Transcript The Skinny on Low-Carbohydrate Diets

The Skinny on
Low-Carbohydrate Diets
Wendy Knapp Pogozelski
SUNY Geneseo
September, 2009
How I got interested in
carbohydrate restriction
1. Invitation from hospital to speak: “all the doctors
here are on Atkins”…
2. Information for my undergraduates
led to a paper, involvement w/Nutrition and
Metabolism Society
Just SOME of what
Biochem
students have to
learn…
(…and what professors
have to make sound
interesting)
Low-carb Diets Abound
U.S.
France
Germany
Australia
U.K.
Russia
Why the Issue is Important
1. Type 2 Diabetes Epidemic
http://www.sanger.ac.uk/Teams/Team35/gfx/graph.png
2. Obesity epidemic, esp.
in children
It’s not just America…
– 37% American children
– 20% European children
– 10% Chinese children
– ↑ in “developing world”
http://www.ehponline.org/docs/2003/111-13/focushead.jpg
(12th European Congress on Obesity, 2003)
Type 2 Diabetes in Children
• 25% of all obese children already have
Type 2 Diabetes.
http://www.iconocast.com/B000000000000162/L3/News1_0.jpg
Diabetes in Animals
• ~1/4 of cats have diabetes
– Can be transient
• Stress-induced (glucocortocoids)
• Drug-induced (steroids)
• Illness-induced
• Also common in horses
Type 2 Diabetes and
Fat Cells
• One Theory:
cross-section of
a blood vessel
• You have all your fat cells by the end of adolescence;
they just get bigger.
• If they get too engorged, they stop responding to insulin.
• The body responds by churning out MORE insulin,
driving MORE fat synthesis.
• Eventually beta cells (where insulin is produced) begin to
wear out, are unable to lower blood sugar.
http://www.proteinpower.com/drmike/wp-content/uploads/2008/05/human-adipose-tissue.jpg
Type 2 Diabetes
• Other Theories:
– Dysregulation of liver enzymes (1-GP ↔6-GP)
– Cytokines (chemicals secreted) by fat cells
cause inflammation
Early Low-Carb Diet Advocates
William Banting
1862: -5’5” 202 lbs, 61 yrs old
-tried Turkish baths, 2h exercise/d,
fasting
-couldn’t tie shoes, walk down stairs
1863: -advised by Dr. William Harvey
-gave up beer, potatoes, bread
-lost 46 lb/yr
•Self-published pamphlet sold over
100,000 copies in England,
America, France,Germany.
•Medical establishment disapproved
of the Banting-Harvey diet
•Banting died at age 81, maintained
wt loss 19 yrs
“to bant” = to diet
http://www.proteinpower.com/drmike/wp-content/uploads/
2007/08/banting-cover-blog-size.jpg
Dr. Robert Atkins
http://rjr10036.typepad.com/.shared/image.html?
/photos/uncategorized/dratkins_youngman_300x330.jpg
• Studied low-carb diet used to control
seizures patients lost weight.
• Experimented on himself, published book
in 1972.
• Reissued, repopularized in ’80’s, ’90’s
Warning: The Subject of LowCarb Diets is Very Polarizing
Resistance to new ideas?
Cultural implications?
Ethical implications?
Lack of distinction between dieting vs. long-term eating plans?
Argument over what is “best”? Reluctance to examine the science?
Reluctance to let go of notions of “balance”?
Individual differences? Personal experience vs. double-blind studies?
What is a Carbohydrate?
– molecule made of glucose (sugar) units
Glucose
www.umanitoba.ca/.../lab2/biolab2_2.html
Starch vs. Sugar
• In plants, glucoses link
together to form starch
(a polysacchardide)
starch
• Table sugar (sucrose)
is a disaccharide of
glucose and fructose.
• Both are broken down
to Glucose
pslc.ws/macrog/kidsmac/starch.htm
Glycogen
• In animals (in muscle and liver), glucose
links together to form glycogen.
http://www.emc.maricopa.edu/faculty/farabee/BIOBK/1glycogen.gif
Glycogen is used for temporary energy storage of glucose.
Carbs are Digested to Glucose
• Glucose enters cells to be
converted to ATP for
energy.
– Insulin required for entry!
• Excess glucose is
converted to glycogen + fat.
http://www.sugar.ca/english/images/tradealliances/stomach.jpg
Glucose Stimulates Insulin
• Glucose doesn’t enter cells on its own.
• Glucose enters via the glucose receptor
protein embedded in cell membranes.
• Insulin “unlocks the gate” (binds to and
opens the receptor) to let glucose into the
cell.
glucose
Insulin +
Receptor
cell
Insulin unlocks the gate (GLUT) of
cells to let glucose enter.
www.answers.com/topic/insulin
http://themedicalbiochemistrypage.org/insulin.html
http://themedicalbiochemistrypage.org/insulin.html
Insulin also promotes fat
storage.
• Insulin leads to activation of fatty acid synthase
(makes fat) and glycogen synthase (makes
glycogen for short-term storage of energy).
• Insulin leads to inactivation of hormone-sensitive
lipase (breaks down fat) and glycogen
phosphorylase (breaks down glycogen).
• Insulin also leads to production of cholesterol
(activates HMG-CoA reductase).
Insulin release is related to the rate at which
glucose enters the bloodstream.
Faster glucose release
 More insulin
 Fat storage activated
 Fat breakdown inhibited
Thus, greater insulin release when:
high carbs (amount)
high concentration
due to fast-release carbs
(simple carbs
or no protein/fat
to slow the entry of glucose
into the bloodstream
What Foods Contain Carbohydrates?
• Grains, root vegetables,
fruits, beans are rich in
starch (polysaccharides).
• Milk contains disaccharide.
http://www.replica.co.uk/images/specials/bread.jpg
– Lactose: disaccharide of
galactose and glucose.
• Most other vegetables are low in
carbs.
• Meat, fat, cheese, cream ~none.
http://rjr10036.typepad.com/.shared/image.html?/photos/uncategorized/vege.jpg
Relationship of Metabolic
Syndrome and Type 2 Diabetes
• Metabolic Syndrome
– Cluster of diseases characterized by 3 or
more of the following
• Insulin resistance
– High fasting blood sugar
– Can lead to type 2 diabetes
• Abdominal obesity
• High blood pressure
• High triglycerides
– Can lead to Cardiovascular disease
Prevalence of Metabolic Syndrome
• 47 million in U.S. (2000)
• Among obese kids, 25%
Abdominal Obesity
• Men: waist > 40 in
• Women: waist > 35 in
• Visceral fat around the middle increase
inflammation markers
• > 50% of U.S. adults over 60 are
abdominally obese.
Waist size predictor
• Recent study: waist size predicted death
from stroke or heart attack better than any
other indicator (including smoking + LDL
cholesterol)
• Every 2-in increase in waist circumference
increased risk of dying from heart attack
by as much as 17%
http://blogs.mercola.com/ImageServer/public/2007/07--july/7.12triglycerides.jpg
Triglycerides
(fats)
• 150 mg/dl or higher
considered risky
• Known to increase
on low-fat, high-carb diets
• YET a low-fat, high-carb diet is
recommended by the ADA and AHA.
• What the heck???????
HDL cholesterol
• the “good cholesterol” – lipoprotein that carries
cholesterol back to the liver for degradation or
recycling.
• Want HDL to be high
– Men: HDL > 40 mg/dL
– Women: HDL > 50 mg/dL
• Government and agency-recommended low-fat,
high-carb regimens LOWER HDL.
• Low-carb regimens RAISE HDL (if not too low in
fat)
http://www.ks.uiuc.edu/Gallery/Science/Structure/discoidalHDL_st.jpg
Metabolic Syndrome Can Be
Improved by Weight Loss
• Low-fat methods work
• Low-carbohydrate methods work
BUT, low-carb diets improve CVD
profiles, improve glycemic control
• Carb restriction
– Less insulin produced  less fat storage, less
hunger, less LDL cholesterol
– HDL increases
– Less glucose release so less taxing an
overtaxed pancreas  glycemic control
improves
– Reverses Metabolic Syndrome!!
• “Carbohydrate restriction is one of several
strategies for reducing body mass but even in
the absence of weight loss or in comparison with
low fat alternatives, CHO restriction is effective
at ameliorating high fasting glucose and insulin,
high plasma triglycerides, low HDL and high
blood pressure. In addition, low fat, high CHO
diets have long been known to raise TAG, lower
HDL and, in the absence of weight loss, may
worse glycemic control.”
Volek, J., Feinman, R. “Carbohydrate restriction improves the features of
Metabolic Syndrome”, Nutrition and Metabolism, 2005.
Why Restrict
Carbohydrates?
http://rjr10036.typepad.com/.shared/image.html?/photos/uncategorized/09_gallery_ornish.jpg
• Rate of glucose release into bloodstream
dictates release of insulin.
• Insulin activates fat storage pathways.
• Insulin inhibits fat breakdown pathways.
– Hyperinsulinemias lead to obesity.
• These pathways reversed by glucagon
(secreted when glucose levels are low).
Atkins Diet
• Replace carbs with protein, fat.
• No bread, pasta, fruit or starchy vegetables
for 2 wks. (“induction”).
• Include cream, butter, red meat.
• Gradually reintroduce carbs as long as wt loss
maintained.
Where Low-carb Diets Differ
• Ketogenic (Atkins) vs. Non-ketogenic (South
Beach)
• Ketogenic - < 20 g carbs/day on induction
– (Most Americans ~ 300 g carbs/day)
– Advantage : fats break down incompletely into
“ketone bodies”
• Loss of efficiency!
• Some ketones used as fuel, others released via breath and
urine
• Fats metabolized faster than usual.
•In ketosis, intermediates (oxaloacetate, etc.) of Krebs’/citric acid cycle are
used for gluconeogenesis (making glucose for the brain).
Insufficient oxaloacetate to condense with Acetyl CoA.
•Acetyl CoA is diverted to ketone formation rather than going through
CAC and being completely oxidized.
Metabolic Changes in Ketosis
• Metabolites normally used for energy are
diverted to glucose-making pathway for
the brain.
• Fat stores break down more rapidly to
meet energy needs.
Calories in, calories out?
• Law of Conservation of Energy still holds.
• But ketosis is less efficient, so weight
loss is faster.
• The composition of the diet does matter.
Advantages and Disadvantages of
Ketosis/Carb Deprivation
•
•
•
•
•
Fat loss is faster, motivating
Eventually, greater energy, improved sleep.
Less hunger (no insulin-mediated swings).
Some people enjoy eating protein, fat.
Most see blood sugar improvements, HDL/LDL
improvements, triglyceride improvements.
• Requires adaptation (3 days – 2 wks).
• Lack of fiber in diet, even for short term.
• Effect of hormones if meat consumption
increases?
• Compliance?
Ketone strips
-Detect ketones in urine
-- Fe(CN)3, turns pink/purple upon reaction with acetoacetate
Low-fat vs. Low-carb
• Both low-fat and low-carb diets lower LDLs, triglycerides, reduce
weight.
• However, low-carb diets show significantly more improvement in
blood sugar, LDLs, HDLs, esp for diabetics.
• Low-fat considered safe in long term, advocated by “establishment”
(AMA, AHA).
• Low-carb advocated by many physicians and researchers (Drs.
Michael and Mary Eades, Dr. Richard Bernstein, Dr. Jeff Volek, Dr.
Eric Westmann, Dr. Mary Vernon)
• I don’t advocate one approach; eating/dieting decisions best made
by individuals in consultation with physicians.
Insulin and Diabetes
• Type 1: Insufficient insulin secreted.
-autoimmune attack on pancreatic cells
• Type 2: Insulin resistance
– Cell receptors don’t respond to insulin, more insulin
gets churned out  obesity
– Insulin-producing cells may become exhausted.
– Former aging disorder, now being seen in overweight
children.
Low-carb Diet Fallout
• …should anything unfortunate happen to you--"even
moles in [your] front lawn," as the New York physician
Blake Donaldson, an early proponent of carbohydraterestricted diets, noted in his 1961 memoirs--everyone will
blame it on your diet.
• This past winter, I was anxious (as I will be next winter)
that I would slip on an icy sidewalk, as Dr. Robert Atkins
did, and crack my head open, thus prompting some
chortling among critics and book reviewers that my fall
was actually the result of a fat-induced coronary.
-Gary Taubes in Prevention magazine
http://www.prevention.com/cda/article/diary-of-a-carb-phobe
/d69f12b73d8e8110VgnVCM10000013281eac____/news.voices/in.the.magazine/may.2008.issue/0/0/2
A “Healthy” Low-fat Lunch for
Elementary School Children
Columbia Public Schools, Missouri
789 calories, 23g protein, 21 g fat (24%)
127g carbohydrate, or the equivalent of
32 teaspoons of sugar.
Thanks to Regina Wiltsire,
http://weightoftheevidence.wordpress.com/
http://www.columbia.k12.mo.us/food/nutrinfo.php
• Since the U.S. government began pushing
low-fat diets in 1977, we have witnessed
significant increases in consumption of
grain products and sugars, significant
increases in obesity and type 2 diabetes,
and no decrease in heart disease. It
questioned whether all this was
coincidence or cause and effect.
Two Studies from the Primary
Literature about Carbohydrate
Restriction
1. Effect of a Low–Glycemic Index or a High–Cereal Fiber
Diet on Type 2 Diabetes
A Randomized Trial
David J. A. Jenkins, MD; Cyril W. C. Kendall, PhD; Gail McKeown-Eyssen, PhD; Robert G. Josse, MB,
BS; Jay Silverberg, MD; Gillian L. Booth, MD; Edward Vidgen, BSc; Andrea R. Josse, MSc; Tri H.
Nguyen, MSc; Sorcha Corrigan, BSc; Monica S. Banach, BSc; Sophie Ares, MA, RD, CDE; Sandy
Mitchell, BASc, RD; Azadeh Emam, MSc; Livia S. A. Augustin, MSc; Tina L. Parker, BASc, RD; Lawrence
A. Leiter, MD
JAMA. 2008;300(23):2742-2753.
210 patients with type 2 diabeteswere randomly assigned to receive a
high-fiber diet or a low-GI diet for 6 months. The low-GI group ate
lower-GI carbs while keeping their overall carb intake the same as that
of the high-fiber group.
“Lowering the glycemic index of the diet
improved glycemic control and risk
factors for coronary heart disease (CHD).
“
2. The effect of a low-carbohydrate, ketogenic
diet versus a low-glycemic index diet on
glycemic control in type 2 diabetes mellitus
Eric C Westman , William S Yancy Jr., John C Mavropoulos, Megan Marquart and
Jennifer R McDuffie
Nutrition & Metabolism 2008, 5:36
Dec 2008
doi:10.1186/1743-7075-5-36
84 subjects with with obesity and type 2 diabetes were randomized to
either a low carbohydrate ketogenic diet (less than 20 g carbs/day) or a
low-glycemic, reduced calorie diet (500 calories/day) for 6 months. Both
groups attended group meetings, had nutritional supplementation and
an exercise regimen.
The volunteers in the low-carb diet group had greater
improvements in hemoglobin A1C and diabetes
medications were reduced or eliminated in 95 percent of the
volunteers, compared to 62 percent in the low-glycemic
group. The low carb diet also resulted in a greater reduction
in weight.
Comparison of the JAMA Results
and the Nutrition & Metabolism
Results
Thanks to Michael Eades, M.D. for graphing the results from these two studi
Thanks to Michael Eades, M.D. for graphing the results from these two studi
Thanks to Michael Eades, M.D. for graphing the results from these two studi
Thanks to Michael Eades, M.D. for graphing the results from these two studi
Thanks to Michael Eades, M.D. for graphing the results from these two studi
Thanks to Michael Eades, M.D. for graphing the results from these two studi
Thanks to Michael Eades, M.D. for graphing the results from these two studi
Reductions in Insulin use
Lectins
• Proteins that bind to cellular receptors
• Lectins in food are sometimes not broken
down into amino acids, can cause
problems if they are absorbed into
circulation.
Wheat Germ Agglutinin (WGA)
•
•
•
•
Can bind to insulin receptors
Can STAY bound to insulin receptors
Activates part of the insulin signaling chain
Can block leptin receptors
From Dr. Weill’s Website
How Dr. Weil Eats
Your diet, and dietary recommendations, have evolved over time, can you take us through that?
When I was a child, I ate a fairly standard American diet, which is to say, a bad one. When I was out of the house and on my own, I became a vegetarian for
many years. Then, based on my research, I decided to add fish to my diet in 1984. Now, I follow my anti-inflammatory diet quite closely.
A common critique one hears among the public at large is that, "even the experts can't agree on what's healthy." Do you think that's true?
No, I don't. Every year, in conjunction with the Columbia University College of Physicians and Surgeons, the Program in Integrative Medicine at the University
of Arizona sponsors one of the leading conferences on science and nutrition. The top nutrition scientists from all over the world come to it. I am always
heartened by the fact that there is now widespread consensus among them on what constitutes the most healthy diet. For example, there is universal
agreement that high fructose corn syrup, white flour, white sugar and hydrogenated fats have no place in any diet. And there is near-universal agreement that
a diet should be rich in vegetables and fruits and quality sources of protein, especially fish. I think there is also consensus that supplementation to cover
nutritional gaps in the diet makes sense for most people.
On the Larry King show, you recently defended Gary Taubes, the science writer who questions the value of low-fat diets, and who says saturated
fats have gotten a bum rap. Is this a change in your views?
No, I have said this in my books. I have never felt that saturated fat was as bad as it is made out to be, if it is eaten in the context of a diet that includes mostly
monounsaturated fats, plenty of omega 3 fatty acids, and plenty of antioxidants. With regard to saturated fat, I tell people that you can have some saturated
fat in your diet; just think about where you want to spend your saturated fat budget. I choose to spend mine on quality cheese.
So what ideas have you changed?
I think there is more of a change in my thinking about carbohydrates. In the past five or six years, there has been a real explosion of quality research into the
glycemic load and its effect on weight gain and insulin sensitivity.
And are you using this insight personally? You were on the Martha Stewart show recently, and she was quite effusive about how good you looked.
Yes, I think I am quite sensitive to high-glycemic-load carbohydrates. Most of the processed, refined, manufactured foods are the ones that are quick
digesting and problematical. Cutting back on them has helped me get my weight down, because my metabolism is certainly carbohydrate sensitive.
http://www.drweil.co
m
Insulin
• Most potent anabolic hormone known
– (stimulates anabolic processes such as protein, glycogen and fat
synthesis)
• Elicits multiple responses by binding to the insulin receptor
• Stimulates pathways to regulate growth, differentiation and
metabolism
• Maintains glucose homeostasis by stimulating uptake, utilization and
storage of glucose in muscle and adipose tissue
• Also stimulates the uptake of amino acids
GLUT-4
• One of a family of glucose-transporter
proteins
• The only one specifically to promote
glucose uptake in insulin-sensitive cells
(muscle, fat)
• In response to insulin, translocates from
intracellular vesicles to the plasma
membrane
How Insulin Stimulates GLUT-4
Translocation to the Membrane
• Insulin binds to the tyrosine kinase receptor
• Activated tyrosine kinase receptor undergoes
autophosphorylation, catalyzes the
phosphorylation of several substrates such as
the insulin-receptor substrate (IRS-1) protein,
which activates downstream components to
result in translocation of GLUT4
Glucagon
•
•
•
•
•
Also a hormone
Has opposite effect of glucose
Causes release of glucose from glycogen
Stimulates gluconeogenesis
Stimulates fat mobilization
Does a VLCarb Diet result in loss
of muscle mass?
• Protein needed for gluconeogenesis
• BUT, liver makes ketones (which it can’t
use), so ketones flow to extra-hepatic
tissues (brain, muscle) for fuel
• Ketones displace glucose utilization by the
brain, thus sparing muscle mass.
•  The brain derives energy from stored
fat via ketosis
How to glycolytic tissues fare on a
vlc diet?
• Glycolytic tissues = red blood cells, renal
medulla (lack mitochondria, rely on
glucolysis)
• They need some glucose, (can’t use
ketones), but produce lactate that goes to
the liver to be reconverted to glucose (the
Cori Cycle)
When carbs are restricted, glucose
comes from protein (and glycerol)
Why Ketosis in Low-Carb Diets ≠
Ketoacidosis in Diabetics
Normally, hyperglycemia (high blood sugar) suppresses
glucagon secretion.
In most diabetics, there is excessive excretion of
glucagon because it is NOT suppressed by
hyperglycemia.
Levels of ketone bodies differ.
Confusion
•
•
•
•
•
•
What is “bad” cholesterol?
What is “good” cholesterol?
Are triglycerides bad?
What are LDLs?
What are HDLs?
What are vLDLs?
Terminology
• Lipids
– Fat-soluble molecules like fat and cholesterol
• Most fat is in the form of triacylglycerol
(triglyceride/triacylglyceride)
– 3 carboxylic acids with long hydrocarbon
chains (fatty acids) + glycerol backbone
Problem: Fats and cholesterol are
not water-soluble
• Won’t they clog your veins and arteries
like grease in the sink?
Lipids are carried in the blood by
lipoproteins
• Lipoproteins wrap the lipid in a protein
coat
– The protein is water-soluble  problem
solved
– The protein allows the lipid to bind to specific
receptors on the outside of cells, so they can
perform different functions, depending on
receptor binding
Chylomicrons and vLDLs are the
lipoproteins that carry most fats
• Chylomicrons: made in intestine for packaging up fatty acids and
cholesterol.
• Transported through lymphatic system
• Released to bloodstream via thoracic duct
• Bind to cells that grab the fat or cholesterol
• Fat used for energy
• Rather short-lived
– The liver vacuums up chylomicron remains and repackages them with
any lipids left over as very-low-density lipoproteins (vLDLs)
• vLDLs – protein + initially rejected fat – repackaged by the liver
• vLDLs return to blood  bind to receptors  cells can again strip
away the fat, use it for energy
• vLDLs also carry fat created by the liver from excess glucose
HDL vs. LDL
• Differ in the protein
• LDLs bind to cell receptors that allow the
cells to extract cholesterol
• HDLs bind to cell receptors that allow
them to take away “used” cholesterol for
recycling in the liver (when cells die, etc.)
Fats carried by lipoproteins are
released by lipoprotein lipase (LPL).
• TAGs are too large to go across cell
membrane
• So lipoprotein lipase hydrolyzes the bond
between the glycerol and the fatty acids,
releasing free fatty acids that cross the cell
membrane.
• Lipoprotein lipases (LPL) regulated by
insulin
Fat Cells remake TAGs
• Cells don’t store free FA, they store TAGs
• Glycerol can’t cross the cell membrane
though, so cells make alpha glycerol
phosphate (precursor to glycerol
backbone) from glucose.
• NOTE: the higher the glucose availability,
the greater the likelihood of TAGs being
made.
Review
• Fat storage requires two things:
– Lipoprotein lipase action on chylomicrons or
vLDLs to free the fatty acids
– Availability of glucose to make the glycerol
backbone of storage TAGs
How are these controlled? BY INSULIN
Insulin is the primary control mechanism for
LPL activity and glucose transport
• More insulin  more LPL activated
• More insulin more glucose in fat cells
• One more component:
– Hormone-sensitive lipase (HSL) inside fat
cells
• Frees the fatty acids from TAGs so they can reenter the bloodstream (carried by albumin)
• More insulin  LESS active HSL
• More insulin  LESS stored fat is broken down
Insulin favors fat storage
• Increased availability of glucose for
glycerol synthesis
• Increased activity of Lipoprotein lipase
(LPL)
• Decreased activity of Hormone-sensitive
lipase (HSL)
Insulin is released in proportion to the rate at
which glucose enters the bloodstream
• Pure glucose  greatest insulin response
– (Refined carbs)
• Starch + protein, fat, fiber  less insulin
response.
– However, there is not THAT much difference
between white bread and “wheat” bread
– AND, total carbohydrate intake is important,
not just whether the carbs are refined or not.
Does Protein Increase Insulin?
• Protein  still raises insulin
• Insulin needed to get cells to open up for
amino acids, etc.
• BUT, protein also causes glucagon to be
released.
• Glucagon action reduces glucose entry
into cells, increases activity of fat-oxidation
enzymes, inhibits fat-storage enzymes
Overconsumption of carbohydrates
drives most obesity
A New Fat Storage Pathway
• Acylation Stimulation Protein (ASP)
ASP
• Also secreted by fat cells
• Can increase LPL activity, making fatty acids available
for transport into fat cells
• Increases the expression of glucose transporters in fat
cells, allowing more glucose to enter cells
• Stimulates production of triglycerides in the fat cells
• Works like insulin but is generated by fat cells, not by
carbohydrate ingestion
• What stimulates ASP?
Chylomicrons have a role in
stimulating ASP
• When fat cells are exposed to
chylomicrons, they generate ASP
– Concentration-dep, time-dep.
• Fat cells DON’T generate ASP in
response to anything else known (glucose,
vLDLs, HDLs, etc.)
Summary
• Eat fat, generate chylomicrons
• Chylomicrons result in ASP secretion
• ASP increases LPL activity so more fatty acids
enter cells
• ASP increases glucose transporters so more
glucose can enter cells
• Even without carbohydrate, fat can be stored.
• BUT, chylomicrons are short-lived, quickly turn
into vLDL that don’t stimulate fat storage.
Why a High-Fat, Low-Carbohydrate
Diet is Not a Starvation Diet
Why People Can Still be Fat on a
Low-Carbohydrate, High-Fat Diet
BUT, the body has other feedback
control mechanisms
Result: ASP can lead to fat
storage, but it is limited.
• Most energy from dietary fat (in the absence of
carbs) leads to fat being USED for energy, not
stored.
• May explain why low-carb diets are sometimes
known to “stall”
• Perhaps may be alleviated with a “fat fast” (but
VERY dangerous)  lean protein “Rabbit
starvation”  conduct only under doctor’s
supervision, short-term
Leptin
• Released when fat cells expand from
storing fat
• Sensitizes the hypothalamus to the effects
of hormones affecting satiety and GI
activity
• When fat cells store fat, they release leptin
that suppresses your appetite
Leptin, cont.
• Leptin probably regulated by insulin in fat
cells
• Gary Taubes: A “downstream effect”, less
important than insulin
– Same probably true for ghrelin, adiponectin,
etc.
• d
Leptin Deficiency
• Knockout mice have huge appetite, become
obese
• Treatment with leptin reverses the effect
• Cushing’s Disease –
– Pituitary tumor that raises hormone cortisol
• Cortisol causes compensatory secretion of insulin
• Cortisol from sympathetic endocrine system, insulin from
opposing parasympathetic endocrine system.
• Patients can eat very little, exercise much, still be obese.
Insulin levels can override leptin
signals
• If glucose dramatically lowered, brain
senses the depletion, overrides leptin,
causes you to be hungry
• If you respond by eating more carbs
Vicious circle
What about studies that contradict
the success of low-carb diets?
• Hirsch and Leibel (then at Rockefeller)
Evidence that Diet Alters Genes
• Homma et al., 2008
• Mice: Group 1 – high-carb, low-fat diet 7 days
Group 2 – low-carb, higher-fat
• Researchers looked at Glucose Transport-1 gene
(encodes the protein GT-1)
– Giving carbs is like turning up the volume in this gene.
The more glucose the mice ingest, the more GT-1
they need, so the more the gene gets a workout.
– The GT-1 gene has histone proteins bound to it.
– Under the high-carb conditions, these histones were
more acetylated.
• d
Diet Can Change Your Genes
• Diet composition isn’t likely to change sequence of
DNA but can change structure. (epigenetic
changes)
• DNA or the proteins that bind to DNA can acquire
or lose chemical tags (such as methyl groups or
acetyl groups)
• Changes can persist and can be passed on.
• Why a mother’s diet during pregnancy can affect
children.
Negative Effects of Low-carb
Diet
• Wang et al. (Steven Lloyd’s lab in
Birmingham)
• Heart glycogen ↓
• ↑ heart injury with ischemia (O2 deprivation)
– With ischemia, heart relies on glycolysis from
glycogen
• However, no ↑ risk of mycardial infarction or
death in women (Halton et al., 2006)
• Low-carb diet associated with many
outcomes considered beneficial for ↓ risk of
CVD (HDLs, TG, etc.)
Positive Effects of Low-carb
Diet
• Weight loss
• TAG ↓ (Foster et al., 2003; Samaha et al
2003)
• HDL ↑
Genes associated with diabetes
• Type 2
– Tenomodulin (TNMD)
• Type 1
What is Diabetes?
• Abnormally high blood sugar
(The sugar is glucose – the primary building block that
enters cells for energy)
– Normal is 80-110 mg/dl (fasting) and up to 140 post-prandial
(after meals)
http://themedicalbiochemistrypage.org/diabetes.html
http://www.fi.edu/learn/heart/healthy/images/large_glucose-insulinsupplies.jpg
Why is High Blood
Sugar a Problem?
• Body tries to dilute the glucose
– Cells become dehydrated,
–  increased thirst, urination
• Glucose gums up proteins
– causes mini-strokes in blood vessels
– Links proteins in eyes  cataracts, etc.
– Hemoglobin (protein that carries oxygen to cells)
hindered
– HbA1c is glycosylated hemoglobin
• Usually ~4-5% is normal
http://knol.google.com/k/anne-peters/type-1diabetes/VxIOS9KU/QWqllQ#
How Many People are
Affected?
•
•
•
•
246 million worldwide
India (40.9 million)
China (39.8 million)
U.S. (19.2 million)
http://cdn.mapquest.com/mqatlasenglish/world
– 18 million are type 2; 1 million are type 1
• Russia (9.6 million)
• Germany (7.4 million).
• Countries with highest prevalence in the adult population:
–
–
–
–
–
Nauru (30.7%)
United Arab Emirates (19.5%)
Saudi Arabia (16.7%),
Bahrain(15.2%)
Kuwait (14.4%).
• Each year an additional 7 million people develop diabetes.
Source: International Diabetes Foundation and Diabetes Statistics in the United States: NID
http://www.idf.org/home/index.cfm?node=37
Statistics for
Age Groups
• In the U.S.:
http://www.ehponline.org/docs/2003/111-13/focushead.jpg
– Age 65+: 18.4 % of all people in this age group
– Age 20-65 years or older: 8.2 %
– Under age 20: 0.16% in 2007 but rising rapidly
– 25% of obese kids are type 2 diabetics
Source: Diabetes Statistics in the United States: NIDDK
Classic Definitions
of Diabetes
• Type 1
– Pancreas makes insufficient insulin
– Can result from autoimmune attack, genetic
defect, trauma
– Treated with insulin
• Type 2
– Cells lose their insulin receptors,
become “insulin-resistant”
– Often due to constant oversecretion
of insulin
- Often mis-regulation by liver
– Often related to obesity and high
levels of carbohydrates in the diet
– Pancreatic cells may become exhausted
– Treated with insulin-sensitizers, beta cell
stimulators, appetite suppressants, insulin
http://www.insightempire.com/diabetes/diabetes1.jpg
http://z.about.com/f/p/440/graphics/images/en/19818.jpg
Type 1.5: Latent Autoimmune
Diabetes in Adults (LADA)
• Diagnosed later in life rather than in
juveniles
• Usually less severe
• Antibodies to GAD65 protein, not islet cells
http://www.phlaunt.com/diabetes/pics/
183820531LADA.gif
MODY: Mature-Onset Diabetes in
the Young
• Genetic form
• Like LADA, usually diagnosed later in life
• Like LADA, pancreas usually makes some
insulin
• Can be an insulin secretion problem
Why is Insulin so Important?
• Glucose doesn’t enter cells on its own.
• Has to go through a “gate” – binds to a
receptor protein that’s in cell membranes
• Insulin “unlocks the gate” (binds to and
opens the receptor) to let glucose into the
cell.
glucose
Insulin +
Receptor
cell
AND, Insulin also…
• stimulates enzymes
that lead to fat
storage +
cholesterol
synthesis
• Inhibits enzymes
that lead to fat
breakdown
More insulin…..more energy storage
(fat)
Less insulin…less energy storage
Insulin drives fat accumulation!
From the following article:
Metabolism: A higher power for insulin
Fiona M. Gribble
Nature 434, 965-966 (21 April 2005)
doi: 10.1038/434965a
Glucose absorbed from the intestine stimulates the release of insulin into the bloodstream, which in turn
inhibits liver glucose production by both a classical direct pathway and a newly identified indirect pathway. The
indirect pathway involves the opening of ATP-sensitive potassium ion channels (KATP channels) in the outer
membranes of neurons in the hypothalamus, resulting in signal transmission to the liver through the vagus
nerve. This contrasts with the concomitant inhibition of KATP channels in pancreatic cells that underlies the
glucose-stimulated release of insulin.
-
Type 2 Diabetes Can Occur When
Cells Lose Ability to “unlock the
gate”
• Inflammation may damage insulin
receptors or fat cells may become
too engorged.
– Cells don’t respond to glucose as well
• Pancreas may at first churn out more
insulin
– Hyperinsulinemia drives MORE fat storage.
• Age/stress on pancreas take a toll.
– (More refined carbs, more insulin needed)
• Lack of exercise can contribute.
– ↑ heart rate, ↑ muscle to help get glucose into cells
http://www.wellnessalternativesstl.com/imagesnew/IR%20receptor%20site.JPG
Human Adipose (Fat) Cells
cross-section of
a blood vessel
• ~All fat cells made by end of adolescence
• They can become so engorged that they
no longer respond to insulin.
http://www.proteinpower.com/drmike/wp-content/uploads/2008/05/human-adipose-tissue.jpg
Stress and
Diabetes
• Stress causes:
– ↓ insulin secretion.
– release of glucocorticoids + hormones of
the sympathetic nervous system.
• epinephrine and norepinephrine, cortisol
• These act on fat cells to make them more insulinresistant.
– “Steroid diabetes” can be induced by glucocorticoid
drugs.
– “An exaggerated stress response is associated with
less well-controlled diabetes.” (Robert Sapolsky, Why
Zebras Don’t Get Ulcers)
How is type 1 diabetes
treated?
• Insulin (pens or pumps)
– Basal insulin (Lantus, Levemir)
– Bolus insulin for meals (Humalog, Novolog,
Regular)
• Easy these days
http://mhts.com.au/slides/insulin-pen.jpg
http://assets.aarp.org/external_sites/adam/graphics/images/en/18035.jpg
How is Type 2
Diabetes Treated?
• Weight loss + exercise
• Low-carb diet
• Oral Drugs: insulin sensitizers and pancreas
stimulators
– Metformin/glucophage (biguanines)
• Keep liver from dumping glucose
– Sulfonylureas
• Stimulate pancreas to produce insulin
– Other insulin sensitizers
• Insulin
http://www.reinventioninc.com/images/email/exercise.gif
Types of Insulins
Humalog, Novolog
Lantus
Diabetes and Heart Disease:
Low-density Lipoproteins (LDLs)
• LDLs that damage arteries:
– Small, dense LDL, (“type A”)
– oxidized LDL
– glycated LDL
– All of these increase as blood sugar
increases.
Glucose Reacts with LDLs and LDL
Receptors (Glycosylation)
• Normally, LDL receptor proteins on liver
cells remove LDL from the blood, tell the
liver to stop making more LDL.
• BUT, glucose can bind to the receptors
AND to the LDL particle  (glycosylation)
 so that LDL isn’t recognized by its
receptors and LDLs aren’t cleared by the
liver.
Glycosylation can be Irreversible
(Glycation)
• Within ~24 hrs, glycosylation becomes
irreversible .
• (Glycolsylation becomes glycation).
•  Proteins become AGEs (Advanced
Glycation End products)
• Reaction can happen with lots of proteins,
not just LDLs.
Advanced Glycation End products
(AGEs) Form Plaques
• AGEs accumulate , can be incorporated
into the walls of arteries, become sticky,
form fatty deposits called atherotic
plaques.
• Other glycated proteins stick to the
plaques  clots, etc.
Glycated Proteins Keep LDL
High
• Since liver LDL production cannot be
turned off by the glycosylated/glycated
LDL and LDL receptors, the liver continues
to make MORE LDL.
Other Contributions to Heart
Disease
•
White blood cells called macrophages ingest glycated LDL + proteins
– swell up with LDL  become large “foam cells”
– Foam cells bind to sticky artery walls, disrupt them
•
•
•
•
Normally, smooth muscle in arteries prevents rupture of plaques.
If nerve cells die (as in diabetic neuropathy), the muscles calcify and can’t
prevent rupture of plaques.
Ruptured or loose plaques can block blood vessels and cause heart attacks.
Heart attacks are also caused by individual tendency of blood to clot (form a
thrombus) .
– Factors that enhance clotting include fibrinogen and factor VII
– Lipoprotein(a), inhibits the destruction of small thrombi before they become large
enough to cause a heart attack.
•
All of these factors have been found to increase in people with chronically high
blood sugars but they tend to normalize when blood sugars become normal.
Facts About Heart Disease
• 50% heart attacks in people with normal
cholesterol
• Best drug to reduce heart attacks is aspirin
 doesn’t affect cholesterol
• Most dangerous plaques aren’t large but
are the most prone to rupture.
Russell Ross’s Hypothesis:
Inflammation Causes Heart
Disease
• 1970’s theory
• Shown in 1990’s when marker for “silent”
inflammation found: C-reactive protein
(CRP)
• CRP produced by liver in response to
inflammation
Fat Cells and Inflammation
• Pro-inflammatory cytokines produced by
fat cells make them resistant to inuslin
Lessons I’ve Learned
•
•
•
•
•
•
•
•
•
I attribute my success to God, my spouse, my family and my friends.
Having diabetes is mostly okay. Sometimes it’s very hard.
Exercise ROCKS! It is SO helpful to go for a walk or exercise after a meal (makes insulin
work better).
Carbohydrate restriction helps with control.
Record-keeping is essential for identifying what works/doesn’t work.
On-line forums are super helpful for emotional support, wisdom from successful diabetics.
SOME books are helpful. (see next slides)
I’m thankful for SOME health care professionals who respect my
reading/research/knowledge.
Some dieticians are helpful, some are COMPLETELY NOT.
–
Find dieticians who keep up with research, not ones who rely on old out-of-date guidelines.
To be a good friend to diabetics:
• Ask what they can eat.
• For a sure-bet treat, give a diabetic an 85% Lindt dark chocolate bar, nuts, cheese, sugarfree jello, or Cheesecake Factory 6-carb cheesecake, NOT “sugar-free” (almost never is)
or fat-free (high in carbs) garbage.
• The ADA does a mediocre job of helping diabetics be successful and does not contribute
much to research.
• Lee Iacocca is DA MAN! He DOES contribute to much to research. Contributions
should go to his foundation!!!!!!
Recommended Reading
• For type 2 diabetes
treatment and prevention
• For the biochemistry behind
carbohydrate control
– Atkins’ Diabetes Revolution
by Dr. Mary Vernon
• For type 1 and/or type 2
treatment
– Dr. Bernstein’s Diabetes
Solution by Dr. Richard
Bernstein
– Diabetes 101 by Jenny
Ruhl
– Protein Power by Drs.
Michael and Mary Eades
– Good Calories, Bad Calories
by Gary Taubes
World Sugar Consumption in Millions of To
Year
1800
1850
1880
1890
1900
1950
1970
1990
2000
Medscape J Med. 2008; 10(7): 159.
Published online 2008 July 9.
Copyright ©2008 Medscape
Sucrose
0.25
1.5
3.8
5.2
11.0
35.0
70.0
110.0
128.0
Fructose
0.125
0.75
1.9
2.6
5.5
17.5
35.0
55.0
64.0
One Wrong Statement
• 1988, Surgeon General C.Everett Koop:
– The American diet is too high in fat, and fat
causes coronary disease
– “The depth of the science base underlying its
findings is even more impressive than that
[Surgeon General’s report] for tobacco and
health in 1964.”
• d
How did the Medical Community
Get it Wrong?
• Information cascade – starts as a guess
then is repeated so often it becomes fact
• Imagery coupled with misunderstanding –
fat clogging pipes
• History
Ancel Keyes
• 1950s, thought that heart disease was
increasing because Americans were eating
more fat than their ancestors had.
• True?
• 1. Antibiotics, etc – people living longer,
contracting heart disease
• 2. 19th century Americans ate a LOT of fat and
meat
• 3. Hunter-gatherers at as much or more fat than
today’s Americans
• Comparied diets and heart disease in
Japan, the U.S., + 4 countries, found
correlation with fat and heart disease in
this group of 6
• Subsequent studies of 22 countries show
no correlation
– (“French paradox” , etc)
• 1957: American Heart Association: the
correlation “does not stand up to critical
examination.”
• 1960, changed mind, (Dr. Keyes on the
committee)
History of the Low-Fat Food
Pyramid
• Keyes’ proclamation taken up by Senate
Committee led by George McGovern
• Report written by non-scientist relying on
advice from one nutritionist, Mark Hegsted
• Assistant Agriculture Secretary Carol
Tucker Foreman hired Dr. Hegsted to write
dietary guidelines for the Dept of
Agriculture  food pyramid
Clinical Trials
• No correlation between low-fat diets and a
lack of coronary disease
Result
• Americans replaced fat with
carbohydrates.
USDA 2010 Dietary
Recommendations
Thanks to Dr. Richard Feinman, Nutrition & Metabolism Society
The Key Enzyme in Cholesterol
Synthesis is Regulated by INSULIN
What textbooks say…
• Gropper and Smith, Advanced Nutrition and
Human Metabolism
– “Despite years of investigation, the mechanism by
which hypercholesterolemic fatty acids exert their
effects has not been conclusively defined.”
– “Contrary to widespread belief, changing the amount
of cholesterol in the diet has only a minor influence on
blood cholesterol concentration in most people. This
is because compensatory mechanisms are engaged,
such as HDL activity in scavenging excess
cholesterol and the down-regulation of cholesterol
synthesis by dietary cholesterol.”
• Gurr, Harwood, Frayn, Lipid Biochemistry:
– “The mechanism for the effects of different
dietary fatty acids on serum cholesterol
concentration is not clearly understood.”
Why I think Normal Blood Sugar
is Crucial to Weight Loss
Malonyl-CoA, a Fat-Storage Metabolite,
Responds to Blood Glucose Levels
• Malonyl-CoA ↑ when blood glucose ↑
• High levels shift fat toward storage
– Stimulates fatty acid synthase
• Converts carbohydrates to fat
– Inhibits CPT-1 that transports fat into
mitochondria
• When blood glucose is low…shift toward fat
burning.
– CPT-1 is uninhibited, moves fat into mitochondria
Normal Blood Sugar
• ~ 4 g or ~1 teaspoon (according to M.
Eades)
• ~85-110 mg/dl
Sugar Content of Foods
Mountain Dew
20 oz (590 ml) Bottle Sugars, total: 77g ; 290 calories
Apple Juice
8 oz (240 ml) Serving
Sugars, total:
Calories, total:
26g
120
1 L (34 oz) Bottle Sugars, 124g Calories: 440
16 oz Bottle
Sugars, total:
Calories, total:
www.sugarstacks.com
52g
240
Note that “sugar” means total carbohydrate.
World Sugar Consumption in Millions of To
Year
1800
1850
1880
1890
1900
1950
1970
1990
2000
Medscape J Med. 2008; 10(7): 159.
Published online 2008 July 9.
Copyright ©2008 Medscape
Sucrose
0.25
1.5
3.8
5.2
11.0
35.0
70.0
110.0
128.0
Fructose
0.125
0.75
1.9
2.6
5.5
17.5
35.0
55.0
64.0
Hemoglobin
http://rjr10036.typepad.com/.shared/image.html?/photos/uncategorized/hemoglobin.jpg
http://rjr10036.typepad.com/.shared/image.html?/photos/uncategorized/leafy.jpg
http://rjr10036.typepad.com/.shared/image.html?/photos/uncategorized/09_gallery_ornish.jpg
http://rjr10036.typepad.com/.shared/image.html?/photos/uncategorized/proteinspread.jpg
The Duke Study confirms that the Atkins Diet is likely the best solution to Type 2 Diabetes.
The majority of study subjects in the Duke study were able to eliminate or reduce medications.
Contrary to the common myth, most subjects were able to remain compliant beyond six months.
Overall for people with Type 2 Diabetes following Atkins in this new Duke study, cholesterol levels stabilized,
dangerous triglycerides were reduced and good cholesterol increased.
http://rjr10036.typepad.com/.shared/image.html?/photos/uncategorized/295111
332_59f8553b86_o.jpg
http://rjr10036.typepad.com/.shared/image.html?/photos/uncategorized/arnie_1.jpg
Studies of the Inuit
http://rjr10036.typepad.com/.shared/image.html?/photos/uncategorized/inuit.jpg
http://www.proteinpower.com/drmike/wp-content/uploads/2007/10/ancel-keys.jpg
Exercise will extend your life by the same number of hours you spent exercising."
http://themedicalbiochemistrypage.org/diabetes.html
As heart-disease rates were skyrocketing in the mid-1900s,
consumption of animal fat was going down, not up. Consumption of
vegetable oils, however, was going up dramatically.
Half of all heart-attack victims have normal or low cholesterol.
Autopsies performed on heart-attack victims routinely reveal plaquefilled arteries in people whose cholesterol was low (as low as 115 in
one case).
Asian Indians - half of whom are vegetarians - have one of the
highest rates of heart disease in the entire world.
Kids who were diagnosed as suffering from ADD have been successfully
treated by re-introducing natural saturated fats into their diets. Your brain
is made largely of fat.
http://www.fathead-movie.com/NoBolognaFacts.htm
High protein diets (30% of total energy intake) vs. low-fat, low-protein
diet (10% protein) 6 month duration
increased diet-induced thermogenesis (DIT)
increased satiety
higher sleeping metabolic rate
average 7.6 pounds more weight lost
decreased insulin
more mobilization of fatty acids
Current Opinion in Endocrinology, Diabetes & Obesity.� Brehm, Bonnie J; D'Alessio, David A.� Benefits of high-protein weight
loss diets:� enough evidence for practice? Current Opinion in Endocrinology, Diabetes & Obesity. 15(5):416-421, October 2008.
A 12 month trial reports that high protein diets account for the largest
beneficial effects on HDL, triglycerides and blood pressure compared to
lower protein diets, however, the results of total cholesterol and LDL were
�less favorable.�� The effects on LDL and total cholesterol may be
attributed to lower fiber consumption in the high protein group.� Two
recent studies show that after one year, patients on higher protein diets had
a significantly sustained reduction in cardiovascular risk factors,
specifically fasting glucose levels, lipids, and CRP.
Current Opinion in Endocrinology, Diabetes & Obesity.� Brehm, Bonnie J; D'Alessio, David A.� Benefits of
high-protein weight loss diets:� enough evidence for practice? Current Opinion in Endocrinology, Diabetes &
Obesity. 15(5):416-421, October 2008.
The effects of high protein intake on glycemic control.��
Benefits shown in several major studies include �improved
insulin sensitivity or lower fasting insulin concentrations
following dietary intervention.�� While these results are
promising, it is still not clear if these benefits are specifically
from the high protein diet, weight loss, or a combination of the
two.� This study also notes that increased glucose metabolism
and insulin sensitivity resulting in weight loss may counteract
the harmful effects that amino acids may have on insulin
sensitivity, however, this concept requires further investigation.
Gary Taubes:
• “My NYT article noted that copious
evidence exists in contradiction to the lowfat-is-good-health hypothesis, while the
alternative hypothesis may fit the data
better but has never been adequately
tested. “
• Squires apparently believes that learned
expert committees and government
agencies are incapable of arriving at
biased and incorrect conclusions on
subjects of national importance, or at least
on this particular subject. I believe they
can and, in this case, that they probably
did.
• Squires faults me for ignoring "high-quality," "significant
and well-known peer reviewed research," including the
2000 Report of the Dietary Guidelines Advisory
Committee (DGAC). The report cites "many years of
epidemiological research" supporting the dangers of
saturated fats, although the one relevant article both it
and Squires discuss in detail was not published in a
peer-reviewed journal, begging the question of whether it
constitutes "high-quality research." This in turn raises the
question: If there is so much significant high-quality
research out there, why do the DGAC and Squires rely
on non-peer-reviewed literature to make their case?
• lard, for instance, has more "good fats" -monounsaturated and polyunsaturated -than "bad fats" -- saturated. Thus, the
overall effect on cholesterol profiles of
eating lard rather than refined
carbohydrates or starches would be at
worst harmless.
• Squires says I reject the findings of The 1998 Clinical
Guidelines on the Identification, Evaluation and
Treatment of Overweight and Obesity in Adults, due to
my "negative personal assessment of the panel's chair."
This is incorrect. Nor do I reject the findings. The report
actually concludes that low-fat diets do not work. It says
reducing calories is crucial to successful weight loss,
something we both agree on, then says on page 95 in
English "Reducing dietary fat alone without reducing
calories is not sufficient for weight loss. However,
reducing dietary fat, along with reducing dietary
carbohydrates can facilitate caloric reduction."
• Squires says I disagree with the findings of the Diabetes
Prevention Study. This is incorrect. I disagree with
Squires's interpretation of the findings: that the DPP data
are compelling evidence for the efficacy of low-fat diets.
The DPP reported that low-fat low-calorie diets and 150
minutes of weekly exercise produced a 5 percent to 7
percent weight-loss (15 to 21 pounds for a 300-pounder)
over six years. Because the study included no control
group for the dietary arm, for all we know exercise and a
low-carbohydrate low-calorie diet might have produced
much greater weight loss.
• Even small dietary trials can easily cost
several hundred thousand dollars and
require entire research teams. The DPP
estimated a cost of $1,075 just to recruit
each participant.
• Fleming reports on a one-year trial of 100 participants
and four diets with extensive follow-up. His paper,
however, has no co-authors; it acknowledges no source
of funding, nor any nurses, dietitians or technicians who
might have helped. Fleming identifies himself as Medical
Director of Preventive Cardiology, the Camelot
Foundation at the Fleming Heart & Health Institute, but if
his Web site or receptionist are any indication, he is the
sole member of each of those.
• Me:” Very unlikely in my opinion (and in that of many of
my colleagues) for one person to have accomplished this
study”
– Angiology. 2000 Oct;51(10):817-26. Links
– The effect of high-protein diets on
coronary blood flow.
– Fleming RM.
– The Fleming Heart and Health Institute and
the Camelot Foundation, Omaha, Nebraska
68114, USA. [email protected]
– Prev Cardiol. 2002 Summer;5(3):110-8. Links
– Erratum in:
• Prev Cardiol 2002 Fall;5(4):203.
– The effect of high-, moderate-, and low-fat diets
on weight loss and cardiovascular disease risk
factors.
– Fleming RM.
– Section of Preventive Cardiology, The Camelot
Foundation at The Fleming Heart & Health Institute,
and the Department of Radiation Oncology, University
of Nebraska Medical Center, Omaha, NE 68114,
USA. rfmd1@...
• I am sure Feinman enjoyed the following
statement:
• "Regardless of the dietary program used, the
key is the same; one must reduce caloric intake
to lose weight. The second law of
thermodynamics still applies!" Second? That
Fleming guy is even more clueless than I
assumed ealier.
• AM
Eric Westman’s comments
•
Re: Fleming RM. Prev Card 2002;5:110-118 Comments
This paper is so seriously flawed that no conclusions can be made
about any of the recommended diets.
There are several violations of standard clinical research practice
methods:
1) Discrepancy of addition in the abstract: 28+16+38+38 = 120 not
100 as stated.
2) It makes no sense to mention "non-significant" results in the
abstract, or highlight them in the text of the manuscript. The
abstract reads: "There were nonsignificant reductions in HDL-C in
those on MF (-1.5%) and HF (-5.8%)." A nonsignificant finding means
that the findings were likely to be there based on chance alone.
Stating the percentage changes when the statistic is nonsignificant
is very misleading, and definitely not common practice. Trends are
sometimes mentioned (p<0.10). I have never seen so many
nonsignificant findings mentioned in an abstract or in the text. Is
this a peer-reviewed journal?
3) Randomization: This statement makes no sense: "Patients had to
commit to staying on the dietary program for a minimum of 1 year and
were randomly assigned to one of the four dietary regimens based
upon dietary preferences." I do not understand how you can
randomize based on dietary preference. The whole concept of
randomization is based upon making the allocation of subject
unbiased.
4) Treatment: While the author lists the dietary regimens, there is
no documentation AT ALL of what the patients actually consumed.
There is no measure of adherence to the regimens to give confidence
about use of any of the dietary regimens. Monthly return visits are
generally too infrequent to ensure adherence: most investigators
have patients return every week or every two weeks.
5) As to the question of whether the High Fat diet represents the
Atkins Diet: there is no food record documentation or urinary
ketone measurement to support the claim that the High Fat diet was
the Atkins Diet. Because there was very little weight loss, and no
change in triglycerides, these people were probably not following
the Atkins Diet.
6) Analysis: It is standard practice to list the sample size in
tables; there are no sample sizes listed. Table II lists percentage
changes without any statistical tests to assist the reader in
knowing which changes were likely to be present beyond chance. Were
there any drop-outs? How were the drop-outs handled in the analysis?
7) Data interpretation: I've never seen such a discrepancy in a
published paper before. The abstract reads, "Patients on HF [high
fat] had a 6.0% (NS) increase in LDL-C." and then concludes "Only
patients following HF diets showed a worsening of each
cardiovascular disease risk factor (LDL-C, TG, TC, HDL-C, TC/HDL
ratio, Ho, Lp(a), and fibrinogen)." The first statement DIRECTLY
CONTRADICTS the second statement. The author clearly does not
understand why statistics are used. This makes me question now
how the statistics were generated. Was a statistician involved in
the study?
In my opinion, this paper provides no relevant information.
“More science and less zealotry”
-Dr. Mary Vernon
World Sugar Consumption in Millions of Tons
Year
Sucrose
Fructose
1800
0.25
0.125
1850
1.5
0.75
1880
3.8
1.9
1890
5.2
2.6
1900
11.0
5.5
1950
35.0
17.5
1970
70.0
35.0
1990
110.0
55.0
2000
128.0
64.0
Medscape J Med. 2008; 10(7): 159.
Published online 2008 July 9.
Copyright ©2008 Medscape
•
•
Vos et al.. obtained information from the Health and Nutrition Examination Survey, conducted
from 1988 to 1994.
It is clear from the analysis that Americans are getting a lot of fructose in their diet.
–
–
–
–
–
Mean daily consumption of fructose was 54.7 g/d
Range 38.4 to 72.8 g/d
0.2% of total daily caloric intake.
Consumption was highest among adolescents (12- to 18-year-olds), who consumed 72.8 g/d, or more than 12% of their total
calories from fructose.
The largest source of fructose was sugar-sweetened beverages (30%), followed by grains (22%) and fruit/fruit juice (19%).
Vos MB, Kimmons JE, Gillespie C, Welsh J, Blanck HM. Dietary fructose consumption among US
children and adults: The Third National Health and Nutrition Examination Survey. Medscape J Med.
2008
•
Dietary fructose was found to predict an increased level of low-density
lipoprotein cholesterol in children.[6]
Aeberli I, Zimmermann MB, Molinari L, et al. Fructose intake is a predictor of LDL particle size in overweight
schoolchildren. Am J Clin Nutr. 2007;86:1174–1178.
•
•
Fructose, unlike other sugars, increases serum uric acid levels.
Nakagawa and colleagues [7] proposed that this happens when fructose is
metabolized in the liver, its major organ for metabolism. Adenosine triphosphate
(ATP) is used by the enzyme phosphofructokinase to phosphorylate fructose to
fructose-1-phosphate. The adenosine-5′-diphosphate that is thus formed can be
further broken down to adenosine-5′-monophosphate, then to inosine 5′-phosphate,
and finally to uric acid. Thus, the metabolism of fructose in the liver leads to the
production of uric acid.
•
These authors proposed that the high levels of uric acid could set the stage for
advancing cardiovascular disease by reducing the availability of nitric oxide, which is
crucial for maintaining normal blood pressure and for maintaining normal function of
blood vessel walls (endothelium).[7]
Nakagawa T, Hu H, Zharikov S, et al. A causal role for uric acid in fructose-induced metabolic syndrome. Am J
Physiol Renal Physiol. 2006;290:F625–F631.
Framingham Study: Individuals consuming at least 1 soft drink/d had
a higher prevalence of Metabolic Syndrome (odds ratio, 1.48; 95% CI,
1.30–1.69) and an increased risk for Metabolic Syndrome over 4 years
of follow-up.
Dhingra R, Sullivan L, Jacques RF, et al. Soft drink consumption and risk of developing cardiometabolic risk factors and the
metabolic syndrome in middle-aged adults in the community. Circulation. 2007;116:480–488.
The most recent relationship shows that
fructose intake is directly related to risk
for gout in men.
Choi HK, Curran G. Soft drinks, fructose consumption and the risk of gout in men: prospective cohort study. BMJ. 2008;336:309–
312
Low-carb diets lead to larger LDL
particles
• Higher HDLs and lower TGs correlate with
larger LDL particles
• Larger LDL particles are less likely to
cause heart disease
How is Type 2
Diabetes Treated?
• Weight loss + exercise
• Low-carb diet
• Oral Drugs: insulin sensitizers and pancreas
stimulators
– Metformin/glucophage (biguanines)
• Keep liver from dumping glucose
– Sulfonylureas
• Stimulate pancreas to produce insulin
– Other insulin sensitizers
• Insulin
http://www.reinventioninc.com/images/email/exercise.gif
Thiazolidinediones (Glitazones)
• Bind to PPARs (peroxisome
proliferator- activated
receptors)
– Normal receptors for PPARs
are fatty acids and eicosanoids
– Upregulate a host of genes
resulting in:
• Decreased insulin resistance
• Inhibition of VEGF-induced
angiogenesis
• Decreased leptin (leads to
increased appetite)
• Decreased IL-6 and other
cytokines, interleukins
• Increased adiponectin
*withdrawn due to hepatitis
Rosiglitazone
(Avandia)
Pioglitazone (Actos)
Troglitazone*
(Rezulin),
How do these drugs increase
insulin sensitivity?
• Mechanism to be determined…
• May depend on reducing levels of
circulating nonesterified fatty acids
(NEFA), reducing lipolysis, increasing
glyceroneogenesis and increasing
reesterification of NEFA in TAGs in
adipose tissue
PPARs
www.wikipedia.org
Side effects
• Fluid retention in 5% of patients  heart
failure risk for some
Types of Insulins
Humalog, Novolog
Lantus
Fat Metabolism
Fat Breakdown
Lipases (3 of them) hydrolyze triglycerides
to glycerol + 3 FA
– Glycerol  Glyceraldehyde-3-phosphate
(G3P)
• Then G3P goes to glycolysis or gluconeogenesis
– Fatty acids oxidized to acetyl CoA
• Acetyl CoA then enters citric acid cycle or ketosis
Lipolysis
• Three lipases break down TAGs:
1. Triacylglycerol lipase
- (hormone-sensitive; activated by epinephrine
[adrenaline] and glucagon)
2. Diacylglycerol lipase
3. Monoacylglycerol lipase
• Hormonal Control:
– Lipolysis activated by glucagon and epinephrine
(low blood sugar/immediate energy needs.
– Lipolysis inhibited by insulin.
Fatty Acid Activation and
Transport
• Liver cells take fatty acids from the
bloodstream.
• FA are activated to form acyl-CoA
– If short-chain FA, activated in mt
– If longer-chain FA, activated in ER
– Longer-chain FA can’t diffuse across mt
membrane, require carrier CARNITINE
Carnitine
• Derivative of Lysine
• Found in red meats, dairy products, also
synthesized by body
• People w/low carnitine levels are weak,
irritable, also have lipid deposits in
muscles.
Fatty Acid Oxidation
• In mt, even # FA broken down by βoxidation.
– (The β-C is attacked)
• Broken down to acetyl CoA
1.
2.
3.
4.
Dehydrogenation
Hydration
Oxidation
Thiolysis
• Req NAD+ and FAD+
Fats: New Nutritional
Paradigms
http://www.tcd.ie/Communications/assets/img/omega3
.jpg
http://media.photobucket.com/image/lard/SmileyMags/Humor/Signs/l
ard.jpg
From Dr. Michael Eades’ Blog
As we were eating breakfast on the last morning, a man was eating alone while reading the paper at the
table next to us. He looked to be about 70 or so and was fairly thin with a pot belly. He had on two
pressure stockings on his lower legs and bruising in the crook of one of his arms from where,
obviously, blood had recently been taken.
Watching him eat, I created an entire story about him that I’ll bet is not too far from the mark. Even if it
is not accurate in this man’s case, it is totally (and sadly) accurate in many thousands of others.
The man was eating a bowl of oatmeal. He had a glass of skim milk so fat free it was almost blue that he
poured little bits of into his cereal from time to time. Along with his oatmeal, he was eating one of the
giant pieces of toast the restaurant serves. He took one pat of butter (I assume there was no margarine
available) and cut it in half. He carefully spread one half pat on one half of his toast then loaded it with
an entire individual serving of jelly. After eating the first half piece of toast, he prepared the second half
the same way and ate it. The only fat he got from his entire meal was that that came from that one pat of
butter. Based on the size of the bowl of oatmeal and the size of the toast (and the skim milk), I
calculated that this guy consumed about 100 grams of carbohydrate. (Thirty grams in the oatmeal; at
least 30 in the toast; 15 in each container of jelly; and about 10 in the skim milk.)
I imagine (here is where I’m speculating) that he has elevated cholesterol and has been told by his
doctor to watch his fat. And he is complying. He got a whopping 4 grams of fat in his one pat of butter
(36 calories-worth) while getting 100 grams of carb in the rest of his meal (400 calories-worth). The tiny
bit of fat he got contained short-chain fatty acids that are immune enhancing whereas the 100 grams of
carb he got provided really no health benefit. Since the 100 grams represents 20 times the amount of
sugar circulating in his blood, his pancreas had to release a large amount of insulin to deal with it. His
pot belly indicates that he is already insulin resistant with an abdomen full of visceral fat, so he no
doubt secreted a lot more insulin than a person without insulin resistance. This excess insulin help him
store fat in his liver, increase his level of visceral fat, ratchet up the inflammatory process, injure his
blood vessels even more and increase his risk for heart disease, the very thing his doctor was trying to
prevent by putting him on a low-fat diet.
How much better off this guy would have been had he joined me in the Mike’s Special. But, his
cardiologist, I’m sure, would have been apoplectic. A sad state of affairs indeed.
Vegetable Oils
• In the past: vegetable seed oils expensive to
produce
– Most fats were from butter, lard, olive oil (low amts
omega-6 FA)
• 1920s  industrial processing of vegetable seeds
(soybeans, corn) made these oils cheap.
– Subsidized from ‘20’s on  most calories per acre
• 2007: $20 billion/yr in subsidies
– Comparitively : $0 subsidies for fruits, vegetables
• Vegetables oils are rich in omega-6 FA
Sears, B. Toxic Fat, 2008
Soybean:
http://vinniey.files.wordpress.com/2006/10/4216246844.jpg
Rapeseed: (Canola oil)
http://i.treehugger.com/images/2007/10/24/rapeseed%20
oil.jpg
Omega-6 vs. Omega-3 Fats
(ω-6 vs. ω-3)
• Until ~1920s, ratio of omega-6-to omega-3
fats ~2:1.
– Pre-1920’s diet: more fish, more cod liver oil,
~no vegetable oils
– Post-1920’s diet: more margarine, Crisco,
soybean oil, corn oil, vegetable shortening
• Current typical American ratio: 20:1
Sears, B. The Anti-Inflammation Zone,
http://www.nutritionexpress.com/images/Articles/americanconsume2
much.gif
What’s Wrong with Omega6’s?
• Building blocks for arachidonic acid
• Increase inflammation
What’s wrong with
inflammation?
• Acute (after injury good)
• Silent/Chronic (bad)
– destabilizes cholesterol deposits on arteries of
heart  CVDisease
– attacks brain cells, nerve cells  Alzheimer’s
– triggers cell division  cancer
Dr. Paul Dudley White
• Eminent cardiologist,
pioneer in
electrocardiograms
• Wrote twelve books
and more than 700
scientific articles.
• Author of the famous
text Heart Disease
(1931) -classic in the
field
• Cardiologist to
President Eisenhower
"See here, I began my practice as a
cardiologist in 1921 and never saw a
myocardial infarction patient until 1928.
Back in the MI-free days before 1920, the
fats were butter, whole milk and lard, and
I think we would all benefit from the kind
of diet that we had when no one had ever
heard of corn oil."
http://www.spacedoc.net/heart_disease_carbohydr
ate.htm
Three Pro-inflammatory
Hormones
1. Insulin
2. Cortisol
3. Pro-inflammatory
eicosanoids
What are Eicosanoids?
• Hormones that control inflammation
– Work with inflammation cells (neutrophils,
macrophages)
– Cause release of cytokines
– Involved in cell repair
– Can be pro-inflammatory or anti-inflammatory
– Made by every cell in the body
• Made from Arachidonic Acid (a 20-Carbon
fatty acid)
Eicosanoids
Why Omega-6 Fatty Acids Should
be Limited
• Vegetable oils largely contain:
– Omega-6-Linoleic Acid  converts to
Gamma-Linolenic Acid (can make good or
bad eicosanoids)
– GLA Dihomo-gamma-linolenic acid (DGLA)
– still good, starting point for good
eicosanoids
DGLA (Dihomo-gamma-linolenic acid)
Delta-5-Desaturase (D5D)
Activated by insulin
Inhibited by EPA (in fish oil)
Inhibited by lignans (in sesame oil)
Arachidonic AcidInhibited by tumeric
Good Eicosanoids
Bad Eicosanoids
Insulin
• Allows nutrients (glucose, amino acids) to
enter cells
• Drives fat storage, inhibits fat breakdown
– Activates fatty acid synthase, glycogen synthase
– Inhibits hormone-sensitive lipase, glycogen
phosphorylase
• Increases levels of Interleukin-6 (IL-6), a proinflammatory cytokine that leads to formation
of C-reactive protein (CRP)
Cortisol:
The “Stress Hormone”
• Hormone produced during stress - to lower
levels of pro-inflammatory cytokines
• Increases conversion of amino acids to
glucose (gluconeogenesis)
• Body has to churn our more insulin 
drives fat storage  drives inflammation
• Higher levels associated with more
abdominal fat
http://fastweightloss85.files.wordpress.com/2009/06/cortisol_i
mage.jpg
Sears, B. The Anti-Inflammation Zone, 2005
Fat Cells are a Source of
Inflammation
• Fat cells sequester Arachidonic Acid (AA)
– (May be a protective mechanism to keep AA
out of other cells)
• If AA levels high enough, ↑ production of
pro-inflammatory eicosanoids
– These can lead to release of more proinflammatory cytokines
• Interleukin-6 (IL-6), tumor necrosis factor (TNF)
• More fat  more inflammation
Sears, B. The Anti-Inflammation Zone, 2005
Interleukin-6 (IL-6)
• A cytokine
• Chronically elevated in obesity-related
pathologies
• Partly derived from adipose tissue
• Regulated by proinflammatory prostaglandins
(also produced by adipose tissue)
• *low-dose aspirin lowered IL-6 in humans and
in mice.
Ogston, N.C. et al., Int. J. Obes. 2008, 32, 1807-1815
Russell Ross’s Hypothesis:
Inflammation Causes Heart
Disease
• 1970’s theory
• Shown in 1990’s when marker for “silent”
inflammation found: C-reactive protein (CRP)
• CRP produced by liver in response to
inflammation
• CRP levels don’t singly correlate with heart
disease but do provide marker of general
inflammation
• Levels should be under 1-2 mg/L
Sears, B. The Anti-Inflammation Zone, 2005
Inflammation and Cancer
• Macrophages and other inflammatory cells
create free radicals that can damage DNA
• Pro-inflammatory cytokines are associated
with tumor formation and metastasis.
Dietary Sources of AA
• Egg yolks
• Animal protein
Fish Oil
• Health benefits supported by multiple,
robust, well-designed studies
– Negative correlation with cancer, heart
disease, immune disorders, brain disorders…
• Yes, fish have mercury, PCBs, dioxins
• Larger fish have more contamination
• Japanese (high-fish diet) have high levels
of these toxins (approaching upper limits)
Sears, B. The Anti-Inflammation Zone, 2005
Refined Fish Oil/Fish Oil
Substitutes
• The major omega-3 FAs found in fish are
EPA (eicosapentanoic acid) and DHA
(docosahexanoic acid)
• International Fish Oil Standards (IFOS)
program www.ifosprogram.com
– IFOS Standards: Hg < 10 ppb; PCBs <45 ppt;
dioxins < 1 ppt
Sears, B. The Anti-Inflammation Zone, 2005
Poor Man’s Test for SufficientlyRefined Fish Oil
• Few teaspoons of liquid into a cup
• Crack open a few capsules, put them in
liquid
• Put mix in freezer for a few hours
• Mix should NOT freeze rock-solid if
relatively pure.
Sears, B. The Anti-Inflammation Zone, 2005
How Much Fish Oil?
• Dr. Barry Sears: 2.5-10+ g/d of EPA/DHA
– No chronic disease: 2.5 g/d
– Obesity, CVD, type 2 diabetes: 5 g/d
– Chronic pain: 7.5 g/d
– Neurological disease: > 10 g day
• Very high doses may increase risk of
stroke
Sears, B. The Anti-Inflammation Zone, 2005
Monounsaturated Fats are
Inflammation-Neutral
• Can’t be made into pro-inflammatory
eicosanoids
• In nuts, olive oil, avocados
Sears, B. The Anti-Inflammation Zone, 2005
Diacylglycerol Consumption
• Fat oxidation and resting metabolic rate
significantly greater compared with TAG
oil.
Hibi et al., Int. J. Obesity, 2008, 32, 1841-1847
Two months later, the JAMA published
an editorial in response to Kuo’s article
suggesting that the
“almost embarrassingly high number of
researchers who boarded the
‘cholesterol bandwagon’ had done a
disservice to the field. This fervent
embrace of cholesterol to the exclusion
of other biochemical alterations
resulted in a narrow scope of study.
Fortunately, other fruitful approaches
have been made possible in the past
few years by identification of the
fundamental role of such factors as
triglycerides and carbohydrate
metabolism in atherogensis.”
References – a sampling
Babcock, T. et al. “Eicosapentaenoic acid: an anti-inflammatory omega-3 fat wit
Clinical applications”, Nutrition, 2000, 16, 1116-1118.
Barham, J.B. et al., “Addition of EPA to GLA supplemented diets prevents serum
Arachidonic Acid accumulation in humans, J. Nutr. 2000, 130, 1925-1931.
Cho, H.P. et al., “Cloning, expression, and fatty acid regulation of human delta 5
Desaturase, J. Biol. Chem. 1999, 274, 37335-37399.
Clarke, S.D., “Polyunsaturated fatty acid regulation of gene transcription: a
Mechanism to improve energy balance and insulin resistance.” Br. J. Nutr.
2000, 83, S59-S66.
El Boustani, S., et al., “Direct in vivo characterization of the delta-5-desaturase
Activity in humans by deuterium labeling: effect of insulin. Metabolism,
1989, 38, 315-3321.
Phinney, S. “Potential risk of prolonged gamma-linolenic acid use”, Ann. Intern
Med. 1994, 120, 692.
References, - cont.
Robertson, R. et al., “Inhibition of in vivo insulin secretion by
prostaglandin E1” J. Clin. Invest. 1974, 54, 310-315.
Serhan, C.N. “Lipoxins and aspirin-triggered 15-epi-lipoxin
biosynthesis: an update and role in anti-inflammation and proresolution.” Prostaglandins and Other Lipid Mediations 2002, 69,
433-455.
Shimizu, S. et al. “Sesamin is a potent and specific inhibitor of
delta 5 desaturase in polyunsaturated fatty acid biosynthesis.”
Lipids, 1991, 26, 512-516.
Yam, D.B. et al., “Diet and disease: the Israeli paradox: possible
dangers of a high omega-6 polyunsaturated fatty acid diet.” Isr. J.
Med. Sci. 1996, 32, 1134-1143.
USDA 2010 Dietary
Recommendations
Thanks to Dr. Richard Feinman, Nutrition & Metabolism Society