ketones :from toxic to therapeutic · conagra nutrition mission we believe that everyone deserves...

March 21, 2019

Presenter:Jeff Volek, PhD, RD

Professor, Department of Human SciencesOhio State University

Moderator:James M. Rippe, MD – Leading cardiologist, Founder and Director;

Rippe Lifestyle Institute

Approved for 1 CPE (Level 2) by the Commission on Dietetic Registration, credentialing agency for the Academy of Nutrition and Dietetics.

NUTRI-BITES®

Webinar Series

Ketones: From Toxic to Therapeutic

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Today’s Faculty

Jeff Volek, PhD, RDProfessor, Department of Human SciencesOhio State University

Moderator:James M. Rippe, MD – Leading cardiologist.Founder and Director, Rippe Lifestyle Institute

Learning ObjectivesInsulin resistance manifests functionally as carbohydrate intolerance and is best managed with a carbohydrate restricted diet. This presentation will:

1. Overview the process of switching from a carbohydrate- to a fat-based metabolism through dietary carbohydrate restriction.

2. Discuss ketone metabolism and define nutritional ketosis, and keto-adaptation.

3. Discuss how a well-formulated ketogenic affects the constellation of markers associated with insulin resistant conditions including reversal of type-2 diabetes.

4. Review other clinical and performance applications of ketogenic diets.

NUTRI-BITES®

Webinar SeriesKetones: From Toxic to Therapeutic

Ketones: From Toxic to Therapeutic

Jeff S. Volek, PhD, RDProfessor, The Ohio State University

CSO, Virta Health

βOHB

Introduction to Nutritional KetosisIn the past 6 years, our perspective and appreciation of βOHB have changed radically

Until recently, much of what is taught about ketones to health care providers is flawed or outright wrong

Most physicians have not been taught to differentiate between physiological ketones as a fuel source and the pathophysiology of DKA

Superior energy supplyHormone-like activity regulating oxidative stress/inflammationSynergistic w/ PI3K inhibition

Fatty Acid Composition

Cholesterol/lipid metabolism

Immune/Inflammatory Fx

Cognitive Fx

Mitochondrial Fx

Muscle Adaptations

Cardiac structure/Fx

Body composition

Ectopic fat

Physical/sport performance

Militaryrelevance

Cancer treatment

Metabolic adaptations

Hormone responses

Diabetes/Weight

loss

Other clinical conditions

Keto-AdaptationResearch Kitchen

What My Team Does at OSU

Thought Leader Symposium at The Ohio State University (Aug 16-17, 2018)

The Emerging Science of Carbohydrate Restriction & Nutritional Ketosis

Session 1 – Basic Mechanisms of Ketones

Session Moderator – Dr. Stephen PhinneyUniversity of California – Davis (Emeritus)

Presenters

Dr. Eric VerdinBuck Institute for Research on Aging

Dr. Jon RamseyUniversity of CA –Davis

Dr. Jeff VolekThe Ohio State University

Dr. Dominic D’AgostinoUniversity of South Florida

Emerging Science of Carbohydrate Restriction and Nutritional KetosisScientific Sessions At The Ohio State University

Lunch Session – Thursday August 16th Featuring Keynote Speaker

Dr. Tim Noakes

The Story Behind the Lore of Nutrition

Session 2 – Clinical Applications for Diabetes and DyslipidemiaSession Moderator – Dr. Jay WortmanUniversity of British Columbia – Faculty of Medicine

Presenters

Dr. Andrew MenteMcMaster University

Dr. Jake KushnerBaylor College of Medicine

Dr. Sarah HallbergIndiana University Arnett

Dr. Ron KraussChildren’s Hospital Oakland Research Institute


Dinner Program – Thursday August 16th

Keynote Speaker Nina Teicholz

Session 3 – Clinical Applications for Cancer

Session Moderator – Dr. Maryam LustbergThe Ohio State University – Comprehensive Cancer Center

PresentersDr. Colin ChampUPMC Hillman Cancer Center

Dr. Eugene FineAlbert Einstein College of Medicine

Dr. Angela PoffUniversity of South Florida

Dr. Adrienne C. ScheckPhoenix Children’s Research Inst./Phoenix Children’s Hospital

Parker HydeThe Ohio State University

Session 4 – Clinical Applications for Neurology

Session Moderator – Dr. Ken LeeThe Ohio State University – Food Innovation Center

Presenters

Dr. Stephen CunnaneUniversite de Sherbrooke

Dr. Eric KossoffJohns Hopkins Medicine


Lunch Session – Friday August 17th

Keynote SpeakerGary Taubes

Session 5 – Human PerformanceSession Moderator – Dr. W. David ArnoldThe Ohio State University – Wexner Medical Center

PresentersDr. Tim NoakesNoakes Foundation Dr. Jeff Volek

The Ohio State University

Dr. Stephen PhinneyUC - Davis (Emeritus) Dr. Brianna Stubbs

HVMN

Dr. Dawn KernagisIHMC Dr. Brendan Egan

Dublin City University

Steve TashjianThe Columbus Crew - MLS

Dr. Peter BruknerOlympic Park Sports Medicine Center

https://fic.osu.edu/events/keto.html

For Today

Effects of Well-Formulated Ketogenic Diets:1. Metabolic Syndrome2. Type-2 Diabetes3. Cancer4. Alzheimer's5. Sport Performance

Ketogenesis (50-100 g/d)βHB AcAc

KETOGENICDIET

TG FA

BrainHealth

HeartHealth

OptimizedHealth

βHBAcAc

SIGNAL

FUEL

Muscle/Fat Health

Keto-Adaptationhappens when you are in

nutritional ketosis over consecutive weeks; the full

spectrum of adaptations may take months/years

NutritionalKetosis

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

Keto

nes

(mM

)

Typical of KEs

Typical of KDs

Mixed Diets

10.0Keto-

Acidosis

Starvation Ketosis

0

Ketogenic Diet

High-Carb Diet

↑2x

The new science of ketones

Direct & Indirect Signaling Fx of βHB

Presenter

Presentation Notes

Intro to Virta’s method Virta’s approach uses ketosis, and is based on 2 main innovations: We have built our own technology, specifically an app, to enable highly personalized and continuous remote care by our clinical team in an outpatient setting and ensure safety We have done our own research, including a large-scale clinical trial, and leverage decades of research in nutritional ketosis and personalized carb restriction to support our intervention and ensure efficacy

Ketones decrease inflammation

Ketones extend healthspan

For Today


FavorsKetogenic

Diet

Favors Low-FatDiet

Meta-analyses consistently show benefit of Ketogenic Diets

A ketogenic diet is superior at facilitating weight lossWithout explicit instruction to reduce calories

-25

-20

-15

-10

-5

0

LFD

Wk 0 Wk 12

-25

-20

-15

-10

-5

0

Wei

ght L

oss

(kg)

VLCKD

Wk 0 Wk 12LCD

LCD

LFD

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

• All the markers of MetS improved, significantly better in LC than LF– Except BP (not

shown)• Marker of insulin

resistance (HOMA-IR)improved dramatically for LC than LF

• Total SFA was dramatically lower in LC than LF in serum, even though dietary intake was 3x higher – Likely because

patients are so much better at oxidizing it

LCD LFD

A ketogenic diet is superior at improving metabolic syndrome


-40

-35

-30

-25

-20

-15

-10

-5

0

5

10

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

PAI-1Pe

rcen

t Cha

nge

VLCKD LFD


Keto-adaptation has potent anti-inflammatory effects

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

(m

g/dL

)

Volek et al. Lipids. 44:297-309, 2009

abolism. 2009 July 24

Keto-adaptation improves postprandial lipemic responses and vascular responses to a high-fat meal

A

B

%CHO %PRO2950 kcal/day

%FAT

CDIETS

Anthropometrics LC MC HC

Body mass (kg) 111.1 ± 17.0 112.0 ± 17.2 112.7 ± 17.6

Body Fat (%) 40.0 ± 8.3 39.8 ± 8.5 40.1 ± 8.4

BMI (kg/m2) 38.1 ± 8.5 38.4 ± 8.6 38.7 ± 8.8

Waist (cm) 111.0 ± 14.9 111.1 ± 12.8 111.1 ± 12.9

20%

23%57%

HC

40 g SFA/d

20%

48%

32%

MC

70 g SFA/d

20%

74%

6%

LC

100 g SFA/d

Feeding #1Low-CHO

(LC)

Feeding #2Moderate-CHO

(MC)

MC Diet

Run-In

Week: 1 4 6 10 12 16

Order Randomized

WashoutHabitual

Diet

Feeding #3High-CHO

(HC)

WashoutHabitual

Diet

Testing

16 participants who were obese with

metabolic syndrome

Unpublished

Despite maintaining body mass, low-carbohydrate intake enhanced fat oxidation and was more effective in reversing MetS, especially high

triglycerides, low HDL-C, and the small LDL subclass phenotype.

Metabolic Syndrome

BL

LC

MC

HC

No Metabolic Syndrome

71

29

MC

71

29

HC

%CHOox %FATox

85

15

LCa

b

b

Unpublished

No differences in plasma LDL-C, but LC increased

peak LDL particle diameter and decreased small, dense

LDL particles

214.9

220.0

216.2

213.2

200

205

210

215

220

225

230Peak LDL Diameter (Å)

BL LC MC HC

A

I

B

a

bc

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2

0.4

0.6

0.8

1.0LC MC HC

ab

b

Plas

ma

PL S

FAs

(wt%

chan

ge fr

om B

L)

a

Despite containing 2.5 times more saturated fat, the LC diet

decreased total plasma saturated fat and increased

palmitoleic acid

Unpublished

For Today


The Two Critical Components of Reversing T2D in Outpatients with a WFKD

Science Technology

Using Remote Continuous Care to Safely Reverse Type 2 Diabetes in Outpatients

The Virta Ongoing IUH Clinical Trial (2018)

Hallberg, S.J., McKenzie, A.L., Williams, P.T. et al. Diabetes Ther (2018) 9: 583.

Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study

Bhanpuri NH, et al. Cardiovasc Diabetol. 2018; 17:56

Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open label, non-randomized, controlled study.

N = 262 living with T2D

Location: Central Indiana

Mean Age: 54

Mean BMI: 41

Mean Weight: 257 lbs

Mean T2D Duration 8.4 Yrs

67% Female

The IUH Clinical Trial

Principal InvestigatorDr. Sarah Hallberg

Our Patients

Can it be sustained?

83% engaged at 1 year

Yes, 83% remain active in the app at 1 year

Those not “retained” either requested to terminate Virta services (usually because of unrelated health/family issues or undisclosed personal choice) or were removed from the study due to noncompliance and concerns related to safety.

Source: Hallberg et al. Diabetes Therapy. 2018. https://doi.org/10.1007/s13300-018-0373-9

N = 218 of 262


Can a majority of patients with T2D sustain nutritional ketosis for many months?

A majority of diabetes drug prescriptions (54%) are discontinued...


Diabetes reversed in half of the 262 initial cohort


7.5 average

6.2 average

“Reversal” = HbA1c < 6.5 off all T2D meds except metformin

• 60% reversed among completers at 1 year

• No attributable serious adverse events at 1 year


35 Lbs MeanLoss at 1 Yr

Nutritional Ketosis in the Management of T2D?

BOHB is an excellent fuel (brain, heart, skeletal muscle) at physiologic levels

Potent epigenetic signal regulating oxidative stress, inflammation, and insulin resistance

Nutritional ketosis in outpatients is admittedly difficult to sustain in the face of usual dietary habits and social pressure

Given the rapid reduction in medication requirement, close monitoring and prompt physician attention to medication dosage is essential for safety

Longer term (5 year) data are required to demonstrate a lasting effect on T2D biomarkers and disease progression.

ConsPros

Given intensive, ongoing, online education and support, maintaining NK appears to be feasible in the majority (218 of 262) of an outpatient cohort with T2D (e.g., a mean of 0.5 mM across 8 months), and this has a lasting effect out to 2 years.

However

For Today


Inflammation

TNF-⍺IL-6IL-8IL-1β

Patient Wellbeing

Emotional FxSleep Quality

Proliferation & MetastasisPartial Remission*

Cancer Stem CellsReactive Oxygen SpeciesmTOR inhibition

Nutritional Ketosis in

Cancer Paradigm

MetabolismGlycolytic fluxInsulin sensitivityInsulin SignalingFat oxidation

KETO-CARE StudyGoal: Test feasibility of KD in women with metastatic breast cancer (MBC) receiving chemotherapy as well as

multiple outcomes relevant to disease progression Breast cancer most

common cancer in women worldwide

~1.7 million new cases each year

Direct medical costs in U.S. in 2011 $88 million

20-30% people diagnosed w/ early stage disease will develop MBC

~155,000 Americans living with MBC

MBC accounts for ~40,000 deaths annually in U.S.

5-yr survival rate after MBC diagnosis 22%

Baseline

3-Month

Mean SUV= 11.09

Mean SUV= 6.91

Next generation digital photon counting Vereos system at OSU

FDG-PET/CT

For Today


Figure from Cunnane et al Front Mol Neurosci. 2016 Jul 8;9:53.

Direct linear association of plasma ketones and brain ketone uptake

Ketones 0.5 mM = ~5% of brain metabolismKetones 1.5 mM = ~20% of brain metabolismKetones 4-5 mM = ~50% of brain metabolism

The Brain Prefers Ketones

Are there benefits of a ketone-fueled brain?

Protection from seizures

Protection from low blood sugar ‘bonk-proof’

Decreased inflammation/oxidative stress

Neurodegenerative Disorders/Diseases (AD, PD, ALS, TBI)

↑ Neurocognitive function

Ketones Counteract Neurocognitive Deficits in… Response to insulin-induced hypoglycemia after

infusion of βHB or ingestion of MCT-induced ketosis [Veneman et al. 1994; Page et al. 2009]

Patients with age-associated cognitive decline [Newport et al. 2015; Krikorian et al. 2012; Reger et al. 2004; Henderson et al. 2009; Taylor et al. 2017]

An AD mouse model fed KEs that decreased amyloid β-peptide, lessened anxiety, and improved cognition [Kashiwaya et al. 2013]

Rats administered KEs ran 32% further & completed a working memory maze 38% faster w/ fewer errors [Murray et al. 2016]

Athletes provided KEs during exercise preserved executive function (fewer errors in a multi-tasking test) [Evans et al. 2018]

Old mice fed a KD as reflected by preserved memory in a novel object recognition test [Roberts et al. 2017]

Ketones and Brain Function

For Today


FASTER Study

FASTER StudyFat-Adapted Substrate oxidation in Trained Endurance Runners

Peak Fat Burning

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

0 1 2 3

HCD LCD

Peak

Fat

Oxi

datio

n (g

/min

)

X = 0.67

X = 1.54

High sustained use of fat over 3-hr

Minutes During Exercise

HCD LCD

0%10%20%30%40%50%60%70%80%90%

100%

0 60 120 150 180

Fat

Carbohydrate

0%10%20%30%40%50%60%70%80%90%

100%

0 60 120 150 180

Fat

Carbohydrate

Enhanced Glycogen Efficiency

0

50

100

150

200

250

BL IP PE-120 BL IP PE-120

Muscle Glycogen (mmol/kg w.w.)

HC LC

The KD resulted in greater loss of body mass, whole body and visceral fat without instructions to restrict calories

Tactical Athletes in Nutritional Ketosis (TANK)

↑ relative lower (20%) & upper (9%) body strength

↑ sprint performance (10%) ↑ VO2peak (7%) ↑ obstacle course (6%) ↑ mitochondrial protein

content (9%) ↑ ATP production/O2

(↑ energetic efficiency)

KD MD

Body fat, DXA -5.1% -0.7%

Fat loss, DXA -5.9 kg -0.6 kg

Visceral fat, MRI -44% 8%

0

5

-5

dy M

ass

(kg)

In Press Military Medicine

Summary1. We are now witnessing the ascension of nutritional ketosis as

a powerful therapeutic modulator of disease processes2. Keto-adaptation potently enhances fat oxidation (and

decrease reliance on glucose metabolism) regardless of weight or training status

3. Keto-adaptation reverses most of the signs of metabolic syndrome and T2D, and improves a broad range of markers linked with the insulin resistant phenotype

4. Emerging applications such as cancer, neurological disease, and heart disease are promising

Carb restriction to ↑ ketones >0.5 mMModerate protein (1.2-2.0 g/kg RW)Na, K, Mg, Zn nutriture critical to well-beingA weight maintenance KD is necessarily high-fatFat quality matters more than quantitySaturated fats should be embracedDietary cholesterol isn’t a health riskSatiety is a robust indicator of appropriate dietary energy intake

Well-Formulated Ketogenic Diets

Questions?

1. Overview the process of switching from a carbohydrate- to a fat-based metabolism through dietary carbohydrate restriction.

2. Discuss ketone metabolism and define nutritional ketosis, and keto-adaptation.

3. Discuss how a well-formulated ketogenic affects the constellation of markers associated with insulin resistant conditions including reversal of type-2 diabetes.

4. Review other clinical and performance applications of ketogenic diets.

NUTRI-BITES®

Webinar SeriesKetones: From Toxic to Therapeutic

Based on this webinar the participant should be able to:

Conagra Nutrition Nutri-Bites®

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Thank you for supporting Nutri Bites Webinars for the past 10 years. Regrettably, today’s webinar by Dr. Volek marks the last webinar in the Nutri-Bites series. CEU certificates will be awarded for attending today’s live webinar. However, this webinar will NOT offer the option of taking the online quiz after the live webinar.

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ketones :from toxic to therapeutic · conagra nutrition mission we believe that everyone deserves...

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