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
Emerging Science of Carbohydrate Restriction and Nutritional KetosisScientific Sessions At The Ohio State University
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
Emerging Science of Carbohydrate Restriction and Nutritional KetosisScientific Sessions At The Ohio State University
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
Ketones decrease inflammation
Ketones extend healthspan
For Today
Effects of Well-Formulated Ketogenic Diets:1. Metabolic Syndrome2. Type-2 Diabetes3. Cancer4. Alzheimer's5. Sport Performance
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
Forsythe et al. Lipids. 43(1):65-77, 2008
-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
Forsythe et al. Lipids. 43(1):65-77, 2008
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
Effects of Well-Formulated Ketogenic Diets:1. Metabolic Syndrome2. Type-2 Diabetes3. Cancer4. Alzheimer's5. Sport Performance
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
Source: Hallberg et al. Diabetes Therapy. 2018. https://doi.org/10.1007/s13300-018-0373-9
Can a majority of patients with T2D sustain nutritional ketosis for many months?
A majority of diabetes drug prescriptions (54%) are discontinued...
Source: Hallberg et al. Diabetes Therapy. 2018. https://doi.org/10.1007/s13300-018-0373-9
Diabetes reversed in half of the 262 initial cohort
Source: Hallberg et al. Diabetes Therapy. 2018. https://doi.org/10.1007/s13300-018-0373-9
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
Source: Hallberg et al. Diabetes Therapy. 2018. https://doi.org/10.1007/s13300-018-0373-9
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
Effects of Well-Formulated Ketogenic Diets:1. Metabolic Syndrome2. Type-2 Diabetes3. Cancer4. Alzheimer's5. Sport Performance
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
Effects of Well-Formulated Ketogenic Diets:1. Metabolic Syndrome2. Type-2 Diabetes3. Cancer4. Alzheimer's5. Sport Performance
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
Effects of Well-Formulated Ketogenic Diets:1. Metabolic Syndrome2. Type-2 Diabetes3. Cancer4. Alzheimer's5. Sport Performance
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
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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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