for 2010, and % increase
Zimmet et al. Nature 414: 782, 2001 412 MILLION IN 2014, up 11.7% per yr
T2DM increasing around the world
People with DM (in millions) for 2000, projection for 2010, and % increase
Zimmet et al. Nature 414: 782, 2001 WTF??
The money is not going to hospitals, physicians,
or Big Pharma
The money is not going to hospitals, physicians,
or Big Pharma
It’s going to chronic metabolic disease
Two inconvenient truths
Two inconvenient truths
• There is no medicalized prevention for chronic
metabolic disease
• There’s just long-term treatment
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
Reasons to eat a plant-based diet
1. Religious
Reasons to eat a plant-based diet
1. Religious
2. Animal welfare
Reasons to eat a plant-based diet
1. Religious
2. Animal welfare
3. Environmental/Sustainability
Reasons to eat a plant-based diet
1. Religious
2. Animal welfare
3. Environmental/Sustainability
4. Cost
Reasons to eat a plant-based diet
1. Religious
2. Animal welfare
3. Environmental/Sustainability
4. Cost
5. Metabolic??
Dr. Neal Barnard, What the Health, 2017
“Diabetes is not and never was caused by eating a high carbohydrate diet,
and it’s not caused by eating sugar.
The cause of diabetes is a diet that builds up the amount of fat into the blood.
I’m talking about a typical meat-based animal-based diet.
You can look into the muscle cells of the body and they’re building up tiny
particles of fat, that’s causing insulin resistance.”
Epidemiology
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
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
Prospective Urban and Rural Epidemiology
(PURE)
Dehghan et al. Lancet epub Aug 29, 2017
Villegas et al. Arch Intern Med 167:2310, 2007
Association of Carbohydrate, Glycemic Index and Load, and Food Groups With T2DM and Insulin Resistance in China
NS
NS
Dehghan et al. Lancet epub Aug 29, 2017
Prospective Urban and Rural Epidemiology
(PURE)
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
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
Blood levels of dairy saturated fatty acids
correlate with protection from T2DM
Yakoob et al. Circulation 133:1645, 2016
Surrogate markers
LDL correlates with CVD,
but not all that well
5/12/2014 0 (3000×3535)
http://www.sciencedirect.com/cache/MiamiImageURL/1-s2.0-S0168822713002672-gr2_lrg.jpg/0?wchp=dGLzVlV-zSkWA&pii=S0168822713002672 1/1
Ravnskov et al. BMJ Open 6:e010401, 2016
LDL levels and risk for CVD and T2DM
White et al. JAMA Cardiol 1:692, 2016
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
Atherogenic dyslipidemia—
It’s not about LDL cholesterol,
it’s about LDL particle number
Cromwell et al. J Clin Lipidol 1:583, 2007
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”
Rizzo and Berneis, Quart J Med 99:1, 2006
TG and HDL change with LDL sizing
Insulin resistance determines liver lipid packaging
Low TG
pool Low TG
pool
High High
Adiposity, insulin resistance
VLDL TG-rich
VLDL
LPL
FFA
cytokines
HSL
Atherogenic
Remnants
trapped in the vascular wall while circulating
TG-rich
LDL
TG-rich
HDL
sdLDL
sdHDL
Krauss and Siri-Tarino,
Endocrinol Metab Clin North Am 33:405, 2004
Randomized Clinical Trials
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
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
No improvement in insulin sensitivity or intramyocellular
lipid with LDL reduction due to simvastatin
Szendroedi al. Diab Care 32:209, 2009
LDL reduction with medications and
incident diabetes
Wang et al. Sci Rep 7:39982, 2017
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.
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
New York Times, April 17, 2011
Nature 487:27-29, Feb 1, 2012
New York Times, April 17, 2011
Nature 487:27-29, Feb 1, 2012
Hyperbole?
Toxicity:
The degree to which a substance can damage an organism
• Does not distinguish acute vs. chronic toxicity
Requisites:
• Must be an “independent risk factor”
• Exclusive of calories
• Exclusive of obesity
• Must establish causation
Criticisms of Fructose Toxicity
• Animal models, not human studies
• Administration of excessive doses of fructose
Criticisms of Fructose Toxicity
• Animal models, not human studies
• Administration of excessive doses of fructose
WILL LIMIT DISCUSSION TO:
HUMAN DATA,
HUMAN CONSUMPTION,
IN DOSES ROUTINELY INGESTED
AND CONTROLLED FOR CALORIES AND OBESITY
Sugar and Diabetes
— Plausibility
— Mechanisms
— Human Correlation
— Human Causation
Sugar and Diabetes:
Plausibility
Histology of (N)AFLD
Normal (N)AFLD
MRI Fat Fraction Maps
Obese
Low Liver Fat = 2.6%
MRI Fat Fraction Maps
Obese
Low Liver Fat = 2.6%
MRI Fat Fraction Maps
Obese
Low Liver Fat = 2.6%
Obese
High Liver Fat = 24%
MRI Fat Fraction Maps
Obese
Low Liver Fat = 2.6%
Obese
High Liver Fat = 24%
MRI Fat Fraction Maps
Obese
Low Liver Fat = 2.6%
Obese
High Liver Fat = 24%
Thin
High Liver Fat = 23%
MRI Fat Fraction Maps
Obese
Low Liver Fat = 2.6%
Obese
High Liver Fat = 24%
Thin
High Liver Fat = 23%
NAFLD and Metabolic Syndrome are congruent
(if not the same)
Adults:
Marchesini et al. Hepatology 37:917, 2003
Children: Schwimmer et al. Circulation 118:277, 2008
Epidemiology of NAFLD
Non-alcoholic fatty liver disease (NAFLD) has become epidemic
Steatosis:
45% Latinos
33% Caucasians
24% African Americans
NASH
5.5% of US Adults
Children:
Steatosis in 13% of autopsy specimens ages 5-19
38% in obese autopsy specimens
Browning et al. Hepatology 40:1387, 2004; Schwimmer et al. Pediatrics 118:1388, 2006
NAFLD is a primary predictor of T2DM in Korean adults
Sung and Kim, J Clin Endocrinol Metab 96:1093, 2011
Intrahepatic fat explains insulin resistance
better than visceral fat
Fabbrini et al. Proc Natl Acad Sci 106:15430, 2009
Hepatic
Insulin
Sensitivity
Index
Insulin
Stimulated
Glucose
Disposal
Rate
Insulin
Stimulated
Palmitate
Suppression
Rate
VLDL
Secretion
Rate
Contribution
Of Free
Fatty Acids
To VLDL
Sugar and Diabetes:
Mechanisms
(20%)
(80%)
Can you name an energy source that is:
Can you name an energy source that is:
Not necessary for life
Can you name an energy source that is:
Not necessary for life
There is no biochemical reaction in the body that requires it
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
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
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
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
(80%)
(100%)
Welsh et al. JAMA 303:1490, 2010
Variation of HDL and triglyceride levels
based on consumption of added sugars
in NHANES adults
Meta-Analysis of Effects of Sugar on Triglycerides
Te Morenga et al. Am J Clin Nutr doi: 10.3945/ajcn.113.081521, May 7, 2014
Sugar and Diabetes
(Prospective Correlation)
Bazzano et al. Diab Care 31:1311, 2008
RR 1.18 [1.10-1.26]
Fruit juice consumption increases risk for T2DM
in women (Nurse’s Study)
Romaguera-Bosch et al. Diabetologia 56:1520, 2013
SSB’s and BMI-adjusted risk of diabetes in
EPIC-Interact (Europe)
Sugar Sweetened Beverages (n=17)
Not Adjusted for Adiposity: Relative Risk
I2 Adjusted for Adiposity:
Relative Risk
I2
Meta-analysis, crude: 1.25 (1.14 to 1.37) 89 — —
+multivariable adjusted 1.18 (1.09 to 1.28) 89 1.13 (1.06 to 1.21) 79
+calibration for
information bias 1.43 (1.20 to 1.70) 86 1.28 (1.12 to 1.46) 73
+calibration for
publication bias 1.42 (1.19 to 1.69) 85 1.27 (1.10 to 1.46) 73
Fruit Juices (n=13)
Not Adjusted for Adiposity: Relative Risk
I2 Adjusted for Adiposity:
Relative Risk
I2
Meta-analysis, crude: 0.97 (0.90 to 1.06) 79 —
+multivariable adjusted 1.05 (0.99 to 1.11) 58 1.07 (1.01 to 1.14) 51
+calibration for
information bias 1.06 (0.98 to 1.14) 49 1.10 (1.01 to 1.20) 29
+calibration for
publication bias Not detected — Not detected —
Associations between consumption of sugar sweetened beverages
and fruit juice and incident type 2 diabetes:
meta-analysis of prospective cohort studies
Imamura et al. BMJ 351:.h3576, 2015
Added Sugar Quintiles - Mean sugar (g/day)
Pre
vale
nce
Od
ds
Rat
io
1 Adjusted for age, BMI z-score, energy intake, and physical activity * Statistically significant compared to 1st quintile (p < 0.05) ¥ Statistically significant compared to 2nd quintile (Wald test, p < 0.05 )
*
*¥ *
Rodriguez et al., Public Health Nutr 40:2424, 2016
30g
Sugar and Diabetes
(Econometric Analysis)
An international econometric analysis of
diet and diabetes
Diabetes prevalence rose from 5.5% to 7.0% for 175 countries 2000-2010
Basu et al. PLoS One, e57873, 2013
An international econometric analysis of
diet and diabetes
Diabetes prevalence rose from 5.5% to 7.0% for 175 countries 2000-2010
Sugar
Sugar+controls
Sugar+controls+period
Overall
Model # countries Effect (95% CI)
Basu et al. PLoS One, e57873, 2013
An international econometric analysis of
diet and diabetes
Basu et al. PLoS One, e57873, 2013
An international econometric analysis of
diet and diabetes Only changes in sugar availability predicted changes in diabetes
prevalence
Every extra 150 calories increased diabetes prevalence by 0.1%
But if those 150 calories were a can of soda, diabetes prevalence
increased 11-fold, by 1.1% (95% CI 0.03 — 1.71%, p <0.001)
This study meets the Bradford Hill criteria for Causal Medical
Inference:
—dose —duration —directionality —precedence
We estimate that 25% of diabetes worldwide is explained by sugar Basu et al. PLoS One, e57873, 2013
Sugar and Diabetes
(Causation)
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
September 2017 cover article
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
Oral glucose tolerance test
before and after isocaloric fructose restriction
Lustig et al. Obesity 24:453, 2015
Fasting 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
Fasting 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
Fasting TG (mM) 1.4 ± 0.9 1.0 ± 0.5 -0.4 [-0.6, -0.2] 0.002
Fasting LDL-C (mM) 2.4 ± 0.6 2.1 ± 0.6 -0.3 [-0.4, -0.1] <0.001
Fasting HDL-C (mM) 1.2 ± 0.2 1.0 ± 0.2 -0.1 [-0.2, -0.1] <0.001
Fasting FFA (mM) 0.6 ± 0.2 0.7 ± 0.2 +0.1 [+0.1, +0.2] <0.001
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
0
20
40
60
80
100
120
140
160
Day 0 Day 10
DNL AUC Pre and Post Fructose Restriction
Schwarz et al. Gastroenterology 153:743,, 2017
Changes in liver, visceral, and subcutaneous fat (n = 37)
Schwarz et al. Gastroenterology 153:743,, 2017
Triglyceride-rich Lipoprotein DNL AUC (n=17)
0.00%
2.00%
4.00%
6.00%
8.00%
10.00%
12.00%
14.00%
0 1 2 3 4 5 6 7 8
D0 D10
hour
Frac
tio
nal
TR
L –D
NL
AU
C
Schwarz et al. Gastroenterology 153:743,, 2017
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
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
Changes in triglyceride and VLDL lipoproteins
correlate with change in insulin sensitivity
(Spearman R)
DHOMA-IR DC-peptide DFasting insulin
DApo-B (mg/dl) 0.43 (0.01) 0.51 (0.001) 0.41 (0.01)
DApoC-II (mg/dl) 0.45 (0.005) 0.54 (<0.001) 0.48 (0.003)
DApoC-II! (mg/dl) 0.40 (0.01) 0.43 (0.01) 0.41 (0.01)
DTG / HDL ratio 0.31 (0.04) 0.50 (<0.001) 0.34 (0.03)
Gugliucci et al. Atherosclerosis 253:171, 2016
What the data say • Epidemiologic and randomized controlled trials do not support a
positive association between animal-based fat, LDL, and diabetes
• Red meat may be promotive of diabetes (likely due to iron/oxidative
stress, BCAA, or TMAO); yet dairy appears to be protective — does
not suggest that insulin resistance is due to saturated fat.
• Prospective correlational data demonstrate associations between
added sugar and and diabetes, exclusive of calories or obesity
• Econometric data show causal medical inference for added sugar
and diabetes, exclusive of calories or obesity
• Interventional isocaloric glucose for fructose exchange shows
improvements in fatty liver disease, insulin resistance, metabolic
health, and lipids in children in just 10 days
Foodstuffs and metabolic syndrome
• Transfats
• Branched chain amino acids
• Ethanol
• Fructose
• Liver is the only site for energy metabolism
• Not insulin regulated
• No glycogen popoff, mitochondria are
overwhelmed
Bremer et al., Pediatrics 129:557. 2012
Sugar and disease
• Causation
– Diabetes
– Heart Disease
– Fatty Liver Disease
– Tooth Decay
• Correlation
– Cancer
– Dementia
Lustig, JAMA Pediatrics 171:212, 2017
PROCESSED food is high-sugar, low fiber
PROCESSED food is high-sugar, low fiber
REAL food is low-sugar, high-fiber
PROCESSED food is high-sugar, low fiber
REAL food is low-sugar, high-fiber
All diets that work are REAL food
PROCESSED food is high-sugar, low fiber
REAL food is low-sugar, high-fiber
All diets that work are REAL food
Oh, and by the way, sugar is plant-based
We acknowledge that the Sugar Research Foundation
should have exercised greater transparency in all of its
research activities, however, when the studies in question
were published funding disclosures and transparency
standards were not the norm they are today.
The Sugar Association Statement on Kearns
JAMA Study
by The Sugar Association
September 12, 2016
Generally speaking, it is not only unfortunate but a disservice
that industry-funded research is branded as tainted.
Most concerning is the growing use of headline-baiting articles
to trump quality scientific research—we’re disappointed to see
a journal of JAMA’s stature being drawn into this trend.
The Sugar Association Statement on Kearns
JAMA Study
by The Sugar Association
September 12, 2016
And sugar is a primary cause of liver fat and insulin resistance
UCSF
Ayca Erkin-Cakmak, M.D. M.P.H.
Andrea Garber, Ph.D., R.D.
Patrika Tsai, M.D., M.P.H.
Emily Perito, M.D., M.P.H.
Touro University Dept. of Biochemistry
Jean-Marc Schwarz, Ph.D.
Alejandro Gugliucci, Ph.D.
SFGH Depts. of Medicine & Radiology
Susan Noworolski, Ph.D.
Kathleen Mulligan, Ph.D.
Stanford Prevention Institute
Sanjay Basu, M.D., Ph.D.
Union of Concerned Scientists
Environmental Working Group
Dietitians for Professional Integrity
Collaborators
UCSF Clinical/Translational
Science Institute
Laura Schmidt, Ph.D.
Claire Brindis, Dr.P.H.
Cristin Kearns, D.D.S.
Stanton Glantz, M.D.
UC Hastings College of the Law
David Faigman, J.D.
Marsha Cohen, J.D.
UC Berkeley Dept. of Nutr. Sciences
Pat Crawford, R.D., Ph.D.
Kristine Madsen, M.D., M.P.H.
Lorrene Ritchie, Ph.D.
Paula Yoffe, B.A.
Health Evolution Partners
David Brailer, Ph.D.