aspen symposium therapeutic applications of nutritional ... · 3/4/2019 1 nutritional ketosis and...

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

https://www.ncbi.nlm.nih.gov/pubmed/?term=Bhanpuri%20NH%5BAuthor%5D&cauthor=true&cauthor_uid=29712560

Phinney Metabolism 1983 Shimazu Science 2013 Volek FASTER 2016

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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

http://www.nature.com/reviews/immunol

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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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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


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

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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 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

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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, )

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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

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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:




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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


-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


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

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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:




Impaired

Glucose

Tolerance

Insulin

Resistance

Late

Diabetes

Hyperinsulinemia

b-Cell Defect

(↓ insulin secretion)

Early

Diabetesb -Cell Failure

Obesity

↑ Carbs

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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

aspen symposium therapeutic applications of nutritional ... · 3/4/2019 1 nutritional ketosis and...

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