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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

Zimmet et al. Nature 414: 782, 2001 285 MILLION IN 2010, up 8.9% per yr

Zimmet et al. Nature 414: 782, 2001 412 MILLION IN 2014, up 11.7% per yr

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

• 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

2. Animal welfare

1. Religious

2. Animal welfare

3. Environmental/Sustainability

1. Religious

2. Animal welfare

4. Cost

1. Religious

2. Animal welfare

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

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

High High

Adiposity, insulin resistance

VLDL TG-rich

cytokines

Atherogenic

Remnants

trapped in the vascular wall while circulating

TG-rich

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

Low Liver Fat = 2.6%

High Liver Fat = 24%

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

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

Insulin

Stimulated

Glucose

Disposal

Insulin

Stimulated

Palmitate

Suppression

Secretion

Contribution

Of Free

Fatty Acids

To VLDL

Sugar and Diabetes:

Mechanisms

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

Is not nutrition

We love anyway, and it’s addictive

Is not nutrition

We love anyway, and it’s addictive

Answer: Ethanol

(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

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

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)

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

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

diet and diabetes

Diabetes prevalence rose from 5.5% to 7.0% for 175 countries 2000-2010

Sugar+controls

Sugar+controls+period

Overall

Model # countries Effect (95% CI)

diet and diabetes

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)

*)*) *)

Fructose

Palmitate

Acetate

New Tracer Method using MIDA: Hellerstein and Neese, AJP 1999

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)

Triglyceride-rich Lipoprotein DNL AUC (n=17)

10.00%

12.00%

14.00%

0 1 2 3 4 5 6 7 8

D0 D10

L –D

LDL subclasses

Day 10

VLDL MID LDL1 LDL2 LDL3 (sd-LDL)

Day 10

VLDL MID LDL1 LDL2 LDL3 (sd-LDL)

Day 10

HDL subclasses

Large Intermediate Small

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

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)

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

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

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.

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