Transcript Insulin

The Skinny on Insulin
March 2012
George Gillson MD PhD
Meet Jane
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42 years old
Teacher
Married
3 children
• 30 lbs overweight
Couch potato
Terrible diet
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“I just feel old”
Hot flashes at night
Anxiety
Breast tenderness, puffy ankles, migraines
Menses regular but heavier
Some hair growth on upper lip
Weight gain at waist and hips
Heartburn
Poor muscle tone: “I’m mushy”
Low sex drive
“Runs out of gas” by midmorning
Complains her hair is prematurely grey
Avoids sun exposure
“I think my hormones are out of balance.”
Jane: Objective Data
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185 lbs
5’6”
BMI 30
Waist 40” (102 cM)
Hips 45”
BP 135/87
Skin tags
7 mercury fillings
• Triglycerides (TG) high
• Total cholesterol: high
• HDL cholesterol: low
• Chem: slightly increased
GGT, uric acid
• Fasting glucose: normal
Skin
Tags
Typical MD Approach to Jane
• Patient is treated as a collection of problems, and given
pathway-blocking drugs to “solve” the problems
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“Your blood pressure and cholesterol are too high.”
Statin drug for cholesterol
ACE inhibitor for blood pressure
“Lose weight”
+/- Proton pump inhibitor for acid reflux
+/- SSRI for anxiety and vasomotor symptoms
• Can we do any better than this?
• Yes, but we need an integrating framework
Visceral
Obesity
Elevated
Insulin
Metabolic
Syndrome
NCEP* CRITERIA
Three or more of :
Half of the
North American
population
> 45 yrs old !
Insulin
Resistance
Abdominal obesity
Elevated triglycerides
Low HDL
Hypertension
Elevated fasting glucose
* NCEP: National Cholesterol Education Program
Why is it called Metabolic Syndrome?
• Metabolic Syndrome is an increasingly wellunderstood collection of all or many of the
following metabolic abnormalities:
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Borderline/High blood pressure
High insulin, insulin resistance
Problems regulating blood sugar
Abnormal lipids (low HDL and high triglycerides)
Impaired vasodilation
Evidence of inflammation on blood tests
Abnormal steroid hormone levels (some high, some low)
High serum uric acid
Abnormal liver function tests
Abnormal “appestat”: endorphins, α-MSH, leptin
MetS Prognosis
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Economic crisis of Biblical proportions
Decreased quality of life
Shortened lifespan/accelerated aging
Degeneration/metabolic decompensation
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Diabetes
Cardio/cerebrovascular disease
Arthritis
Osteoporosis
Cancer
Dementia?
MetS and College Football Players
Prevalence of MetS was 19% ( 1 in 5) in
2010 paper looking at University of
Tennessee NCAA Div. 1 football players
J Athl Train 2010;45:67-74. Identification of
cardiometabolic risk among collegiate
football players. Wilkerson GB, Bullard JT,
Bartal DW.
The football players are not alone:
Pre-MetS in Prepuberty
By Bill Berkrot
NEW YORK
Tue Nov 23, 2010 12:11am EST
(Reuters) - More than half of
Americans will have diabetes or
be prediabetic by 2020 at a cost
to the U.S. health care system of
$3.35 trillion if current trends go
on unabated, according to
analysis of a new report
released on Tuesday by health
insurer UnitedHealth Group Inc.
Mauras N et al.. J Clin Endocrinol Metab
2010 ;95:1060-1068.
Obese children with normal lipids, normal
fasting glucose and normal blood pressure
were found to have:
Insulin resistance
↑ IL-6
↑ PAI-1 (plasminogen activator inhibitor -1)
↑ hs CRP
↑ fibrinogen
http://www.reuters.com/article/idUSTRE6AM0NH20101123
Obesity/MetS Determinants
• Genetics, ethnicity
• Prenatal history
• Lifestyle
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Diet
Sleep pattern
Activity pattern
Stress management (or lack thereof)
• Colonic flora
• Environment
– e.g. EM pollution, endocrine disruptors
Genetics
• MetS is strongly inherited
• Harsh environments select for fat storage genes
which promote survival in times of famine
• These same genes don’t serve us well when food is
abundant (“thrifty gene hypothesis)
• Mutations involving insulin signaling, vitamin D,
thyroid hormone, gut hormones, fat metabolism,
muscle development are linked to MetS
– Song Q, Wang S, Zafari M. Genetics of the Metabolic Syndrome.
Hosp Physician 2006. http://www.turnerwhite.com/pdf/hp_oct06_genetic.pdf
Prenatal History
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Intrauterine malnutrition
Premature birth
Low birth weight
Maternal smoking
• All can predispose to MetS in adulthood
• Infant is programmed to accumulate fat
– Epigenetic modification, hard wiring of HPA axis
Fast
Eat
Burn fat
Take up nutrients/utilize some
Build muscle/prevent muscle
breakdown
Store nutrients not used
immediately
Provide glucose for brain
Build muscle/prevent muscle
breakdown
FASTED
FED
Metabolic Switch must flip between fasted and
fed states multiple times throughout 24 hours
HOW IS JANE”S SWITCH WORKING?
Enter Growth Hormone…
High Average GH
Muscle
Low Average GH
Muscle
Energy
Energy
Fat
Fat
Obesity = Low
Growth Hormone
Utz A et al. J Clin
Endocrinol Metab
2008;93: 4033-4040
25-35 yo women
What is Growth Hormone (GH)?
High blood glucose
suppresses GH release
Pituitary gland
GH
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Peptide hormone: 191 amino acids
Blocks muscle uptake of glucose
Stimulates lipolysis ( releases fatty acids)
Stimulates fat burning in muscle
Promotes liver synthesis of glucose
Promotes growth of muscle tissue
Prevents breakdown of muscle
GH
Endocrine IGF-1
IGF-1
Insulin-Like Growth Factor-1
-same basic actions as insulin
GHR
Target tissues:
Bone
IGFR
Fat
Muscle
IGF-1
Paracrine IGF-1
-longer half-life than insulin due to
protein binding
-free IGF-1 rises then falls after
meals
-helps dispose of amino acids after
initial work of insulin is done
When do you make Growth Hormone?
When you’re asleep
Stage III Sleep  GH
Age
When you’re young
During and after Exercise !
When you’re hungry!
hunger  ghrelin  GH
-Increased core temperature (sweating)
-Increased lactic acid (anaerobic respiration)
-Muscle damage (amino acids released into blood)
Godfrey RJ, Madgwick Z, Whyte GP. Sports Med 2003;33:599-613. The exerciseinduced growth hormone response in athletes.
Why does Jane have low GH?
• Overweight: obesity ↔ low GH
• Age-related decline
• Lifestyle choices/habits:
• Eating pattern
– high blood sugar due to snacking in late evening suppresses sleeponset GH release
– Snacking on refined carbs and saturated fats during the day
• Sleep
– Not enough sleep
– Doesn’t initiate sleep well
• Exercise
– She hardly does any, and what she does is low intensity
What can Jane do about her low GH?
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Change what she eats and when she eats it
Improve her sleep (quality and quantity)
Hot bath/sauna before bed
Progesterone supplementation at bedtime *
DHEA supplementation**
Start an exercise program and gradually bring in a high
intensity component
• Growth hormone secretagogues
• GH injections?
* Oral DHEA administration increases GH in women
Genazzani AD et al. Fertil Steril 2001;76:241-248
Von Muhlen D et al. Osteoporos Int 2008;19:699-707
** Progesterone stimulates GH release
Clin Endocrinol (Oxf) 2009 ;71:535-542. A potential role of endogenous
progesterone in modulation of GH, prolactin and thyrotrophin secretion during
normal menstrual cycle. Caufriez A, Leproult R, L'Hermite-Balériaux M, MorenoReyes R, Copinschi G.
Sleep and Weight
• People who sleep less weigh more
• Increased sleep promotes weight loss
• If you’re trying to lose weight, skimping on
sleep causes you to lose less fat
– Eur J Endocrinol 2008;159 Suppl 1:S59-66. Sleep and the
epidemic of obesity in children and adults. Van Cauter E,
Knutson KL.
– http://www.medscape.com/viewarticle/729995
Jane:
Sleep history
• 5-6 ½ hours/night on week nights
• Sleeps in on weekends
• Many nights, sleep is unrefreshing; hot
flashes wake her up frequently
• Can’t get to sleep some nights (her brain
just won’t switch off)
Salivary Cortisol
(ng/ml)
Jane's Salivary Cortisol Profile
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18
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10
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2
0
600
1000
1400
1800
Time (hours)
2200
Jane tells us she “crashes”
before lunch, has low energy
during the middle part of the
day, and can’t sleep at night
Her symptoms fit her cortisol
pattern
What can Jane do about her sleep?
• Make a conscious decision to get more sleep!
• Determine whether she has sleep apnea
– Severe OSA is 6-7 times more likely in MetS patients
– Eur Heart J 2004;25:735-741. Obstructive sleep apnoea is
independently associated with an increased prevalence of metabolic
syndrome. Coughlin SR, Mawdsley L, Mugarza JA, Calverley PM,
Wilding JP.
– J Endocrinol Invest 2010;33:192-196. Growth hormone/insulin-like
growth factor-I axis in obstructive sleep apnea syndrome: an update.
Lanfranco F et al.
• Oral progesterone at bedtime (metabolites are sedativehypnotic)
• Supplement with melatonin (0.5 – 1 mg hs to start)
• Promote melatonin synthesis (5-HTP, B6 and magnesium)
• Magnesium glycinate (100 – 300 mg at hs)
Growth Hormone Enhancing Workout
168 beats/min
52 yrs old
220 – Age = 168
www.mercola.com
http://www.youtube.com/watch?v=OKczVO37cEw&feature=related
Growth Hormone Secretagogues
(1) Nutrients which support pituitary synthesis of GH
(2) Peptides which encourage release of GH
- ghrelin analogues
(3) Amino acids (arginine, lysine, ornithine, glutamine)
Muscle
Damage
Free amino
acids
Brain
GH release
Protein
sparing
(Endogenous)
Exogenous
amino acids
Fast
Eat
Burn fat
Take up nutrients/utilize some
Build muscle/prevent muscle
breakdown
Store nutrients not used
immediately
Provide glucose for brain
Build muscle/prevent muscle
breakdown
FED
FASTED
Growth hormone
X
Metabolic Switch
JANE’S SWITCH ISN”T
FLIPPING TO THE GH SIDE!
Jane isn’t hungry when she wakes up…
• Jane has high fasting triglycerides and high normal glucose
• Jane is waking up with too much fuel in her tank
Saturated fat
Triglyceride (TG)
glycerol
Monounsaturated fat
Monounsaturated fat
or Polyunsaturated fat
Glycerol
Glucose
Kreb’s Cycle
Acetyl
CoA
Fatty
Acids
Dietary fat
Triglycerides (TG)
Stored fat (TG)
Insulin regulates the amount of fuel
in circulation
Insulin promotes uptake of macronutrients
Glucose
+
Free fatty acids
Glycogen
+
Stored fat
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Free triglycerides
Eat food
Amino
acids
Glucose
Free fatty acids
Free triglycerides
+
Protein
-
Amino
acids
Insulin
Insulin blocks release of stored energy and protein
Lipoprotein Lipase
Dietary
TGs
GUT
Chylomicrons
Capillary
LPL
VLDL
Liver
Free fatty acids
bound to albumin
Free fatty acids
Adipose
Insulin upregulates LPL
If insulin is too low, fatty acids won’t be available for
uptake into muscle
Fatty acid
transport
proteins
Muscle
Jane’s Insulin/TG Paradox
• Insulin 21.6 μU/ml (150 pmol/L) : Borderline High
• Fasting triglycerides: High
• How can Jane’s TG’s be high? Insulin should suppress TG’s
and her insulin is high…
• How can Jane’s insulin be high? Insulin goes up after you
eat. She didn’t eat anything while she was sleeping …
β cell
Fatty acids
Fats determine basal insulin secretion
Jane’s Insulin/TG Paradox
• Jane’s fat cells are leaking TG’s and fatty acids at night
• These fatty acids are driving her pancreas to make more insulin (to clear
the fatty acids)
• That extra insulin is still not able to suppress lipolysis and the fat cells are
resisting uptake of the fatty acids in the first place
• Jane’s adipocytes are resistant to the effect of insulin
• Jane has:
– high fasting insulin
– insulin resistant visceral fat
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Insulin
Pituitary gland
↓GH
Liver
↓ IGF-1
High Fasting Insulin = Low GH
Insulin suppresses
GH and IGF-1
High fasting insulin
= low fasting IGF-1
Clasey JL, Weltman A, Patrie J
et al. Abdominal visceral fat
and fasting insulin are
important predictors of 24-hour
GH release independent of
age, gender, and other
physiological factors. J Clin
Endocrinol Metab
2001;86:3845-3452.
Insulin Resistance
• Must be specific when we use these words
• Should refer to a specific target tissue:
muscle, liver, adipose
• Should refer to a specific nutrient: glucose,
fatty acids
• Should refer to a timescale:
transient/postprandial (hours) vs ongoing
(days, months, years)
Fast
Eat
Burn fat
Take up nutrients/utilize some
Build muscle/prevent muscle
breakdown
Store nutrients not used
immediately
Provide glucose for brain
Build muscle/prevent muscle
breakdown
FASTED
FED
Growth hormone
Insulin
X
X
Metabolic Switch
JANE’S METABOLIC SWITCH IS STUCK!
Enough is Enough
• There is another way to look at insulin
• Insulin is both a satiety signal and an
adiposity signal
• Satiety: “I’ve had enough to eat for now.”
• Adiposity: “I’ve got lots of stored energy”
Obese people are resistant
to leptin. High leptin levels
don’t result in reduced
appetite
Leptin is proportional to fat mass
Inhibit insulin release
Shrink fat cells
Leptin
Eat less
Adipocytes
Eat less
Make bigger fat cells
Insulin
-Amount of insulin you make is also proportional to fat mass
-Insulin is a central appetite suppressant
-High insulin in AM  Lots of stored energy
Neurochemistry of Appetite/Satiety
First order neurons
Serotonin
Serotonin
Second-order neurons
Brake
Gas pedal
Increased
outflow here
results in
appetite
suppression
Decreased
outflow here
results in
appetite
suppression
Clin Pharmacol Ther. 2007 May;81(5):748-52. New targets for
obesity pharmacotherapy. Aronne LJ, Thornton-Jones ZD.
MSH and serotonin are important signaling molecules wrt appetite
HOMA-IR
Homeostatic Model for Metabolic Assessment of Insulin Resistance
• Go to: http://www.dtu.ox.ac.uk
• Click “HOMA calculator” link on sidebar at left side of page
• Download a program that installs this desktop calculator…
Use and abuse of HOMA modeling. Wallace T, Levy J, Matthews D. Diabetes
Care 2004;27:1487-1495.
JANE’S HOMA-IR
• Fasting glucose or fasting insulin in isolation may not tell the
whole story
• Glucose 5.6 mmol/L: Insulin 150 pmol/L
• % S = 35.6 (Normal = 100%)
• Jane’s sensitivity to insulin is only 35.6 % of normal
• HOMA-IR = 100/ (% S) = 100/35.6 = 2.8
• Around 1: normal
• < 1: better
• > 2 : increased suspicion of Insulin Resistance
• % B = 154 (Normal = 100%)
• Her pancreas is working one and a half times harder than normal
Write talks on Metabolic
Syndrome
Perform
physical
work
Insulin
sensitive liver
Insulin sensitive
Don’t make
glucose if
insulin is hi
skeletal muscle
burn FA’s &
glucose
ENERGY
Store
glycogen
(FA’s, glucose)
Store
glycogen
Make TGs
Generate heat
Converts glucose to TG
Insulin sensitive visceral adipose
tissue absorbs excess energy
Stores TGs imported from blood
Appropriately releases TG and fatty acids to circulation
Adipose Insulin Resistance:
Failure to Store Energy
Atherosclerosis
“Metastatic Fat”
Blood
Increased cholesterol synthesis
vessels
Inflammation*
Fat
cells
Marbling
Impaired
fat burning
Muscle
Fatty liver
Increased
liver enzymes
Liver
Increased serum triglycerides/free fatty acids
Epicardial
fat
* Increase in adipocyte size/macrophage recruitment/secretion
of inflammatory cytokines e.g. TNFα, IL-6
Insulin and Cholesterol
Glucose
Acetyl
CoA
Triglycerides
+
Kreb’s Cycle
HMG CoA
Reductase
Insulin
Cholesterol
↑ Insulin  ↑ HMG CoA Reductase  ↑ Cholesterol
Blocking cholesterol synthesis could backfire in some
people and cause them to make more insulin (in an
attempt to increase cholesterol)
Statins Worsen Insulin
• Int J Clin Pract 2011;65:1141-1148. Comparison
of the effects of simvastatin vs. rosuvastatin vs.
simvastatin/ezetimibe on parameters of insulin
resistance. Moutzouri E et al
• 3 month study of 156 patients who did not meet
LDL-C targets through diet and exercise
modification
• “At week 12, all three treatment regimens were
associated with significant increases in HOMA-IR
and fasting insulin levels (p < 0.05 compared with
baseline).”
This person’s
adipocytes are quite
insulin sensitive!
These guys
have insulin
resistant
adipocytes
She is able to
continuously gain fat
They have stopped gaining fat
High
glycemic
load
↑ Insulin
↑ Fat storage
Energy is overflowing into other
places it shouldn’t be!
+ feedback
Fat mass
Insulin sensitive
Insulin resistant
Insulin
Hepatic synthesis of glucose
from various substrates
Gluconeogenesis
Insulin suppresses
hepatic glucose
synthesis
One of the roles of insulin is to temporarily shut off glucose production by the liver
(since insulin rises after a meal, there will be glucose in circulation from the meal, so
the liver doesn’t need to make any more)
Hepatic insulin resistance refers to the loss of the ability of insulin to suppress
gluconeogenesis
This has the effect of augmenting the postprandial rise in glucose
Insulin Sensitive Liver
Insulin
Fed
Glucagon
X
Fasted
Fat
Liver
Glucose
cells
Liver
Insulin
X
Glucose
Lipid
accumulates
in liver
Hepatic Insulin Resistance:
Failure to Suppress Gluconeogenesis
Liver
Glucose
Hepatic before Peripheral
• Hepatic insulin resistance develops before
peripheral resistance
• Diabetes 2003;52:2453-2460. Primacy of
hepatic insulin resistance in the
development of the metabolic syndrome
induced by an isocaloric moderate-fat diet
in the dog. Kim SP et al.
Skeletal Muscle Insulin
Resistance:
Failure to Dispose Glucose
Glucose
Glucose “overflows” into blood
Fat
cells
Skeletal Muscle
Glucose
Increased TG synthesis
Skeletal Muscle Insulin
Resistance:
Failure to Burn Fat
Fatty Acids
-Work
-Heat
Skeletal Muscle
Fat deposits intercalate
between muscle fibres
Fatty Acids
“Marbling”
GH
Insulin
Insulin Resistance/Low
Growth Hormone
“Stuck”Metabolic Switch
Fast
Progressive failure to
manage energy
The energy still has to go
someplace…
Eat
Elevated serum glucose, elevated
urine glucose
Elevated serum triglycerides
Elevated free fattyFat
acids
Fat deposits in liver (fatty liver)
Fat deposits in muscle (marbling)
Fat deposits in vascular tree
Increased epicardial fat
How did what Jane eats get her in
this (pun intended) pickle?
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Skips breakfast (not hungry, too rushed)
Coffee & pastry en route to school
Lunch in cafeteria (slice pizza, bag of chips)
Eats out 1-2 nights/week-fast food
Sit-down meals 2-3 nights/week-leans toward
packaged food. Few meals from scratch
Doesn’t eat many whole foods
2-3 diet soda/day
Snacks on chips or a chocolate bar, midmorning
but especially in evening
4-6 cups coffee with cream/day
Jane’s Diet and Insulin
Resistance
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Low antioxidants
High trans fats
Unbalanced “natural” polyunsaturated fat intake (ω6 vs ω3)
Low monounsaturated fat (almonds, olive oil, avocados)
High saturated fat
High refined carbohydrates (sucrose)
High refined fructose intake (high fructose corn syrup)
High refined salt
Low chromium
Low zinc
Low magnesium
– Diabetes Care. 2005 May;28(5):1175-81. Magnesium deficiency is associated with
insulin resistance in obese children. Huerta MG, Roemmich JN, Kington ML,
Bovbjerg VE, Weltman AL, Holmes VF, Patrie JT, Rogol AD, Nadler JL.
Jane’s Oxidative Stress Load
• Jane doesn’t eat any highly antioxidant, richly-coloured foods (corn
and ketchup don’t count!)
• She eats a lot of unsaturated fats (mostly ω6) and a lot of trans fats
which are easily damaged by free radicals
• Jane’s diet promotes oxidative stress
• Inflammation in visceral fat drives MetS
JANE’S CHOLESTEROL
– Jane’s high cholesterol is not the root cause of her (currently
asymptomatic) CAD
– It is a symptom of widespread metabolic
derangements/inflammation
– High cholesterol (known antioxidant) ? compensatory
reaction to oxidative stress
Oxidative Stress and Sleep Apnea
• Sleep apnea may be caused/worsened by oxidative
stress in the brainstem and the tissues of the airway
High oxidative
stress
BRAINSTEM
MetS
Impaired GH output
OSA
Uric Acid
• Considered to be an
antioxidant: elevated
UA seen as a
compensatory reaction
to oxidative stress
• Elevated insulin
causes kidneys to
retain both uric acid
and sodium
• Several prospective
studies have shown
that elevated uric acid
is a risk factor for
future development of
MetS
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Metabolism 2012;61:281-288.
High serum uric acid level and low
urine pH as predictors of metabolic
syndrome: a retrospective cohort
study in a Japanese urban
population. Hara S, Tsuji H,
Ohmoto Y et al
Am J Physiol 1995;268:E1-5.
Effect of insulin on uric acid
excretion in humans. Quiñones G
et al.
Atherosclerosis 2012;220:525-531.
Uric acid level as a risk marker for
metabolic syndrome: A Chinese
cohort study. Yang T, Chu CH, Bai
CH, et al
Fatty Acids and Appetite
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Jane eats a lot of saturated fat
She eats too little monounsaturated fat (oleic acid OA)
She eats too little N-3 unsaturated fat (EPA and DHA)
Saturated FAs are orexigenic
DHA and OA are anorexigenic
• Int J Obes (Lond). 2011 Mar;35(3):336-44. Epub 2010 Aug
17. Effects of central administration of distinct fatty acids
on hypothalamic neuropeptide expression and energy
metabolism. Schwinkendorf DR, Tsatsos NG, Gosnell BA,
Mashek DG.
Food intake
Body weight
Int J Obes (Lond). 2011 Mar;35(3):336-44. Epub 2010 Aug 17. Effects of
central administration of distinct fatty acids on hypothalamic neuropeptide
expression and energy metabolism. Schwinkendorf DR, Tsatsos NG, Gosnell
BA, Mashek DG.
Sunflower, corn, safflower, soy
cottonseed, sesame, various nuts
Anti:
13 HODE
Nitrated LA
Pro:
9 HODE
Leukotoxin
Leukotoxin diol
Omega 6
Linoleic (LA)
Essential
“Parents”
γ-linolenic (GLA)
DGLA
Arachidonic acid
AA n20
Anti-inflammatory:
Epoxyeicosatrienoic
acids
16-HETE
Lipoxins
Proinflammatory:
PGE2
LTB4
Hemp seeds, fish, flaxseeds,
walnuts, green leaves
Omega 3
Alpha-linolenic
(ALA)
Nutr Metab (Lond) 2009 ;6:8.
Quantitation of alpha-linolenic acid
elongation to eicosapentaenoic and
docosahexaenoic acid as affected by
the ratio of n6/n3 fatty acids. Harnack K,
Andersen G, Somoza V.
Eicosapentaenoic acid
EPA
Epoxyeicosatetraenoic
acids
Docosahexaenoic acid
DHA
Prostaglandins Leukot Essent Fatty Acids 2008 ;79:173-517. Too much linoleic acid promotes
inflammation-doesn't it? Fritsche KL.
EFA Take Home Points
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EFA’s are complicated!
We have to have some carbon chains longer than 18 carbons
LA is not categorically “bad”
EPA is not categorically “good”
– Antithyroid effects, immunosuppression, free radicals
• http://raypeat.com/articles/articles/unsaturated-oils.shtml
• A proper LA:ALA balance is essential; this balance is likely
somewhere around 1:1 (range 2:1 to 1:2)
• Jane’s ratio LA: ALA is likely >10:1
• Trans fats are categorically bad, and interfere with the utilization
of the parent 6 and 3 fats
• You are what the animals you eat ate!
Burn or Store?:Saturated Fat Metabolism
Kreb’s Cycle
“Shorter-by-two” saturated fat
-C-C-(C-C)n-C-C- + Acetyl CoA
BURN
-C-Cmitochondria
Conversion to
ketone bodies
β-oxidation
-C-C-(C-C)n-C-C-C-CSaturated fat
desaturation
-C=C-(C-C)n-C-C-C-CMonounsaturated fat
e.g. oleic acid
Incorporation into triglycerides
STORE
β-oxidation
Shorter saturated fat
Saturated Fat
e.g. stearic acid C18
(animal fat)
Stearoyl CoA
desaturase (SCD)
Desaturation
Unsaturated Fat of same chain
length
e.g. oleic acid C18:1
Excessive activation of SCD leads to obesity
SCD -/- mice are obesity resistant
*J Biol Chem. 1994 Nov 4;269(44):27773-7. Insulin and
dietary fructose induce stearoyl-CoA desaturase 1 gene
expression of diabetic mice. Waters KM, Ntambi JM.
How do we avoid excessive upregulation of SCD?
Keeping the lid on SCD
Saturated Fat
e.g. stearic acid C18
(animal fat)
Glucose
Insulin
N-3 fatty acids
-
+
Central appetite
suppressant
SCD
Fructose*
+
Cortisol
+
Monounsaturated Fat
Oleic acid doesn’t raise
postprandial insulin as much
as saturated fat
Central appetite suppressant
Keep fructose intake to “natural” levels
Keep cortisol under control, especially at night
Adequate intake of N-3 fatty acids and oleic acid
Don’t pile refined sugars on top of saturated fats
Avocados, olive oil, almonds
Am J Clin Nutr. 2008;88:638-644. Distinctive
postprandial modulation of beta cell function
and insulin sensitivity by dietary fats:
monounsaturated compared with saturated fatty
acids. López S, Bermúdez B, Pacheco YM,
Villar J, Abia R, Muriana FJ.
Isocaloric combinations of
various types of fats layered
over a basic carb meal
Avoid combining excessive carbs and excessive saturated fats
-Coconut oil contains medium-chain triglycerides (MCT’s) which are
8-12 carbons
-MCT’s don’t raise insulin very much
-MCT’s bypass the liver, so they can provide immediate energy
-They burn fast like carbs but they are not carbs!
ROO: olive oil | HPSO: high palmitic sunflower oil
VEFO: vegetable/fish oil
Why didn’t the Inuit get fat?
• They ate a lot of blubber which is higher in
monounsaturated fat
• They didn’t eat any sugars to excessively
raise insulin and redirect their fat intake
away from β-oxidation
• Their fish oil intake also worked to prevent
redirection (n-3 FA’s suppress SCD)
• Their mix of fats was appetite suppressant
Starch = Polyglucose
Some are slower
release
Glucose
Increased need for
nutrients needed to
metabolize the
sugars:
Sucrose
(Glucose – fructose disaccharide)
Glucose
Fructose
Faster
release
High fructose corn syrup
Fructose
Mg, lipoic acid,
riboflavin, niacin,
thiamine,
pantothenic acid
Fructose
does not
raise insulin
Fruit juice
Slower
release
Fruit
Fructose
Fructose
creates other
issues !
(in general)
Sugars and Insulin Resistance/Obesity
Fructose aka “Corn sugar”
• Fructose raises uric acid; uric acid may be
causative in MetS
– Am J Physiol Renal Physiol. 2006 Mar;290(3):F625-31. Epub
2005 Oct 18. A causal role for uric acid in fructose-induced
metabolic syndrome. Nakagawa T, Hu H, Zharikov S et al
• Fructose is associated with systolic hypertension
– J Am Soc Nephrol. 2010 Sep;21(9):1543-9. Increased fructose
associates with elevated blood pressure. Jalal DI, Smits G, Johnson
RJ, Chonchol M.
• Fructose is preferentially metabolized to
triglycerides in the liver
– J Nutr. 2008 Jun;138(6):1039-46. Dietary sugars stimulate fatty
acid synthesis in adults. Parks EJ, Skokan LE, Timlin MT,
Dingfelder CS.
A SEA OF FRUCTOSE
NHANES 2004:
95th percentile > 100 g/day
Elliott S et al. Am J Clin Nutr 2002;76:911-922
Artificial Sweeteners
• Consumption of low-cal “diet” foods can lead
people to overeat high calorie foods (people think
they have “headroom” because of the diet food)
• Consumption of sweet-tasting foods devoid of
calories can result in “uncoupling” of normal
responses to ingestion of sugars, e.g. heat-generating
response
– Behav Neurosci 2009;123:772-780. General and
persistent effects of high-intensity sweeteners on body
weight gain and caloric compensation in rats. Swithers
SE, Baker CR, Davidson TL.
Obesity and Endorphins
• Obesity and MetS are accompanied by βendorphinemia
– Int J Obes Relat Metab Disord. 1998 Feb;22(2):143-8.
Relationship between insulin sensitivity, obesity, body fat
distribution and beta-endorphinaemia in obese women.
Percheron C, Colette C, Mariano-Goulart D et al.
– Eur Surg Res. 1998;30(6):409-13. Serum beta-endorphin
levels in morbidly obese patients: the effect of vertical
banded gastroplasty. Karayiannakis AJ, Zbar A, Makri GG
et al.
Endorphins and Sugar
• High endorphin exposure is associated with increased
sugar intake/preference for high-sugar foods
– J Opioid Manag 2010:445-452. The relationship between
opioid and sugar intake: review of evidence and clinical
applications. Mysels DJ, Sullivan MA.
• Sugar indirectly activates and sensitizes brain reward
pathways
– Neuroreport 2001;12:3549-3552. Excessive sugar intake alters binding to
dopamine and mu-opioid receptors in the brain. Colantuoni C et al.
– Anesth Analg. 2005 Jul;101(1):64-8, table of contents. Sugar solution analgesia:
the effects of glucose on expressed mu opioid receptors. Kracke GR, Uthoff KA,
Tobias JD.
Loss of negative feedback on pancreas
Initiating
factor or
factors
↑ circulating endorphins
↑ insulin
↓ mu opiod receptor expression
↓ effect of mu opioids
↑ craving for sweets
↓ pleasure from sweets
Loss of negative feedback
sensitivity for endogenous
opioids
-There is a lot of literature on the role of β-endorphin in regulating the
pancreatic insulin response to glucose
-The pancreas may make its own endorphins for local regulation of insulin
-High endorphin may represent failure of negative feedback
Self Injection
• MetS patients with β-endorphinemia are
self-injecting opioids
• This suggests a way to intervene…
• We’ll get to this in a few slides…
Insulin and Zinc
Insulin Insulin
Insulin-Zn-Zn-Insulin
Insulin is stored
as a hexamer in
the pancreas
Insulin Insulin
• Secretion of insulin cannot take place without
sufficient zinc
– Biochem Biophys Res Commun. 2006 ;351:165-170. Epub 2006 Oct 11.
Oral administration of a zinc complex improves type 2 diabetes and
metabolic syndromes. Adachi Y et al
– Biol Trace Elem Res. 2006;112:109-118. Effect of zinc supplementation
on serum leptin levels and insulin resistance of obese women. Marreiro N
et al.
– Indian J Exp Biol 2006;44:705-718. Long term excessive Znsupplementation promotes metabolic syndrome-X in Wistar rats fed
sucrose and fat rich semisynthetic diet. Taneja SK, Mandal R, Girhotra S.
Insulin and Chromium
Activation by chromium
Insulin
(Ins)
Insulin
receptor
Ins-IR
Cr Ins-IR Cr
(IR)
Complex
Complex
Cr
Cr deficiency:
– more insulin will be required
to deliver the same message
– chromium polynicotinate
1000 ug/drop
– 1-10 drops per meal
Cr
Downstream signalling
more effective with Cr
Vanadium
Insulin
(Ins)
Insulin
receptor
Ins-IR
(IR)
Complex
V
V
Ins-IR
V
Complex
V
Vanadylated insulin signaling complex is slower to
break down  more prolonged signaling
• Vanadium can inhibit some of the anabolic effects of insulin,
such as amino acid uptake and cell growth
– Mol Cell Biochem. 1998 May;182(1-2):109-19. Multifunctional actions
of vanadium compounds on insulin signaling pathways: evidence for
preferential enhancement of metabolic versus mitogenic effects. Fantus
IG, Tsiani E.
• Vanadium is not found in significant amounts in food,
compared to chromium: supplementation with mg amounts of
vanadium may not be a good long term option
Other Contributors to Insulin
Resistance
• “Bad” adipose tissue/inflammation in visceral fat
• Vitamin D deficiency
• Things “getting in the way of insulin”:
– Too much anti-insulin activity
• Loss of muscle mass/thyroid hormone issues
Visceral Fat
“Pinchable” fat
http://www.uchsc.edu/sm/ch
s/research/ctscan_read.html
Obes Res 2003;11:1488-1494. Methods
of estimation of visceral fat: advantages
of ultrasonography. Ribeiro-Filho FF,
Faria AN, Azjen S et al.
Visceral Fat is directly proportional to Waist Circumference
Inflammation and MetS
(Fat is not just a storage depot!)
Adipocytes
Adipokines + FA metabolites
IL-6
ACP
TNFά
PAI-1
Adrenals
VEGF
-steroidogenesis
Vascular tree
-endothelial dysfunction
-hypercoagulability
Brain
-satiety
-appetite
Muscle
J Atheroscler Thromb2010;17:332-341. Adipose tissue,
inflammation and atherosclerosis. Gustafson B.
Am J Biomed Sci 2009;1:133-142. Regulation of Microvascular
Function by Adipose Tissue in Obesity and Type 2 Diabetes:
Evidence of an Adipose-Vascular Loop. Zhang H, Zhang C.
NF kappa B, Obesity and POMC
• Nat Med 2011;17:883-837. Uncoupling the mechanisms of
obesity and hypertension by targeting hypothalamic IKK-β
and NF-κB. Purkayastha S, Zhang G, Cai D.
• NF kappa B pathway drives obesity-related hypertension
in mice
• Inhibition of NF kappa B signaling reversed
hypertension
• Inflammation in hypothalamus interferes with central
appetite regulation
Jane the Cave Dweller
• If Jane doesn’t get outside much, and if she
wears sunscreen when she does, what is her
Vitamin D status?
• Her serum 25-hydroxyvitamin D level is low
(< 25 nmol/L)
• What does Vitamin D have to do with insulin
resistance and MetS?
Vitamin D and Insulin
• Low Vitamin D is associated with MetS in North
American adults
– Horm Metab Res 2011;43:72-74. Low vitamin D levels in Northern American
adults with the metabolic syndrome. Devaraj S et al
• Low Vitamin D is associated with insulin resistance
– Kayaniyil S et al. Association of vitamin D with insulin resistance and beta-cell
dysfunction in subjects at risk for type 2 diabetes. Diabetes Care 2010;33:13791381.
• Vitamin D supplementation improves insulin
sensitivity
– Borissova AM et al. The effect of vitamin D3 on insulin secretion and
peripheral insulin sensitivity in type 2 diabetic patients. Int J Clin Pract
2003;57:258-261.
How much Vitamin D does Jane need?
JANE
The accepted standard to assess Vitamin D is serum 25-hydroxyvitamin D:
– Deficiency: 0-25 nmol/L
– Insufficiency: 25-40 nmol/L
– Sufficiency: 40-100 nmol/L
– Desirable: 75-160 nmol/L (minimum needed for fracture prevention)
– Toxic: >220 nmol/L
We would like to raise Jane’s 25-hydroxyvitamin D level by 100 nmol/L
Long-term intake of 1000 IU/d cholecalciferol (Vitamin D3) will raise serum
25(OH)Vitamin D by 25 nmol/L*
She needs around 4000 IU per day. (4000/1000 x 25)
* Vitamin D supplementation, 25-hydroxyvitamin D concentrations,
and safety. Vieth R. Am J Clin Nutr. 1999 May;69:842-856.
Things “Getting in the Way” of Insulin
JANE
Profession: Teacher
Stress level: High
Stress type: Sandwich stress
Adequate growth hormone/non obese
Ins Ins Ins
GH
C
Epi
Jane has had years of over-secretion
of cortisol and epinephrine due to
stress, lack of sleep and excess
caffeine
As she has gained weight, her GH has
dropped
Overproduction of cortisol and
epinephrine, plus low GH leads to
increased need for insulin
Ins
Ins Ins
Epi
C
Epi
Ins Ins Ins
C
Epi
C
Insufficient growth hormone
Excess cortisol and epinephrine
What is the relationship between
sleep deficit and cortisol?
• Sleep deprivation causes elevated cortisol in the
latter half of the following day
– Elevated bedtime cortisol and sleep deprivation. Spiegel
K, Leproult R, Van Cauter E. Lancet 1999;354:14351439.
Salivary Cortisol
(pg/ml)
Diurnal Salivary Cortisol Profile
12
11
10
9
8
7
6
5
4
3
2
1
0
600
1000
1400
1800
Time (hours)
2200
What is the eventual price of oversecretion of epinephrine?
PNMT
norepinephrine
epinephrine CH3
Cu
CH3
methyl donor
Continual stress  methyl donor depletion
Continual stress  copper depletion
Methyl Donors
O=
SAMe
O=
CH3 – S -- CH3
MSM or dimethylsulfone
Methyl donor precursors:
–
–
–
Folate: green leafy vegetables, legumes, citrus
fruits, berries, nuts
B12 (cyanocobalamin): animal products (milk,
meat, cheese, eggs)
Choline: liver, egg yolks, wheat germ, green leafy
vegetables, cauliflower, cucumber, soybeans,
legumes
Methyl donors:
–
–
MSM: supposedly found in all fresh food
Betaine: legumes, beets, shrimp, fish, wheat germ,
wheat bran, spinach
Betaine
Methyl Donors and Gastric Acid
Histamine
Gastric acid secretion
Methyl donor CH3
CH3
Methylated
Histamine
Does not promote acid secretion
Methyl donor deficiency could lead to prolonged gastric acid output
Acid reflux (“heartburn”) is probably a symptom of methyl donor deficiency
Jane is using up her methyl donors trying to keep up with epinephrine
synthesis in her adrenal glands
MetS and H. Pylori
• Patients with H.Pylori infection had higher
HOMA-IR, higher TG’s, lower HDL compared to
controls
• Eradication of H.Pylori led to improvements in
these parameters whereas failure to eradicate
infection did not lead to improvement
– South Med J 2010 Feb 3. [Epub ahead of print] Effect
of Helicobacter pylori Eradication on Insulin
Resistance, Serum Lipids and Low-Grade
Inflammation. Gen R, Demir M, Ataseven H.
Copper and Vascular Disease
Copper
+
Elastin
Supple
Lysyl oxidase
aorta
Hypertension
Stiff aorta
Menke’s Disease:genetic
disorder involving copper
transport: increased incidence
of aortic aneurysm
Aortic aneurysm
Copper depletion
Hypercholesterolemia*
*Atherosclerosis. 1978 Jan;29(1):81-93. Cholesterolemia and cardiovascular
abnormalities in rats caused by copper deficiency. Allen KG, Klevay LM.
Copper and the Skin
Tanning
Melatonin
Melanin
Hair pigmentation
Epinephrine
Copper and methyl donors
• Synthesis of melanin depends on copper and methyl donors
• Jane doesn’t tan well; she burns
• Jane’s failure to tan and her gray hair might be symptoms that
she is methyl donor and copper deficient
• Her low antioxidant intake is another reason why she doesn’t tan
well (poor protection against free radicals)
Jane’s Aldosterone
Jane’s fluid retention (puffy ankles) and hypertension
suggest she is retaining sodium
Altered fatty acid
metabolites (visceral fat)
Adrenals *
Increased aldosterone
MetS
Increased insulin
Kidneys
remain
insulin
sensitive
Sodium retention
Paradoxical hyperaldosteronemia and sodium retention in the face of
excess sodium intake
Hypertension 2004;43:358-563. * Epoxy-keto derivative of linoleic acid
stimulates aldosterone secretion. Goodfriend TL et al.
Hypertension 2006;48:239-245. Plasma aldosterone is independently associated
with the metabolic syndrome. Bochud M et al.
Work
Heat
Fatty acids
Glucose
Muscle and
Energy Disposal
Skeletal
Skeletal muscle is a significant glucose
and fatty acid “sink”
Muscle
Well muscled individual:
Insulin sensitivity
-High resting consumption of fuel
-Highly insulin sensitive
Jane’s Muscles
Muscle mass
“I’m mushy”
Sarcopenia: loss of muscle
She is telling us she is low on Growth
Hormone
Sarcopenia is also a clue that she isn’t
getting enough T3 in muscle
Cortisol
T3
Skeletal muscle
mitochondria
ATP
Check ferritin !
Iron
Mitochondria with beefier cell
membranes
More electron transport chains
More ATP
Often takes place in target tissue
Most active form of thyroid hormone
Iodine
Deiodinase
T4
Zinc ?
+
T3
ATP
Selenium
Copper
Growth Hormone
Prevents
loss of
muscle
Iron
↑Bromine
↓Iodine
↓Copper
Deiodinase
↓T4 X Cadmium X ↓T3
↓ATP
Mercury
Low protein intake
Low growth hormone
High Cortisol
reverse T3 (inactive)
↓Iron
↓Muscle
Is there a link between T3 and
Insulin Resistance?
Clin Endocrinol (Oxf) 2007;67:265-269. Free triiodothyronine and
thyroid stimulating hormone are directly associated with waist
circumference, independently of insulin resistance, metabolic
parameters and blood pressure in overweight and obese women.
De Pergola G, Ciampolillo A, Paolotti S, Trerotoli P, Giorgino R.
Mutation in skeletal muscle deiodinase has been associated with
degree of insulin resistance in diabetic patients:
J Clin Endocrinol Metab 2005;90:3472-3478. The type 2
deiodinase A/G (Thr92Ala) polymorphism is associated with
decreased enzyme velocity and increased insulin resistance in
patients with type 2 diabetes mellitus. Canani LH, Capp C, Dora
JM et al.
Curr Opin Clin Nutr Metab Care 2010 Aug 4. [Epub ahead of print]
Adipocyte-myocyte crosstalk in skeletal muscle insulin resistance;
is there a role for thyroid hormone? Havekes B, Sauerwein HP.
Is there a link between T3 and
Insulin Resistance?
Clin Endocrinol (Oxf) 2007;67:265-269. Free triiodothyronine
and thyroid stimulating hormone are directly associated with
waist circumference, independently of insulin resistance,
metabolic parameters and blood pressure in overweight and
obese women. De Pergola G, Ciampolillo A, Paolotti S,
Trerotoli P, Giorgino R.
201 euthyroid, apparently healthy women
Serum fT3 in the higher end of the “normal” range is
independently associated with visceral obesity, but not insulin
resistance
High normal serum fT3 does not reflect tissue stores!
Metabolic Issues: Summary
•
•
•
•
•
•
•
•
Growth hormone: low growth hormone
Insulin: hyperinsulinemia, insulin resistance
Failure to manage energy
Inflammation originating in visceral fat
Thyroid axis: poor tissue activity of T3
Mineralocorticoids: hyperaldosteronemia
β-endorphinemia
Vitamin D: insufficiency
Jane’s Mustache
• From her history, we already know Jane has
elevated androgens, but we can measure them
just to check
–
–
–
–
Salivary Testosterone 63 pg/ml (15-45 pg/ml) : Hi
Salivary DHEAS 18 ng/ml (2-11 ng/ml) : Hi
Salivary estradiol 15 pg/ml (1-9 pg/ml) : Hi
Salivary progesterone 22 pg/ml (50-250 pg/ml) : Low
• What’s going on?
High insulin upregulates several key enzymes
in the steroidogenic pathways in the ovaries
and adrenals
Abnormal fatty
acid metabolites
With high insulin, progesterone is diverted to androstenedione and pregnenolone
is diverted to DHEA. The net result is increased DHEA and androstenedione
(leading to higher testosterone and estradiol)
Insulin enhances the
response to ACTH
So what if insulin is too
low??
Eur J Endocrinol. 2011 Feb;164(2):197-203. Epub 2010 Nov 8.
Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in
hyperandrogenic women. Tosi F, Negri C, Brun E et al.
Gynecol Endocrinol. 2009 Jul;25(7):423-6. Hyperandrogenism in oligomenorrhoea with minimal or nil 'unwanted hair growth'. Bhattacharya SM.
Women in Groups A and B had fewer than 7 cycles per year
Women in Group B had significant hirsutism
Group C were controls
Group B women had the same fasting insulin, the same SHBG, the same serum
total testo and the same BMI, but much higher hirsutism scores than Group A
Leads to concept of “ovarian hyperandrogenicity” i.e. enough excess androgens
production in ovary to mess up folliculogenesis, but not enough to manifest
systemically (Group A)
Impact of High Insulin in Women
• High DHEAS
• High Testosterone
– These imbalances contribute to Jane’s irritability and
increased facial hair growth
• Low Progesterone
• High Estradiol
– These imbalances contribute to Jane’s symptoms of
estrogen dominance: breast tenderness, fluid retention,
and irritability, as well as heavier menses
PCOS and MetS
• “The majority of patients with PCOS are insulin resistant and PCOS is
characterized by an increased inflammatory state with abdominal
obesity and increased secretion of interleukins, chemokines, and
adipokines. PCOS is therefore associated with an increased risk of the
metabolic syndrome and type 2 diabetes”
• Gynecol Endocrinol 2010;26:281-296. An update on the pathogenesis,
inflammation, and metabolism in hirsutism and polycystic ovary
syndrome. Glintborg D, Andersen M.
Adrenal
gland
DHEA
Increased
adiposity
Why does Jane
have high estradiol?
Adipose
Upregulation of
aromatization
tissue
Increased androgens
Androstenedione
aromatization
Testosterone
Estrone
aromatization
Estradiol
Upregulation of
aromatization
Same story for males:
J Androl 2010;31:155-162.
Estradiol and metabolic
syndrome in older italian men:
The InCHIANTI Study.
Maggio M et al.
pancreas
Estradiol
Potentiates Insulin
E2
Insulin
+
glucose
cell
+
Is high E2 an attempt to
compensate for insulin
resistance?
-Cheng CM et al. Estrogen augments glucose
transporter and IGF1 expression in primate
cerebral cortex. FASEB J 2001;15:907-915.
-Nadal A et al. Rapid insulinotropic effect of 17betaestradiol via a plasma membrane receptor. FASEB
J 1998;12:1341-1348
Zn
B6 deficiency  sluggish detachment of estradiol/receptor complex from
DNA  leads to/may worsen Estrogen Dominance
Estrogen supplementation (including OCP) and high endogenous
estrogens increased need for B6  leads to eventual B6 depletion
Methyl Donors and Estrogens
Estradiol
Estrone
hydroxyestradiols
R-Me
methoxyestradiols
Estrone Sulphate
(E1S)
4-OH estrone
Associated with
breast cancer
hydroxyestrones
R-Me
methoxyestrones
Proper breakdown of estrogens demands an adequate supply of
methyl donors.
Adrenal
gland
DHEA cell
membrane
receptor ?
DHEA
DHT
Am J Physiol Endocrinol Metab 2008;294:E961-968.
Testosterone and DHEA activate the glucose metabolismrelated signaling pathway in skeletal muscle. Sato K et al.
Moves glucose
transporters to
adipocyte cell
surface uptake
DHEA acts like Insulin
High DHEA/S in insulin resistance may be viewed as a compensatory response
(DHEA can increase glucose uptake independent of insulin)
In women with PCOS, higher DHEAS is associated with less insulin resistance:
Fertil Steril 2009;91:1848-1852. Dehydroepiandrosterone sulfate and insulin
resistance in patients with polycystic ovary syndrome. Brennan K, Huang A,
Azziz R.
Strategies to lower androgens in
women with metabolic syndrome
– Decrease insulin (diet, pharmaceuticals)
– Licorice (not DGL!!)
– Armanini D et al. Licorice reduces serum testosterone in healthy women.
Steroids 2004;69:763-764
– Armanini D et al. Treatment of polycystic ovary syndrome with
spironolactone plus licorice. Eur J Obstet Gynecol Reprod Biol
2007;131:61-67.
– Cinnamon extract (acts like thiazolidinediones)
– Progesterone
– Naltrexone
• Fruzzetti F et al. Fertil Steril 2002 May; 77: 936-944. Effect of longterm naltrexone treatment on endocrine profile, clinical features, and
insulin sensitivity in obese women with polycystic ovary syndrome.
AUC after OGTT
Insulin AUC
Plasma insulin
OGTT
Plasma
Curr Pharm Des. 2006;12(8):1001-12. Role of opioid antagonists in the
treatment of women with glucoregulation abnormalities. Guido M,
Romualdi D, Lanzone A.
Premenopausal PCOS patients given 6 weeks of naltrexone (50 mg orally qd)
Fertil Steril. 2004 Apr;81(4):1047-54.Use of naltrexone in postmenopausal
women with exaggerated insulin secretion: a pilot study. Cucinelli F, Soranna
L, Perri C et al.
-41 postmenopausal women age 47-57
-Segregated into normoinsulinemic and hyperinsulinemic groups after OGTT
-Randomization to naltrexone (50 mg/d oral x 5 weeks) or placebo was then
done, resulting in 4 equal study groups
↑ Insulin
Adrenals and
ovaries
Naltrexone
Increased hepatic
extraction of insulin
-Naltrexone lowers insulin by increasing
the hepatic extraction rate of insulin
-Lowered circulating insulin decreases
the effect on androgen synthesis
-Naltrexone did not decrease the
pancreatic synthesis of insulin in the
foregoing study
↑ Androgens
Naltrexone treatment may also
serve to normalize signaling at
various mu opioid receptors e.g.
brain, by upregulating receptor
density
POMC
• Pro-opiomelanocortin
• Neuropeptide which is a precursor for
multiple signaling “daughters” called
Melanocortins
• Pituitary, hypothalamus, skin, hair follicles,
gut, bone marrow
Lipotropins
Liberate stored fat
from adipocytes and
in bone marrow, helps
create hematopoietic
factors
Enkephalins are small
peptides which
replicate part of the
endorphin molecule
They don’t come from
POMC
Melanocyte stimulating hormones:
-appetite
-energy utilization
-blood pressure
-anti-inflammatory
-immunomodulation
-skin and hair pigmentation
-tissue differentiation (bone, cartilage)
Endorphins
-analgesia
-immunomodulation
-sex hormone
regulation via LH
-glucoregulation
POMC
MSH
β-endorphin
Appetite suppression
Satiety
↓ food intake
↓ food intake
• “The melanocortin system, as is now known, is far more
complex than most of us could have imagined in 1997, and,
similarly, the importance of this system for regulating
energy homoeostasis in the general human population is
much greater than we would have predicted. Of the known
factors that can cause human obesity, or protect against it,
the melanocortin system is by far the most significant.”
• Biochem J. 2010 May 27;428(3):305-24. Functions for proopiomelanocortin-derived peptides in obesity and diabetes.
Mountjoy KG.
Estradiol and POMC expression
Estradiol
-Insulin
-Leptin
+
POMC
gene
↑ POMC expression
↑ MSH
+
↑ Appetite suppression
If E2 drops, may be losing a key regulator of appetite and weight control
This may in part explain why ERT results in weight loss if done properly
Eur J Pharmacol 2011;660:181-187. The estrogen receptor α colocalizes with
proopiomelanocortin in hypothalamic neurons and binds to a conserved motif present
in the neuron-specific enhancer nPE2. de Souza FS, Nasif S, López-Leal R et al.
Progesterone and Insulin
• Progesterone acts on the pancreatic beta cells to decrease
insulin production
– Progesterone inhibits insulin secretion by a membrane delimited, nongenomic action. Straub SG et al. Biosci Rep 2001;21:653-666.
• Patients in Helene Leonetti’s study of progesterone cream and
vasomotor symptoms who had high triglycerides (TG) at
inception, had lower TG after one year of Pg cream, 20 mg
qd.
• There are widespread, but anecdotal reports of improvement
in PCOS with topical progesterone (lower androgens,
resumption of regular menses)
• Bottom line:
– progesterone appears to ameliorate problems associated with increased
insulin
– In reasonable doses, there is no evidence that progesterone causes or
worsens insulin resistance
Why does Jane have increased
aromatase activity?
Androgens
Cortisol
-
Aromatase
Adipose tissue
Enzyme
DNA
Adipose
tissue
Estrogens
Pg*
*Schmidt M, Renner C,
Loffler G. J Endocrinol
1998;158:401-407
(1) Cortisol trapping in visceral fat
(2) Low progesterone
(3) Zinc deficiency
Obesity and Cortisol
• Must distinguish between what we can measure
and what we can’t measure
• Obese people don’t have high serum or salivary
cortisol. (They have high 24 hour urinary cortisol.)
Morning Cortisol
(ng/mL)
Salivary First Morning Cortisol vs Waist Circumference
10
9
8
7
6
5
4
3
2
1
0
y = -0.0201x + 8.0658
R2 = 0.4708
60
70
80
90
100
Waist Circumference (cM)
110
120
We have to look at what
is going on with cortisol
in places we can’t
directly measure
What is Cortisol Trapping?
Cortisone
(inactive)
Many fresh hits on
PubMed for this
enzyme
Cortisol
(active)
11 βHSD Type 1
GH/IGF-1
+
TNFα
Obese
Lean
Cortisone
Cortisol
Cortisone
Cortisol
↓11 βHSD1
High GH
↑11 βHSD1
Low GH
Low TNFα
High TNFα
Serotonin Depletion &
Cortisol Trapping
Ann N Y Acad Sci 2010;1199:1-14. Metabolic syndrome,
age-associated neuroendocrine disorders, and
dysregulation of tryptophan-kynurenine metabolism.
Oxenkrug GF.
Pro-inflammatory cytokines
+
Carbohydrate
Ingestion
+
Hepatic TP
Tryptophan
TP: tryptophan pyrolase
↑Kynurenine
+
Serotonin
Blood
glucose
Stress
Depletion
Failure of
appetite
suppression
GH Suppression
Cortisol
More cortisol trapping due to low GH
Increased visceral fat
Metabolism 1995;44(2 Suppl 2):38-41. Neuroendocrine abnormalities in human obesity. Björntorp P.
Tryptophan and Niacinamide (B3)
B3
Tryptophan
TP
Kynurenine
B3 supplementation
5 HTP
Tryptophan
5 HTP
X
Serotonin
TP
Kynurenine
B3 supplementation “steers” tryptophan
toward serotonin and away from
kynurenine
Serotonin
SHBG and MetS
• Low SHBG has been shown to be predictive of
MetS in women and men
– Arch Intern Med. 2008 Jul 28;168(14):1568-75.
Menopause and the metabolic syndrome: the Study of
Women's Health Across the Nation. Janssen I, Powell
LH, Crawford S, Lasley B, Sutton-Tyrrell K.
– Diabetes Care 2004;27:1036-1041. Testosterone and
sex hormone-binding globulin predict the metabolic
syndrome and diabetes in middle-aged men.
Laaksonen DE et al.
SHBG
SHBG
SHBG
Insulin
Ingestion of glucose and
fructose lowers liver synthesis
of SHBG
SHBG
SHBG
Estrogens
Sugar intake
T3
Mol Cell Endocrinol 2010;316:53-59. Sex hormonebinding globulin gene expression in the liver: drugs
and the metabolic syndrome. Pugeat M, Nader N,
Hogeveen K et al.
Regulation of SHBG Synthesis
HNF-4
+
SHBG gene promoter
+
SHBG
HNF-4: Hepatocyte Nuclear Factor-4: ancient, highly structurally-conserved
protein
Is a nuclear receptor found in the gut, liver, kidney, intestines and pancreas
The HNF-4 receptor is sensitive to the metabolic state of the liver, in particular,
the fatty acids and it is also sensitive to T3, Vitamin D, progesterone, bile acids,
vitamin E, and xenobiotics
Key regulator of growth and development tied to the availability of energy
HNF-4
-
SHBG gene promoter
-
SHBG
Palmitate
16 carbon fatty acid
Excess glucose and fructose intake
Excess glucose and fructose have a suppressive effect on SHBG which occurs
independent of insulin
SHBG is sensitive to the metabolic disruption in fatty acids caused by overload
with simple sugars especially fructose
SHBG is also sensitive to genetic factors involving fatty acid metabolism which
might predispose to the development of MetS
* This is probably why low SHBG is a long lead time marker for risk of MetS *
J Clin Invest. 2007 Dec;117(12):3979-87. Monosaccharide-induced
lipogenesis regulates the human hepatic sex hormone-binding
globulin gene. Selva DM, Hogeveen KN, Innis SM, Hammond GL.
Ways to Raise SHBG
–
–
–
–
–
–
–
–
–
Weight loss
Restrict simple sugar intake
Low/modest saturated fat intake
Increased exercise/weight training
Increased fibre intake ? (probably indirect effect)
Linoleic acid
Isoflavones
Green tea extract
Thyroid hormone supplementation/measures to improve
tissue levels of T3
– Testosterone/Estrogen supplementation
– PPAR gamma agonists
• N-3 fatty acids, cinnamon extracts, thiazolidinediones
Jane’s risk of Breast Cancer
• High insulin
• High bedtime cortisol
• There is increasing evidence that hyperinsulinemia is associated
with increased risk of cancer (e.g. breast and prostate cancer)
• Cancer cells can only burn glucose; cancer cells are therefore
heavily armed with insulin receptors
High bedtime cortisol
suppresses melatonin
Decreased melatonin is
associated with increased risk
of breast cancer
Salivary Cortisol
(ng/ml)
Jane's Salivary Cortisol Profile
20
18
16
14
12
10
8
6
4
2
0
600
1000
1400
1800
Time (hours)
2200
Jane’s risk of Breast Cancer
• Iodine/seaweed
– Asia Pac J Clin Nutr 2009;18:145-154. Could dietary seaweed reverse
the metabolic syndrome? Teas J, Baldeón ME, Chiriboga DE, Davis JR,
Sarriés AJ, Braverman LE.
– J Nutr. 2009;139:939-944. Dietary seaweed modifies estrogen and
phytoestrogen metabolism in healthy postmenopausal women. Teas J,
Hurley TG, Hebert J et al.
• Epidemiologic studies and animal models indicate that iodine is protective
against breast cancer
• Iodine is involved in regulating the cell cycle (antiproliferation, apoptosis)
–
Prostaglandins Other Lipid Mediat. 2009;89:34-42. A complex between 6-iodolactone and the peroxisome proliferatoractivated receptor type gamma may mediate the antineoplastic effect of iodine in mammary cancer. Nuñez-Anita RE et
al.
• Iodine also upregulates p450 enzymes involved in estrogen metabolism and
may increase 2-OH estrone
Things to do for High Bedtime
Cortisol
• Phosphatidyl serine, theanine, melatonin, low dose
metformin, progesterone, Holy basil
• Some practitioners report success with:
– a protein/complex carbohydrate snack at bedtime
– low glycemic index foods during the day
– protein snacks between meals
• Adrenal support might also be indicated
Hormone Patterns in Metabolic Syndrome
↓ SHBG
↓ GH
IGF-1: ↓ , normal or ↑
↑ serum fT3 ?low in skeletal muscle
↑ Cortisol in abdominal fat
↓ Vitamin D
↑ Aldosterone
↑ β endorphins
WOMEN
MEN
•
•
•
•
•
•
↑ T (not always)
↑ DHEAS (as inflammation gets out of
control, this may decrease DHEAS)
↑ E2, ↓Pg
¥ Eur
↓Testosterone
↑ DHEAS ¥ (associated with fatty liver*)
↑ E2
J Clin Invest 2009 Dec 30. [Epub ahead of print] Elevated serum
dehydroepiandrosterone sulphate level correlates with increased risk for metabolic
syndrome in the elderly men. Chen YC et al.
* Int J Androl 2009 Feb 10. [Epub ahead of print] Hepatic steatosis is associated with
low serum testosterone and high serum DHEAS levels in men. Völzke H et al.
Hormonal Do’s and Don’ts
• Don’t throw estradiol at female patients just because they
have hot flashes
• Do try progesterone (progesterone alleviates VM
symptoms)
– Obstet Gynecol 1999 Aug;94:225-228. Transdermal progesterone
cream for vasomotor symptoms and postmenopausal bone loss.
Leonetti HB, Longo S, Anasti JN.
• Don’t throw testosterone at women just because they have
low libido (many of them already have high testosterone)
• Do try testosterone supplementation in men with low
testosterone, but will need to block aromatase if they have
excessive fat accumulation
Hormonal Do’s and Don’ts
• Consider T3 supplementation/measures to
promote T3 formation
• Work on increasing growth hormone
secretion by natural means
• GH therapy is not a panacea for obesity, and
not all obese people are low on GH
• Fix cortisol if abnormal day curve
• Treat obesity as an inflammatory illness
Testing
• Insulin-glucose axis:
– HOMA-IR
•
•
•
•
•
•
•
Sex hormones (saliva, serum, urine)
SHBG
Salivary Cortisol 4 point profile
Thyroid hormone status
25-hydroxy Vitamin D
Fasting amino acids
Nutritional analysis:
– Elements: Zn, Cr, Mg, I, Br, Hg, Cd, Se
– Other metabolic analysis
Live Long and Prosper:
How to Avoid Metabolic Syndrome
• Choose good parents
• Avoid being born prematurely
• Eat a low glycemic index/low glycemic load diet, and a
high fibre diet
• Don’t eat high fructose corn syrup or excessive amounts of
sugary fruits (bananas, melons)
• Have a moderate intake of saturated fats and LA, eat fish
and ω-9 fats (olive oil, almonds, avocados)
• Eat an antioxidant-rich diet (highly coloured foods)
• Eat methyl donors/supplement with methyl donors
• Limit sodium intake; eat lots of potassium
• Optimize tissue conversion of T4 to T3
– Iodine, Se, Zn
– Address heavy metal intoxication
Live Long and Prosper:
How to Avoid Metabolic Syndrome
• Limit aromatization if indicated (Zn, Pg, pharmaceuticals)
• Increase estrogen excretion where indicated (Ca-D glucarate, fibre
intake)
• De-stress your lifestyle (decrease cortisol and epinephrine)
• Get lots of sleep
• Get enough sun/supplement with Vitamin D
• Boost endogenous GH : sleep, exercise, eating habits
Mark Sisson
My Blog: www.MarksDailyApple.com
My Book: www.PrimalBlueprint.com
My Store: www.PrimalNutrition.com
Connect with me on:
Twitter: http://twitter.com/Mark_Sisson
Facebook: http://www.facebook.com/mark.sisson1
Closing Remarks
• All the common sense stuff that our species worked
out over the eons now makes sense from a
biochemical standpoint
• If you don’t identify metabolic syndrome patients up
front, you will never get very far with basic HRT
• Practice what you preach
• Don’t blame the patient
• Everything is related to everything else
“It’s amazing that any of us
are even alive.”
Davis Lamson MSc ND