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ASPEN Symposium Therapeutic Applications of Nutritional Ketosis
March 25, 2019 4:15 – 5:45 PM
Stephen Phinney MD, PhD and Jeff Volek PhD, RD Topics to be addressed
1. Definitions of Nutritional Ketosis and Keto-adaptation 2. Metabolic and epigenetic actions of BOHB 3. Epigenetic effects include increased insulin sensitivity and reduce inflammation 4. Demonstrated effects include reversal of T2D and reduced progression of Pre-D to T2D 5. Reversal of atherogenic dyslipidemia, but highly variable response of calculated LDL-C 6. Dramatic increase in fat oxidation at rest and exercise with keto-adaptation 7. Benefits for endurance performance and power-to-weight in casual and elite athletes 8. The potential roles of ketone supplements in health and sport
Topics 1-4: Steve Phinney 35 min
Title: Nutritional Ketosis and its Application to the Management of Type 2 Diabetes Topics 5-8: Jeff Volek 35 min
Title: the Effects of Keto-adaptation on Blood Lipids and Fat Oxidation at Rest and During Exercise
Q&A: 20 min Learning objectives Key References Bhanpuri NH et al. 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. Cardiovasc Diabetol. 2018 May 1;17(1):56 Bistrian Diabetes 1976 Boden 2005 Forsythe 2008 Hallberg 2018
Phinney Metabolism 1983 Shimazu Science 2013 Volek FASTER 2016
3/4/2019
1
Nutritional Ketosis and its Application to the Management of Type 2 Diabetes
Stephen Phinney MD, PhD
Prof of Medicine, emeritus UC Davis
CMO, Virta Health
Disclosures
Commercial Interest What Received Role
Virta Health Corp Ownership Interest Chief Medical Officer
Co-founder
Beyond Obesity, LLC Book Royalties Author
Atkins Nutritionals, Inc Honorarium Science Advisor
Introduction to Nutritional Ketosis
In 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 supply
Hormone-like activity regulating
oxidative stress and inflammation
Synergistic with PI3K inhibition
βOHB
The Ketone Zone: Nutritional Ketosis versus DKA
StateKetones (mmol/L)
Moderate-carbohydrate diet(fed state)
<0.1
Moderate-carbohydrate diet
(fasted state)0.1 to 0.3
Very low-carbohydrate diet
(<50 g/day)0.5 to 3.0
Very low-carbohydrate diet(post-exercise)
1.0 to 5.0
Keto-acidosis
(insulin insufficiency)10 to 20+
10X
10X
Inflammation and Type 2 Diabetes
February 2011 / Volume 11
Volume 127 / Number 1 / January 2017
Marc Y. Donath and Steven E. Shoelson
Alan R. Saltiel and Jerrold M. Olefsky
www.nature.com/reviews/immunol
The New Science of BOHB
Reduced oxidative
stress reduces aging
and inflammation
Possible direct
effects on insulin
resistance
3/4/2019
2
βOHB Inhibits Inflammatory Gene Expression
▪ βOHB does not just reduce
isoprostane production
(prostaglandin-like compounds
formed by ROS-perioxidation of
essential fatty acids like ARA)
▪ It intervenes at the regulatory
level by blocking NLRP3
inflammasome-mediated
inflammatory disease
Source: Youm et al.; “Ketone body β-hydroxybutyrate blocks the NLRP3 inflammasome-mediated inflammatory disease”; Nature Medicine (2015)
What Goes into a Weight MaintenanceWell Formulated Ketogenic Diet?
Carbs (5–10%; <50 g)
Protein
(15-20%)
Fat
(70-75%)
▪ Protein-based food (5–10 g)
▪ Vegetables (10–15 g in 4-5
servings per day)
▪ Nuts/seeds (5–10 g)
▪ Fruits (5–10 g)
▪ Miscellaneous (5–10 g)
Typical Macronutrient Dynamics Across 1 Year of a WFKD
▪ In insulin resistant adults, carbs
initially limited to 30 grams per day,
then liberalized slowly while
maintaining ketosis
▪ Daily protein prescribed in a range
between 1.2 and 2.0 g/kg reference
weight (approx 15% daily energy
expenditure)
▪ Fat is consumed to satiety
▪ ‘Counting calories’ is seldom
practiced and rarely usefulDaily caloric intakes and expenditure for a 5’6” woman going from 180
to 140 lbs with a well-formulated ketogenic diet. Assumes 30 kcal/kg
before and 32 kcal/kg after weight loss.
First Modern Report Diabetes Reversal (1976)
Source: Bistrian et al., “Nitrogen Metabolism and Insulin Requirements in
Obese Diabetic Adults on a Protein-Sparing Modified Fast” Diabetes (1976)
This is the FIRST
modern use of a
ketogenic diet to
reverse T2D, and it
worked in EVERY
patient (7/7)
▪ Obese T2D patients, all on insulin
▪ Age: 47–63 years; 5/7 female
Demographics:
▪ Inpatient (6/7) in metabolic ward to ensure safety (1.5 - 4 months)
▪ Then followed as outpatients (1.5-12 months)
▪ Treated with a ketogenic PSMF = protein-sparing modified fast
▪ Extreme caloric restriction = 350-750 kcal/day
▪ Included vitamin/mineral supplements (Na+, K+, Mg++, Ca++)
Method:
Case report series N = 7
▪ Weight Loss: 5/7 maintained 9-74 kg weight loss after 12
months
▪ Insulin: withdrawn within 0-19 days for all patients
Results
Study: The Prompt Action of a WFKD Against T2D (Boden, 2005)
Source: Boden et al.; “Effect of a Low-Carbohydrate Diet on Appetite, Blood Glucose Levels, and Insulin Resistance in Obese Patients with Type 2 Diabetes”; Ann Intern Med. (2005)
▪ Obese T2D patients
▪ Age: 51 ± 9.5 (36–64)
▪ BMI: 40.3 ± 5.7 (33–52)
Demographics
▪ Inpatient, metabolic ward for 3 weeks
▪ Fed SAD 7 days, then low carb (<21 g/d) diet for 14 days
▪ No calorie restriction — buffet-style eating, all food weighed
Methods
N = 10
▪ Daily kcal - 1000 (from 3100 to 2100 kcal/day)
▪ Weight -2 kg, Hunger reduced
▪ Fasting BG: 7.5 → 6.3 mmol/L
▪ HbA1c: 7.3 → 6.8% (in just 2 weeks)
▪ Insulin sensitivity: increased ~75% (euglycemic hyperinsulinemic clamp)
▪ Diabetes medications reduced
▪ Plasma TG decreased 35%, Plasma cholesterol decreased 10%
Results
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3
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 Investigator
Dr. Sarah Hallberg
Our Patients
Can it be sustained?
83% engaged
at 1 yearYes, 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?
3/4/2019
4
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 Mean
Loss at 1 Yr
▪ Mean change in calculated
LDL cholesterol was +9.9%
(P<0.00001)
▪ Changes in LDL-C varies
widely between patients
Distribution of Calculated LDL-C Changes at 1-Year
Source: Bhanpuri NH, Hallberg SJ, Williams PT, McKenzie AL, Ballard KD, Campbell WW, McCarter JP, Phinney SD, Volek JS. 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.
Cardiovasc Diabetol. 2018 May 1;17(1):56. doi: 10.1186/s12933-018-0698-8
Related publication: Hallberg SJ et al. Diabetes Therapy. 2018;9(2)583-612.
Distribution of CVD Risk Factor Changes
Source: Bhanpuri NH, Hallberg SJ, Williams PT, McKenzie AL, Ballard KD, Campbell
WW, McCarter JP, Phinney SD, Volek JS. 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.
Cardiovasc Diabetol. 2018 May 1;17(1):56. doi: 10.1186/s12933-018-0698-8
Note: Remaining proportion of patients had no change in the risk factor at one year
P-value for beneficial change < 10-6
Not significantNS
Related publication: Hallberg SJ et al. Diabetes Therapy. 2018;9(2)583-612.
NS
NS
Posted 28 November 2018
Presented 14 November 2018
3/4/2019
5
IUH Diabetes Reversal Study2-Year Weight Change (lbs)
Retention 74%
Usual Care
IUH-CCI
Athinarayanan S, et al. Bioxrivdoi: https://doi.org/10.1101/476275
IUH Diabetes Reversal Study2-Year HbA1c Change
Athinarayanan S, et al. Bioxrivdoi: https://doi.org/10.1101/476275
7.6 average
6.6 average
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
Thank you to our co-authors and clinical team!
The Effect of Keto-Adaptation on Blood Lipids and Fat Oxidation at
Rest and during Exercise
Jeff S. Volek,
PhD, RD
Professor, The Ohio
Disclosures
❑ Royalties from nutrition books (Beyond Obesity, LLC)❑ Co-Founder and Stock Holder (Virta Health Corp)❑ Research support (Dairy Management Inc, Malaysian Palm Oil Board, Pruvit, Hecht
Foundation) ❑ Advisory Boards (Atkins Nutritional Inc, UCAN Inc, Virta Health Corp, Axcess Global,
Advancing Ketone Therapies, )
3/4/2019
6
For Today
Keto-Adaptation:
1. Effects on fat oxidation
2. Effects on blood lipids and other biomarkers of metabolic syndrome
3. Importance of weight loss in determining response to a KD
Keto-Adaptationhappens when you are in
nutritional ketosis over
consecutive weeks; the full
spectrum of adaptations may
take months/years
Nutritional
Ketosis
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
Keto
nes
(m
M)
Typical
of KEs
Typical
of KDs
Mixed Diets
10.0Keto-
Acidosis
Starvation
Ketosis
0
Ketogenic
Diet
High-Carb
Diet
↑2x
Insulin Regulation of Lipolysis
0 100 300200
Jenson et al. Diabetes. 38:1591-1601, 1989
Insulin (pmol/L)
Fat
Bre
ak
dow
n
Bonadonna et al. AJP.
259:E736-E750, 1990
Lipolysis is exquisitely sensitive to insulin
❑ Effect is virtually immediate
❑ insulin (low CHO intake or fasting) can easily double lipolysis rates
❑ insulin (CHO intake or infusion) can suppress lipolysis by 80-90%
❑ Moderate insulin can suppress FA levels from overnight fasting levels of 500 mM to <10 mM
❑ Inhibition of insulin secretion can FA >1000 mM
Insulin Resistance and Keto-AdaptationOpposite Ends of a Phenotypic Continuum
Insulin
ResistantPhenotype
Disease Health
Carbs Carbs
Keto-
AdaptedPhenotype
T2DMetabolicSyndrome
Non-Diabetic
Obese
Pre-Diabetic
Overweight
Thin
3/4/2019
7
0.7
0.8
0.9
1.0
BL 3 6 9 12 15 18 21
Week
Re
spir
ato
ry E
xch
an
ge R
ati
o
Week
307 47 47 82 131 179 250 344
Carbohydrate Intake (grams per day)
Controlled 3 week feeding study decreasing, then increasing
carbs in 16 obese participants with metabolic syndrome
RER=1.0
(all carb)
RER = 0.7
(all fat)
Fat oxidation increases as carbs are restricted, and increase linearly as carbs are increased
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
Pea
k Fa
t O
xid
atio
n (
g/m
in)
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
Carbohydrate Stores are Limited
Carbohydrate
Glycogen: ~2,000 kcal (burned as glucose)
Blood glucose: ~80 kcal (burned as glucose)
Fat
Adipose TGs: >25,000 kcal (burned as fat or ketones)
Muscle TGs: ~1,200 kcal (burned as fatty acids)
Glycogen Tank
Fat Tank
2,000
Kcal >25,000
kcal
For Today
Keto-Adaptation:
1. Effects on fat oxidation
2. Effects on blood lipids and other biomarkers of metabolic syndrome
3. Importance of weight loss in determining response to a KD
3/4/2019
8
Favors
Ketogenic
Diet
Favors
Low-Fat
Diet
Meta-analyses consistently show benefit of Ketogenic Diets The KD resulted in greater loss of body mass, whole body and
visceral fat without instructions to restrict calories
Weight and Fat Loss
❑ ↑ 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
-10
-15
DB
od
y M
ass
(kg)
Baseline 12-wk Baseline 12-wk
Unpublished
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
We
igh
t 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-1
Pe
rce
nt
Ch
an
ge
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)
Tri
glyc
eri
de
s (m
g/d
L)
Volek et al. Lipids. 44:297-309, 2009
Pre Occlusion Diameter Post Occlusion Diameter
Volek et al. Metabolism. 2009 July 24
Keto-adaptation improves postprandial lipemic responses and vascular responses to a high-fat meal
3/4/2019
9
Wk 0 Wk 6-50
-40
-30
-20
-10
0
10
20
30
40
50
60
70
80
90
Keto-adaptation has variable effects on LDL-
C, even under highly controlled feeding
conditions
Volek et al. Lipids. 2009 Apr;44(4):297-309.
CRD
LFD
LargerParticles
SmallerParticles
High Carbohydrate/Low-Fat
Low Carbohydrate/High-Fat
Keto-adaptation consistently increases LDL particle size and decreases small, dense LDL particles
BMJ Open Sport Exerc Med. 2018 Oct 4;4(1):e000429
For Today
Keto-Adaptation:
1. Effects on fat oxidation
2. Effects on blood lipids and other biomarkers of metabolic syndrome
3. Importance of weight loss in determining response to a KD
Impaired
Glucose
Tolerance
Insulin
Resistance
Late
Diabetes
Hyperinsulinemia
b-Cell Defect
(↓ insulin secretion)
Early
Diabetesb -Cell Failure
Obesity
↑ Carbs
3/4/2019
10
A
B
%CHO %PRO
2950 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
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
LC a
b
b
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
Pla
sma
PL
SFA
s (w
t%ch
ange
fro
m B
L)
a
Despite containing 2.5 times more saturated fat, the LC diet
decreased total plasma saturated fat and increased
palmitoleic acid
Summary
1. We are now witnessing the ascension of nutritional ketosis as a powerful therapeutic modulator of disease processes
2. Keto-adaptation potently enhances fat oxidation (and decrease reliance on glucose metabolism) regardless of weight or training status
3. Keto-adaptation improve blood lipid and fatty acid composition profiles; an effect that is largely independent of weight loss
4. Keto-adaptation reverse most of the signs of metabolic syndrome and T2D, and improves a broad range of markers linked with the insulin resistant phenotype