METABOLIC FLEXIBILITYThe Rosetta Stone of the Macronutrient Wars?

About Store Gmail Images

Privacy Terms SettingsBusinessAdvertising

optimal

optimal definition

optimal blue

optimal outbreeding

optimal health

optimally

optimal health systems

optimal resume

optimal nutrition

optimal arousal theory

optimal

Only the fringes care about optimal?

NOTHING in Pubmed

Seems a reasonable question, but really hard to pin down!

Is there an OPTIMAL ancestral diet?

Cultures with “diets” that work

Inuit Kitavan

Image Source: MVOrionKitava CC BY-SA 3.0, https://en.wikipedia.org/w/index.php?curid=6701695

Okinawan “Blue-zones”

Images Source:

U.S. Air Force photo/Tech. Sgt. Rey Ramon, http://www.kadena.af.mil/News/Article-Display/Article/418168/okinawan-ancestors-rejoin-families-during-obon/

Anziano Sardo by Jean Bajean - https://www.flickr.com/photos/jeanbajean/4095162162/sizes/o/in/photostream/, CC BY-SA 2.5, https://commons.wikimedia.org/w/index.php?curid=27437962

Commonalities

Largely whole

unprocessed foods

Many common lifestyle

features (much more on

this later)

Oddly missing?

Macronutrients

Population is largely free of Western degenerative disease

Outcomes

Cultures with “diets” that do not work

US (Why??) Processing Increasing palate

complexity

Dedicated engineering to make food hyperpalatable

(Betcha can’t eat just one)

Outcomes

Reference: Derived from NHANES data http://www.cdc.gov/nchs/data/hestat/obesity_adult_09_10/obesity_adult_09_10.html#table1

1971-741960-62 1976-1980 1988-1994 1999-2000 2001-02 2003-04 2005-06 2007-08 2009-10 2030 (Projected)

Obese

Year

10.712.1

12.7

20.5

27.728.3

31.733.8

32.5

35.9

50Prevalence of

Obesity Among U.S. Adults Aged

20-74

Optimal Outcomes

Time for

vs. Optimal DIET

When might a set macro ratio make sense?

High level athletics?Likely a case for seasonal fueling choices

Near competition, “serial killer consistent” (Physique competitors)

Illness/conditions that likely benefit from Low Carb

Gut

Disbiosis

Mitochondrial

Insufficiency

IR/substrate

depletion

Key to fat loss?

Appetite suppression

The assumption we must make:

If there is an optimal diet for humans (LC? HC?)

we should see metabolic and genetic

predilections FOR this specific approach.

The Case for Carbs

Humans SHOULD be able to eat carbs, likely more than all other primates!

what aboutKetosis

So, ?

Body actively “tries” to get out of Ketosis

The Case Against Ketosis, pt. 1

What are the recommended carb levels per day?

+

#context

≠

If Ketosis is THEpreferred state…why it is so hard

to maintain?

A bit of a razors edge to maintain VIA NUTRITION

ALONE

The Inuit largely do not USE Ketosis!

The Case Against Ketosis, pt. 2

CPT-1a (Carnitine palmitoyltransferase)

Increases hypoglycemia

Largely blocks ability to

enter ketosis

3X increase in infant mortality!

Stunning speed of gene spread

Acyl-CoA

Acyl-CoA

Carnitine PalmitoylTranferase 2

Acyl-CoA Acyl-Carnitine

Acyl-CoA Synthase

Carnitine/AcylcarnitineTranslocase

Mitochondrial

Matrix

Beta-Oxidation

Cytosol(-)

Carnitine PalmitoylTranferase 1

Mitochondrial carnitine palmitoyltransferase system

Carntine Palmitoyl Transferase (CPT1 and CPT2). The fatty acids are

transferred from cell cytoplasm to mitochondrial matrix for beta-oxidation.

The CPT1 is activity is regulated by malonyl-CoA feedback inhibition.

Free Fatty Acids

Malonyl-CoA

Acyl-Carnitine

Evolutionary impacts on health might be

more prevalent than currently appreciated.

– Florian Clemente

“

So,carbs good,

low carb badright?

context#

This is NOT the paleolithic, most of us don’t have numbers like HG’s

Reference: Centers for Disease Control and Prevention (CDC), “Long-Term Trends in Diabetes,” April 2016. Americans diagnosed with diabetes, 1958 through 2014.

Perc

en

tage w

ith D

iabete

s

0701960 65 80 85 90 95 2000 2006

Year

6

5

4

3

2

1

7

8

75 2014

Num

ber

with D

iabete

s(in

Millio

ns)

15

10

5

0

20

25

There ARE laudable characteristics of time

restricted feeding, exercise and low carb intake.

Hysteresis.

What is Hysteresis?Dependence of the state of

a system on its HISTORY (A type of memory)

Schmidt Trigger in electronics

Input OutputA

B

+

Glucose Hysteresis: Epigenetics in Action

531 420 0.3 5

Inner mitochondrial membrane

Outer mitochondrial membrane

NADH

NAD+

FADH2

FAD

H2OATP

H+

ADP+Pi

O2

Cyt COX

Cyt COX

H+

H+H+H+

ATP

III

III IV

V

ANT

Inner mitochondrial membrane

Outer mitochondrial membrane

NADH

NAD+

FADH2

FAD

H2OATP

H+

ADP+Pi

O2

Cyt COX

Cyt COX

H+

H+H+H+

ATP

III

III IV

V

Glucose

Glucose-6-phosphate

Fructose-6-phosphate

Fructose-1,6-bisphosphate

DHAP G3P

G3P G3P

NAD+

NADH+H+

NAD+

NADH+H+

-1ATP

Pi Pi

ATP

ADPPFK

-1ATPATP

ADPStep 1:

Step 2:

Step 3:

Step 4:

Step 5:

Step 6:

ANT

Glycolysis Pathway

Inner mitochondrial membrane

Outer mitochondrial membrane

NADH

NAD+

FADH2

FAD

H2OATP

H+

ADP+Pi

O2

Cyt COX

Cyt COX

H+

H+H+H+

ATP

I

III IV

V

ANTII

Pentose Phosphate Pathway

Glucose-6-P

Glucose-6-phosphate dehydrogenase

Oxidative phase

Non-oxidative phase

Gluconolactonase

6-phosphogluconate dehydrogenase

6-Phosphogluconolactone

6-Phosphogluconate

Ribulose-5-phosphate

Ribulose-5-phosphate Isomerase

Ribulose-5-phosphate 3-Epimerase

Ribulose-5-phosphate Xylulose-5-phosphate

Glyceraldehyde 3-phosphate + Sedoheptulose 7-phosphate

Transketolase

Transaldolase

Transketolase

Glyceraldehyde 3-phosphate + Fructose 6-phosphate

Fructose 6-phosphate + Erythrose 4-phosphate Xylulose-5-phosphate

GlycolysisGlycolysis

Glycolysis

NADPHCO2

NADP+

NADP+

NADPH

H2O

H+

Complex 1 vs. Complex 2and Health Span

Reference: https://assets.weforum.org/editor/znQ7FmQNtDn_0zlEk0PyVdgMApRGvh_5Pholu6XM4uo.jpg

Health

0 3010 20 40 50 60 70 80 90 Age

Average Population

Master Athletes

Increased ‘Health-Span’

Compressed Morbidity

The Respiratory Quotient (RQ)

Respiratory Substrate

RQ value

The following table shows the RQ values for different classes of respiratory substrate when they are used for aerobic respiration

If any degree of anaerobic respiration occurs RQ values significantly above a value of 1.0 are obtained

Glucose

1.0

Fatty acid

0.7

Protein

0.9

Kenyan Runners

By Contrast

?Is there a formula forsuccess

Perhaps “optimum” is not a number.

Perhaps “optimum” is a SEAMLESS transition between a wide variety of fuels.

FatsAvocado

Olives

Oils

Flaxseed

Butter

ProteinCarbsGrains

Rice

Potato

Veggies

Fruits

Fatty Meat

Dairy

Eggs

Salmon

Nuts

Seeds

Beans

Lentils

Legumes

Peas

Quinoa

Buckwheat

Whey

Lean Meat

Low fat dairy

Fish

Seafood

Chronic DiseaseCholesterol

HypertensionStroke

Heart AttackArthritis

Diabetes

AsthmaCOPD

Insomnia Thyroid Disorder

ObesityNeuropathy Stroke

Perhaps “optimum” is a relative absence of modern degenerative disease

Asthma

Insomnia

Cholesterol

Sleep Apnea

Chronic Disease

Diabetes

Diabetes

COPDArthritis

Obesity

Stroke

Stroke Heart AttackArthritis

Obesity Neuropathy

Cholesterol

Heart Attack

COPD

Hypertension

StrokeSleep Apnea

Thyroid Disorder

Insomnia

Cholesterol

Cholesterol

Arthritis

Sleep Apnea

The Added ProblemHow we define “normal”

Barely above baseline andlittle decline with age!

Also: ONE HOUR OGTT!!!

Reference: http://wholehealthsource.blogspot.com/2010/11/glucose-tolerance-in-non-industrial.html

Blo

od g

luco

se (m

g/1

00

ml)

3020 50 60

Age

130

120

110

100

90

80

140

150

40

Male

Female

Tecumseh, U.S.A.

Tukisenta, N.G.

190

180

170

160

200

100 mg/dl 200 mg/dl

2-hour OGT test

Our “normal”

Normal: Not good enough

100 mg/dl 200 mg/dl

1-hour OGT test

Pre-Westernized “normal”

Establishing Physiologic norms: The best of Ancestral Health

“Prediabetes” is Inadequate Marker of DM Risk

Type 2

Diabetes

Continuum of Type 2 Diabetes Progression

Early Intermediate Late Progression Progression

Many with glucose 100-110 mg/dL do not

progress to T2DM/

Others with glucose 90-99 mg/dL develop

diabetes in <5 years

Those with late stage progression (e.g. FPG > 110) frequently have

vascular complications and increased pancreatic

dysfunction with high risk of progression to

Type 2 diabetes

UNMET DIAGNOSTIC NEED

“Diagnostic tests should be developed to better

distinguish patients who will progress to diabetes from

those who will not.” 1

80 85 90 95 100 105 110 115 120 125 >125

5.5 5.7 6.0 6.4 >6.4

Plasma Glucose, mg/dL

HbA1c %

Pre-Diabetes“Normal” Glucose

< 100 mg/dL 100-125 mg/dL ≥ 125 mg/dL

Diabetes

DIAGNOSTIC DILEMMA

Risk of diabetic progression is assessed by glucose measures that are the “response”, not

the “cause” of worsening glucose metabolism.

Confidential

Type 2

Diabetes

Insulin Resistance

Insulin Production

β cell Dysfunction

1. AACE Prediabetes Consensus Statement, Endocr Pract. 2008;14(No. 7) 941

Insulin load/glycemic response important due to individual variations

Weitzman inst.

Brain hates glucose

deltas (Remember

Hysteresis!!)

Overeating

Real World Example: 7 Day Carb Test

My Blood Glucose

Nicki’s Blood Glucose

Quantified

Real World Example #2: Is the LC flu a symptom of problems or normal?

Transition to Ketosis

OK,

why can’t we transitionseamlessly?

Dysfunctional Mitochondria

and Antibiotics

Mitochondrial Dysfunction and Obesity

“Excessive energy substrates lead to mitochondrial dysfunction with consequential

effects on lipid and glucose metabolism…maintaining this balance requires normal

mitochondrial function.”

Mitochondrial Dysfunction

and Iron Overload

Mitochondrial Dysfunction and Sleep

Mitochondrial Dysfunction

and Microbiome

Many Roads

TCA cycle

Your Metabolism = your Mitochondria

If your mitochondria are broken, only thing left is

Glycolysis. Complexes 1, 3, 4, etc.

GlycolysisGlucose

Fructose-6P

Fructose-1,6P2

Glyceraldehyde-3P

Glyceraldehyde-1,3P2

Glycerate-3P

Glycerate-2P

Phosphoenolpyruvate

Pyruvate

D-lactate

Acetyl-CoA

Dihydroxyacetone-P

Isocitrate

Cis-Aconitase

Citrate

Oxaloacetate

L-Malate

Fumarate

Succinate

Succinyl-CoA

⍺-Ketoglutarate

Starch and sucrose metabolism

Glucose-6P Glucose-1P

What about multi-generational

epigenetic changes??

MATERNAL SOCIAL TRANSMISSION

F0-F1Mother-infant interactions

F1-F2Mother-infant interactions

F2-F3Mother-infant interactions

F1 Offspring development

F2 Offspring development

F3 Offspring development

Epigenetic variation in F0 sperm

F0Environmental

exposure

PATERNAL GERMLINE TRANSMISSION

Epigenic Variation

Epigenetic variation in F1 sperm

Epigenetic variation in F2 sperm

ENOUGH TALK!

that sounds greatbut what to DO

OK Propeller Head,

?

Reclaiming and maintaining our metabolic flexibility (ie. mitochondrial health)

Lift weights Go fast Go slow Novel experiences

Circadian rhythm

Sleep Light exposure Gut health Meaningful relationships

Regarding Food

Test and track BG response

(WTE-7 Day Carb Test)

Be aware of immunogenic

foods

Eat with the seasons

Get as much variety as possible without getting in trouble -hyperpalatability

Our consistent and fatal mistake:

The “Procrustean Bed” of the Macronutrient Wars

Image Source: http://canacopegdl.com/images/procrustean/procrustean-0.jpg

Make your bed fit you!

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760005/pdf/nihms-509241.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5001554/pdf/nihms401101.pdf

https://www.sciencedirect.com/science/article/pii/S0891584910002649

http://jcsm.aasm.org/Articles/jcsm.10.11.1233.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425813/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382850/pdf/12916_2015_Article_310.pdf

Inuit not in Ketosis:

http://www.jbc.org/content/80/2/461.full.pdf

On the Inuit and Ketosis:

https://chrismasterjohnphd.com/2017/10/26/inuit-genetics-show-us-evolution-not-want-us-constant-ketosis-mwm-2-37/

Works Cited

© 2018 Robb Wolf. All Rights Reserved.