Comment: To clarify the
above, it appears that the likely reason the Keys
equation fails to correctly predict cholesterol levels
in situations such as the Eskimo study above is that it
does not take into account the effects of carbohydrate
on insulin secretion. Hyperinsulinemia now appears as if
it may be one of the largest risk factors for CHD. Both
protein and low-
carbohydrate intakes, which were seen in the Eskimo
study, promote inhibition of excess insulin.
Exactly. Ancestral, pre-
agricultural diets were quite high in animal protein,
and the carbohydrate that was consumed was generally of
a low glycemic index. These populations also selectively
consumed the fatty portions of the killed animal (brain,
bone marrow, depot fat, perinephral fat, mesenteric fat,
tongue, organs, etc.). However, available evidence from
gatherers show that these surrogates of our Stone-
Age ancestors maintain low risk factors for CHD (blood
lipid profiles, blood pressure, insulin sensitivity,
body composition, etc.). All of this on a diet which
contains an average 50-65% of its total calories derived
from animal foods, which therefore necessarily entails
lower carbohydrate consumption.
Clearly, the Keys equation breaks down when either
the macronutrient content (high protein and low
carbohydrate) or the fatty-
acid composition of the diet (or both) varies beyond the
range of conditions from which Keys originally derived
his regression. Although there is much circumstantial
evidence to indicate that the Keys equation is erroneous
under these conditions, there is no empirical data that
I am aware of which has specifically investigated or
confirmed this concept.
of the role of saturated fats in promoting high
Comment: Some who promote
diets based on those of traditional peoples--
who may at times have eaten higher levels of saturated
suggest that the modern (high) levels of CHD do not have
anything to do with saturated fat from animal sources.
Rather, they point to modern processing techniques as
having introduced new food substances into the human
diet with detrimental effects, particularly excess
polyunsaturates, hydrogenated oils, and refined
There is much evidence to support the second half of
this sentiment, but the evidence does not agree with the
- Hydrogenated oils (trans fatty acids), refined
carbohdrates, and polyunsaturates. There is now
substantial evidence that hydrogenated oils (trans
fats) are atherogenic via their hypercholesterolemic
effects [Willett et al. 1994]. And in
terms of their cholesterol-
raising properties they may be worse than saturated
fats, because they cause a decrease in HDL
cholesterol [Ascherio et al. 1997].
Refined carbohydrate (sucrose in particular) has
been known for more than 30 years [Yudkin 1972] to
be implicated in its CHD-
promoting effects, probably through increases in
VLDL (the precursor to LDL), triglycerides, total
cholesterol, and perhaps decreases in HDL [Hollenbeck
et al. 1989]. Recently it has been
recognized that although dietary polyunsaturates may
lower serum cholesterol levels, they may actually
increase the risk for CHD by increasing the
susceptibility of LDL to oxidation [Louheranta et
So I am in agreement that hydrogenated fats,
refined carbohydrates, and excessive polyunsaturated
fats (primarily linoleic acid, 18:2n6) contribute to
the development of CHD via hypercholesterolemic and
- Saturated animal fats in overall dietary
context. However, I cannot agree with the
statement that saturated fats from animals in modern
diets have nothing to do with CHD. It may be
possible that the hypercholesterolemic effects of
saturated fats (12:0, 14:0, 16:0) can be negated or
somewhat ameliorated by extremely low levels of
dietary carbohydrates (particularly in insulin-
resistant subjects) or by high levels of dietary
protein (>20% of total calories) via protein's
suppressing effects [Kalopissis et al.
However, it is clear beyond a shadow of a doubt
that dietary saturated fats (12:0, 14:0, and 16:0)
elevate serum cholesterol levels within the context
of the "average American diet." A recent
analysis of 224 published studies encompassing 8,143
subjects (many under metabolic ward conditions) has
unequivocally demonstrated the hypercholesterolemic
effect of dietary saturated fats [Howell et
al. 1997]. The cellular basis for this
observation stems from the regulation of low-
density lipoproteins (LDLs). When the amount of
cholesterol or saturated fat coming into the body is
increased, there is an expansion of the sterol pools
within liver cells, and to a lesser extent,
peripheral cells, which causes a down-
regulation of LDL receptors. As a consequence, LDL
in plasma increases [Dietschy 1997].
Some have argued that increases in total plasma
cholesterol and LDL may not necessarily have a
direct relationship to mortality from CHD [Stamler et
al. 1986]. Clearly, there are a wide variety
of independent risk factors for CHD including
hypertension, homocysteine (increased by
deficiencies primarily in folate, vitamin B-6, and
secondarily in B-12), catecholamines, n6/n3 fatty-
acid ratio, antioxidant status (vitamins E, C, beta-
carotene, phytochemicals, etc.), dietary fiber,
cigarette smoking, and ethanol (alcohol)
consumption, which influence a variety of
physiological systems involved with CHD. However,
there is powerful evidence (n =
356,222) to indicate that the relationship between
serum cholesterol levels and the risk of premature
death from CHD is, nevertheless, continuous and
graded [Stamler et al. 1986].
Therefore, the recommendation by some that it is
harmless to consume high levels of dietary saturated
fats within the context of the "average
American diet" appears to not only be
erroneous, but probably deadly. Our hunter-
gatherer ancestors consumed high levels of animal
food (probably >55% of their total daily
calories); however, the context under which this was
done was much different than present-
As I have previously mentioned, the carbohydrate
content of the diet was low (~<35% of total
calories) and composed of plant foods with high
soluble fiber and low starch content. The protein
content of the diet would have exceeded 20% and may
have been as high as 30-40%. The polyunsaturated
fats consumed would have had a low n6/n3 ratio, and
there would have been both ample levels of 20 and
22-carbon fats of both the n6 and n3 variety. Since
marrow contains 70-75% monounsaturated fats and was
a favored food, it is likely that although the fat
content of the diet may have been as high as 40%, it
was composed of not only a much more favorable n6/n3
polyunsaturated fat ratio, but higher levels of
monounsaturated fats and non-
atherogenic saturated fats such as stearic acid
(18:0) as well.
|The role of
essential fatty acids (EFAs) and the balance of
omega-6 to omega-3 fats.
saturated fats in context, is it not the case
The first part of this is
essentially correct. Indeed, levels of EFAs (essential
particularly the chain-
elongated 20 and 22-carbon forms of both n6 and n3
families) are inversely related to levels of coronary
heart disease (CHD). Paradoxically (at least in terms of
the American Heart Association dietary recommendations),
Hindu vegetarians from India whose diet is composed
largely of low-fat grains and pulses (legumes) maintain
CHD rates equal to [Begom et al. 1995] or
higher [Miller et al. 1988] than those in
the USA and countries of Europe, despite their diets'
lower total fat content when compared to American and
- A low-fat diet that is deficient in
(polyunsaturated) essential fatty acids (EFAs) will
cause heart disease, whereas
- A diet high in saturated fat but containing plenty
of polyunsaturated n3 fats (i.e., omega-3s, found in
animal foods) will keep arteries clear, such as in
Indian populations have
consistently exhibited high plasma n6/n3 ratios, low
levels of 20:5n3 and 22:6n3, and high levels of 18:2n6
when compared to Western populations [Miller et
al. 1988; Reddy et al. 1994;
Ghafoorunissa 1984; McKeigue et al. 1985].
All of these EFA profiles are conducive to CHD and occur
because of the lack of an appropriate balance of n6/n3,
and because of the almost total lack of 20 and 22-carbon
fatty acids in commonly consumed plant-
Regarding the second part of
the above comment, it is partially correct to say that
omega-3 (n3) fats provide protection against CHD, but it
has little to do, directly, with keeping the arteries
clear (i.e., atherosclerosis). N3 fats provide
protection from CHD in that they lower triglycerides and
perhaps VLDL; additionally, they reduce platelet
adhesitivity and decrease thrombotic tendencies as well
as reducing cardiac arrhythmias [Leaf et al.1988].
However, recent large-
analyses [Harris 1997] show that n3 fats actually cause
a 5-10% rise in LDL cholesterol and a small rise (1-3%)
in HDL. Eskimo populations indeed do consume higher
levels of both saturated fat and polyunsaturated n3 fats
than do Western populations; they also exhibit
significantly lower serum LDL and total cholesterol
levels than Europeans [Bang and Dyerberg 1980].
Thus, logic (derived from
analytical data) dictates that the n3 fats are not the
element responsible for the lower total and LDL serum
cholesterol in these populations. Careful analysis of
Bang and Dyerberg's data  reveals a much higher
protein intake (26% of total calories) compared to the
11% value in Danes. High protein intakes are known to
cause drastic inhibition of hepatic VLDL synthesis [Kalopissis
et al. 1995] (VLDLs are the source of LDLs),
protein diets in humans have been clinically shown to
reduce total cholesterol, LDL cholesterol, and
triglycerides while simultaneously increasing HDL [Wolfe
1995]. Further, acute consumption of high levels of
low-fat (6.5%), lean-
beef protein is not associated with a post-
prandial rise in insulin but rather an increase in
glucagon levels [Westphal et al. 1990].
Consequently, the major
reason why Eskimo diets keep serum cholesterol levels
low and atherosclerosis at bay is because of their high
protein content primarily. There is no doubt that n3
fats also contribute to lowering CHD, but it is not
directly mediated by a lowering of LDL cholesterol but
rather by other mechanisms previously outlined.
fat, protein, and carbohydrate on glucagon
Follow-up question: To
clarify the above statement that low-fat (6.5%) beef
stimulates higher glucagon levels, isn't it the protein
content of beef rather than the fact it is also low in
fat that stimulates glucagon? My impression was that fat
intake level has little effect on the insulin/
glucagon response to food. (Editorial note: Release of
insulin not only causes uptake of glucose into cells,
but also promotes fat storage. Glucagon is the other
side of the equation, causing mobilization of body fat
for conversion to energy; that is, it causes fat to be
As far as I know, there are
no good, recent data evaluating the effects of varying
fat mixtures upon insulin/
glucagon responses in humans. Most of the data involves
manipulating carbohydrate, with varying amounts of fat;
protein is usually held constant. The Westphal et
al.  paper evaluates protein/
carbohydrate mixtures on serum glucagon responses. Pure
dietary carbohydrate (50g glucose) shows no rise in
plasma glucagon, whereas pure protein (actually 93.5%
lean beef, 6.5% fat, as mentioned above) causes the
greatest rise in glucagon after 1 hour;
with roughly equal areas under the curve after 3
hours when comparing pure protein to protein/
carbohydrate mixtures (50g glucose/
Thus, there appears to be a
response effect on glucagon with protein/
carbohydrate mixtures, and from the data, it can
probably be interpreted that there is a dose/
response effect with pure protein. As far as insulin
response goes (as opposed to glucagon response), fat/
carbohydrate mixtures cause a greater rise than
carbohydrate meals alone, presumably because of the
stimulatory effect of fat upon glucose-
dependent insulinotropic peptide (GIP) [Collier et
Thus, as indicated by the
question, there is a dose-
dependent effect of dietary protein upon glucagon
secretion which is largely independent of either
carbohydrate or fat.
levels and their effect on blood lipids
Some would dismiss the idea
that dietary protein can have any influence upon
cardiovascular disease with the argument that there is
no difference in CHD incidence in populations consuming
high vs. low-
protein diets. However, a serious problem with this
argument is the lack of much substantial variability in
current protein consumption levels worldwide to produce
support for this line of reasoning via epidemiological
Global surveys of the
world's populations indicate a remarkably limited range
of protein consumption that varies from about 10 to 15%
of total calories [Speth 1989]. Further, except for
reports of Inuit and Eskimo diets, I know of no
references showing any contemporary populations
consuming 15-20% of their calories as protein, much less
protein diets in the 30-40% range of consumption such as
our ancestors or recent hunter-
gatherers have sometimes eaten.
Speth  has extensively
studied protein intakes in contemporary worldwide
populations and notes that most human populations today
obtain between 10-15% of their total energy requirements
from protein. For Americans the value is 14%, for Swedes
it is 12%; for Italian shipyard workers it is
12.5-12.8%; for Japanese it is 14.4%, and for West
Germans it is 11.1%. Even among athletes, values rarely
exceed 15%. Speth  shows that Italian athletes
consumed between 17-18% of their caloric intake as
protein; Russian athletes consumed 11-13%; and
Australian athletes competing at the 1968 Olympic Games
consumed 14.4% of their daily calories as protein. This
data clearly demonstrates the relative homogeneity
amongst contemporary global populations in their protein
That protein consumption may
have anything to do with the atherosclerotic process and
hence CHD is an obscure topic which has been rarely
examined by the medical and nutritional communities. It
is not surprising that few are aware of the literature
which supports this concept. However, there are now at
least three human clinical trials [Wolfe et al.
1991; Wolfe et al. 1992; Wolfe 1995]
demonstrating that isocaloric (calorie-
calorie) substitution of protein (ranging from 17-27% of
total daily calories) for carbohydrate reduces
triglycerides, VLDL, LDL, and total cholesterol while
increasing HDL cholesterol. Further, acute consumption
of high levels of beef protein without carbohydrate
evokes an extremely small rise in serum insulin levels
and a concomitant substantial rise in glucagon [Westphal
et al. 1990]. Both of these acute responses
would tend to be associated with a reduced risk for
Lastly, in animal models,
high levels of protein are known to dramatically inhibit
hepatic VLDL synthesis [Kalopissis et al.
1995]. VLDLs are the precursor molecules for LDL
cholesterol. In their classic study of Inuit, Bang and
Dyerberg  have shown that the serum cholesterol
levels of the Inuit were 0.48 mmol/liter lower than what
would have been predicted by the Keys equation, which
estimates plasma lipid levels from dietary saturated
fats, polyunsaturated fats, and cholesterol. At the time
(1980), it was suggested that the paradoxically low
serum cholesterol levels may have resulted from the
higher omega-3 (n3) fats found in the Eskimo's seafood-
However, after almost 30
years of research, meta-
analytical studies have shown that n3 fatty acids
slightly elevate (by 5-10%) LDL cholesterol
concentrations, but do not materially affect total
cholesterol [Harris 1997]. Consequently, it may have
been the higher dietary protein intake (23-26% of total
calories) in the Inuit compared to the Danish controls
(11% of total calories as protein) which accounted for
these differences. However, since the Keys equation
considers dietary monounsaturated fats as neutral (which
more recent research indicates is not the case [Gardner et
al. 1995]), it is possible that the higher
monounsaturated fat content (57.3% of total fat) in the
Inuit diet (vs. 34.6% in the Danes) may have also
contributed to the plasma cholesterol differences.
diets by themselves do not eliminate the
raising effects of high-
Many people who have been
influenced by the recent interest in low-
carbohydrate dieting would argue that the cholesterol-
lowering effect of the Eskimo diet stemmed from its low
carbohydrate content. However, in one of the few (and
controlled) metabolic ward trials of a carbohydrate-
free (<20 gm/day) diet, Phinney and colleagues [Phinney
et al. 1983] demonstrated a rather large
rise in serum cholesterol (159 to 208 mg/dl) in nine
lean, healthy males who participated in this 35-day
The protein content of the
diet was estimated to be 15%, whereas the fat content of
the diet represented between 83-85% of total daily
calories. Consequently, during the dietary trial, the
protein content remained similar to the average daily
intake in the U.S. and was not increased. This
experiment shows that a carbohydrate-
free diet composed of "ground beef, breast of
packed tuna fish, powdered egg solids, and cheddar
cheese with mayonnaise, heavy cream, sour cream, and
cream cheese as primary lipid sources" was
In a less-
publicized but highly controlled clinical research
center (CRC) study, Gray et al. showed
similar results in a 3-week study of 10 healthy males
who consumed a diet composed of 73-75% fat, 7-9%
carbohydrate, and 16-20% protein. Compared to their
carbohydrate) diet, the high-
fat diet increased total cholesterol from 156.5 mg/dl to
167.6 mg/dl, and LDL cholesterol increased from 46.6
mg/dl to 55 mg/dl. The total cholesterol/HDL ratio,
however, improved on the high-
fat diet, going from 3.36 to 3.20.
as in the Phinney  and Gray studies--
characteristically induce other beneficial lipid
profiles such as increased HDL levels and decreased
triglyceride levels. These blood lipid changes
(increased HDL and reduced triglycerides) have also been
frequently demonstrated in reduced-
carbohydrate diets [Jeppesen et al. 1997;
Coulston et al. 1983] in which carbohydrate
has been reduced, but not as drastically as in the
Phinney and Gray trials.
So in summary, the animal
foods of our Stone-
Age ancestors were probably non-
atherogenic because they contained high levels of
protein (>20% of total calories), lower levels of
saturated fats, higher levels of monounsaturated fats,
higher levels of n3 polyunsaturated fats, little or no
trans fats, and higher levels of HUFA (>18-carbon)
fats of both the n6 and n3 varieties than modern Western
based diets. The higher consumption of animal-
based foods would have necessarily reduced the
carbohydrate content of the diet, and this would have
also benefited certain aspects of the lipid profile as
response of fat combined with carbohydrate
In a previous comment, I
suggested that meals of pre-
agricultural peoples tended to produce less of a
glycemic response than do modern Western meals. This was
based on the observation that hunter-
gatherer meals generally were not the elaborate mixtures
protein that are typical of Western meat/
potato meals. Hunter-
gatherers quite often would eat only the animal killed
for a meal without added plant courses. Thus, protein/
fat macronutrient mixtures were the norm. Carbohydrates
generally were consumed as they were collected, or
separate from animal-
based meals. It has been well-
established that by mixing fat with carbohydrate, the
glycemic response worsens [Collier et al.
|What is the
relevance of genetic differences in individual
blood lipid response to high and low-fat
In view of recent
discussions about low-
carbohydrate diets and reevaluation of the effects of
carbohydrate diets, there have been speculations
regarding human blood-
lipid responses to high and low-
carbohydrate diets, and whether or not there is a
genetic basis for differential responders. To follow up
on this, there is substantial evidence to show that
lipid response to variation in dietary fat and
cholesterol intake varies widely among individuals [Mistry
et al. 1981; Jacobs et al.
1983; Katan et al. 1988], and that this
variability is likely attributable to genetic factors
with polymorphisms [variant forms of a gene] at several
genetic loci, including genes for apolipoproteins and
density lipoprotein (LDL) particle size and density [Dreon
et al. 1992].
There is an LDL subclass
called pattern "B" which is characterized by a
preponderance of small, dense LDL particles, elevated
triglycerides, low high-
density cholesterol (HDL), and increased coronary heart
disease (CHD) risk. LDL pattern "B" occurs in
approximately 30% of the male population [Austin et
al. 1988]. LDL subclass pattern "A" is
characterized by larger, more buoyant LDL particles.
carbohydrate diets induce a reduction in the atherogenic,
small, dense LDL in individuals displaying pattern
"B", and also cause reductions in LDL
cholesterol greater than in subjects displaying pattern
"A" [Dreon and Krauss 1997]. These data
clearly suggest that low-
carbohydrate diets may be more effective in lowering LDL
cholesterol and small, dense LDL in about 30% of the
population, and less effective in 70% of the population.
LDL subclass pattern
"B" is influenced by a major gene or genes
with a prevalence in the American population estimated
to be 25% [Austin et al. 1988]. The
specific gene or genes responsible for this trait have
not been identified, but there is evidence to show
linkage to polymorphic markers near the LDL receptor
gene on chromosome 19p [Nishina et al.
To date, there are no
experimental data evaluating the effects of quite low-
carbohydrate diets (<30% of total energy) upon blood
lipid responses in LDL subclasses "A" or
"B". However, Krauss et al.
 have clearly shown that all subjects (n =
105), whether subclass "A" or "B",
responded to a high-
fat diet (46% energy) by substantial increases in LDL
cholesterol, and responded to a low-
fat diet (23.9% energy) by decreases in LDL cholesterol.
The difference was simply in the magnitude of the
negative effect experienced, not whether it occurred or
This information does not
support the contention by some that differential
responders to high and low-
fat diets bias the interpretation of dietary
intervention trials, nor does it lend support to the
proposal that high-
fat diets can improve blood-
lipid profiles. I contend that any improvement in total
cholesterol or LDL cholesterol by uncontrolled, self-
carbohydrate diets are an artifact of:
Further, improvements in
triglycerides, VLDL, and HDL can be mainly attributed to
reductions in carbohydrate.
- Reductions in total caloric intake,
- Increases in total protein,
- Unknowing changes in the dietary
saturated fat (P:M:S) ratio, and
- Combination of the three.
calorie) controlled conditions in which dietary
saturated fat is increased at the expense of any other
lipid or macronutrient, there will be a characteristic
increase in LDL cholesterol, as shown time and again
analyses [Howell et al. 1997], under
metabolic ward conditions [Phinney et al.
1983], and corroborated by in vitro
and in vivo data showing that LDL
receptors are down-
regulated by dietary saturated fat [Brown and Goldstein
As I hope the foregoing has
demonstrated, further studies that have been performed
in the years since the low-fat, high-
carbohydrate viewpoint first became standard have
revealed additional factors affecting blood lipids, and
that the previous view has been too simplistic. Serious
drawbacks have become apparent in the conventional
wisdom about low-fat, high-
carbohydrate diets. No longer does this view adequately
explain what we have come to know about the effects of
macronutrient content with increasing resolution at the
biochemical level over the last decade.
We are entering an era of
dietary research where the details of underlying
biochemical processes that govern lipid responses are
being increasingly well-
understood. Certain of these details validate the
positive health effects that may accrue from the dietary
pattern suggested by recently emerging studies of diet
in human evolution. Hunter-
gatherers who eat high levels of protein, lower levels
of carbohydrate, and similar or even higher levels of
fat (but with a much different lipid profile) compared
to modern Western diets exhibit extremely positive blood
lipid profiles and quite low rates of CHD. This presents
a serious challenge for researchers, since this result
would not be predicted by previous theories about fat in
While the detrimental role
of high levels of saturated fat by itself has been
validated, the overall picture of the various other
types of fat is turning out to be more complex. Fat is
as essential a nutrient as the other macronutrients.
More important than the overall level of fat in the diet
are the roles and ratios of specific types of fat, such
as the positive role of monounsaturated fats and a high
n3/n6 polyunsaturated ratio, and the negative effects of
trans fatty acids and deficiencies in EFAs.
Where the polyunsaturated
fats are concerned, modern diets contain excessive
amounts of the n6 fat linoleic acid (that would have
been present in lesser amounts in preagricultural
diets), which promotes oxidation of cholesterol and
consequently formation of atherosclerotic plaque. Also,
what saturated fats are consumed by pre-
agricultural peoples come from wild animal tissues.
Compared to modern domesticated animals, these animal
tissues are much higher in the non-atherogenic saturated
fat stearic acid and lower in the 14:0 and 16:0 fats
that promote high cholesterol.
At the same time, as the
roles of various fats in the diet are becoming more
understood, attention has recently begun to turn to
investigation of the biochemical effects on blood lipids
of the other macronutrients. By comparison with the
voluminous studies performed in recent decades on fatty
acids, these have been relatively ignored. However, only
by devoting the same detailed attention to the effects
of carbohydrate and protein on blood lipid response will
we fully understand the role of all the macronutrients
on health in relation to each other. As previously
mentioned, the hyperinsulinemic effect of excess
carbohydrates is looming large as a subject warranting
much further study. And what studies have been performed
initially on higher protein consumption levels show that
they exert very positive effects on blood-
In this ongoing
investigation, the "paleolithic" picture of
the foods and macronutrient ratios that would have
prevailed during human evolution provides a valuable
template: One that can yield key insights for guiding
future study into the food consumption patterns to which
the human species is genetically best adapted.
--Loren Cordain, Ph.D.
For further Paleodiet
research from Dr. Cordain, you can download
printable PDFs of his research group's peer-reviewed
papers (more than 20 at last count) at his website,
plus get information about his 2002 book, The
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