METABOLIC FLEXIBILITYThe Rosetta Stone of the Macronutrient Wars?
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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.