A series of articles originally published on the Crossfit website by Prof Tim Noakes

1. IT’S THE INSULIN RESISTANCE, STUPID:
PART 1
ByProf. Timothy Noakes July, 2019
When medical scientists propagate a false hypothesis, two things happen, and both of them are bad.
First, the wrong idea causes direct harm to those who adopt practices based on that incorrect hypothesis. Second, the wrong idea suppresses any attempts to
discover the correct hypothesis. Such suppression occurs as a result of (enforced) scientific consensus.
Anyone who dares to question the false but agreed-upon hypothesis is labeled a “hypothesis skeptic” or “hypothesis denier.” Very soon, that individual finds herself
a scientific pariah, shunned and publicly humiliated by her colleagues, no longer able to secure research funding. In this way skeptics are conveniently and very
effectively removed from the scientific mainstream. This technique is now recognized as academic mobbing (2) and ritual degradation (3). The consequences for the
victim of academic mobbing and ritual degradation are usually calamitous.
Having personally traversed this academic minefield for the past nine years, I understand it rather too well (4).
But the reality is that science is never settled, and skeptics will always play a crucial role in driving scientific progress.
Ancel Keys’ incorrect diet-heart hypothesis that saturated fat is the direct cause of heart attacks and death from coronary heart disease (CHD) led directly to its
offspring, the lipid hypothesis, which holds that an elevated blood cholesterol concentration is the singular cause of CHD. This in turn led to a multibillion-dollar
industry focused on reducing blood cholesterol concentrations, principally through the prescription of cholesterol-lowering statins and “aided” by a low-fat, high-
carbohydrate (LFHC) diet. This diet recommendation was enshrined in the 1977 U.S. Dietary Guidelines for Americans (USDGA) (5).
The 1977 USDGA and other forms of continued support for the diet-heart and lipid hypotheses have led to at least three dire consequences (4).
First, the incidences of obesity and Type 2 diabetes mellitus (T2DM) have more than doubled in this period (6). The reasons for this will be explained. Importantly,
the key pathological feature of T2DM is widespread progressive obstructive arterial disease in all the major arterial systems in the body but especially the arteries
supplying the kidneys and lower limbs — thus the growing global pandemic of kidney failure and lower-limb amputations.
As a result of the worldwide adoption of the USDGA based on Keys’ false diet-heart hypothesis, the LFHC diet has been promoted as the ultimate intervention to
prevent obstruction of the coronary arteries. Yet, very inconveniently, the promotion of this diet has clearly produced a much more devastating outcome — the
worst possible forms of obstructive arterial disease in persons with T2DM.
Second, despite the almost universal prescription of statin drugs to anyone considered at even the slightest risk of ever developing CHD, after five or more decades
in decline, the global incidence of CHD has begun to increase in some countries (7). Clearly, the billion-dollar statin drug industry that thrives by promising to
prevent all future heart attacks is not delivering on its puffery. Evidence of the ineffectiveness of statins is perhaps the final repudiation of both the diet-heart and
lipid hypotheses.
Third, because these two hypotheses were embraced so fanatically (and without proper due scientific process), any attempts by skeptics to develop alternate
hypotheses have been rigorously suppressed in part by labeling the challengers as “cholesterol-skeptics” or “cholesterol-denialists” (8).
The ultimate tragedy is that the one theory that best explains why the adoption of the LFHC diet has destroyed global health has been ignored. It is not taught in even
a minority of medical schools around the world. This theory holds that a single biological state, insulin resistance syndrome (IRS), is the key driver of most of the
chronic medical conditions to which modern humans fall prey. This theory is the work of a single researcher, Dr. Gerald Reaven, recently deceased, and his small
team of researchers at Stanford University in Palo Alto, California.
It is my argument that Reaven’s work is perhaps the most important body of medical research of the last five decades. His work is so far ahead of current medical
thinking that, sadly, Reaven died before his work’s value was properly recognized with a Nobel Prize. But his time of recognition will come. The moment is rapidly
approaching when the medical profession will be forced to admit the genius in Reaven’s work. The truth cannot be denied forever.

2. THE DISCOVERY OF INSULIN RESISTANCE SYNDROME
Reaven spent 60 years describing the condition that would become his trademark, insulin resistance syndrome (IRS).
His academic interest (1, 9) was stirred early in his career when he read the work of Harry Himsworth (10), who already in the 1930s had proposed that there are
two forms of diabetes. The first, insulin-deficient Type 1 diabetes mellitus (T1DM), is caused when the pancreatic insulin-secreting beta cells are destroyed by an
autoimmune process of unknown origin. As a result, the affected person is left without any ability to produce insulin. Such persons cannot live without regular
insulin injections.
It was this group of patients whose lives were so dramatically changed with the discovery of insulin by Frederick Banting, John Macleod, Charles Best, and James
Collip in December 1921 (11). Because insulin is present in the blood in such small amounts, at the time of insulin’s discovery, it was not possible to accurately
measure blood insulin concentrations. (Banting and Macleod won the Nobel Prize for isolating a pancreatic substance that reduced blood insulin concentrations in
those with T1DM. At the time, they knew only that insulin was a protein present in pancreatic tissue. The structure of insulin was first characterized by another
Nobel Prize winner, Dorothy Hodgkin, in 1968 (12)). The natural assumption, then, was that all forms of diabetes are caused by the same mechanism: an absolute
deficiency in circulating blood insulin concentrations, as found in T1DM.
But Himsworth came up with a different explanation, seemingly from nowhere (10). He understood that in all forms of diabetes, the tissues have a reduced capacity
to take up glucose. He did not agree, however, that this was always due to the complete absence of the hormone insulin, one action of which is to promote glucose
uptake by the tissues, particularly the liver, heart, and skeletal muscles.
Instead, he proposed, “The diminished ability of the tissues to utilize glucose is referable either to a deficiency of insulin or to insensitivity to insulin, although it is
possible that both factors may operate simultaneously.” Accordingly, he argued that diabetes should be subdivided into two categories: “insulin-sensitive and
insulin-insensitive types.” He also noted that there were clear differences in the clinical expression of these two subtypes so that “insulin-sensitive diabetes, which is
thought to be due to a deficiency of insulin, tends to be severe … whereas diabetes due not a lack of insulin but to insensitivity to insulin, is generally less severe.”
So by 1949, Himsworth had concluded, “It appears we should accustom ourselves to the idea that a primary deficiency of insulin is only one, and then not the
commonest, cause of the diabetes syndrome” (13). It would take another 40 years before the National Diabetes Data Group would formally acknowledge this
distinction (14).
Today, we understand that in persons with IRS, especially those who ultimately develop T2DM, the target cells on which insulin normally acts, especially those in the
pancreas and liver but also in many other organs, become progressively more resistant to the normal action of insulin over years and even decades. As a result,
insulin must be secreted in increasingly greater amounts, producing the progressive IRS that Reaven’s methodical research ultimately discovered.
But after perhaps two to three decades of this daily need to oversecrete insulin, the pancreatic beta cells become exhausted; the pancreas fails; blood insulin
concentrations fall; and the patient develops the characteristic features of T2DM, including very high blood glucose concentrations with the appearance of glucose in
the urine.
Reaven demonstrated that most persons with IRS do not develop T2DM. However, this does not mean those who have IRS that does not progress to T2DM will live
long and disease-free lives.
In fact, Reaven’s unique contribution has been to show that IRS is the precursor for essentially all the chronic medical conditions that currently plague modern
humans, from acne and Alzheimer’s disease or dementia to hypertension, peripheral vascular disease, polycystic ovarian syndrome, coronary heart disease, and
perhaps even cancer.
Thus, while we fret over the growing pandemic of T2DM, we need to understand that this is only the tip of the disease iceberg; hidden underneath lies an even
greater epidemic of chronic modern diseases caused by IRS in those who will not ever develop T2DM but who will nevertheless suffer from any number of a wide
array of conditions that, in our ignorance, we continue to call “diseases of lifestyle.” These diseases, as I will show, are more correctly termed “diseases of the modern
industrial diet” of highly processed foods.
Since IRS is the key driver of elevated blood pressure (hypertension) (15) and coronary artery disease (16), in his repudiation of the simplistic diet-heart and lipid
hypotheses, Reaven also established that “coronary heart disease risk factors in normotensive, nondiabetic individuals includes more than a high LDL cholesterol
concentration” (1).
To fully comprehend the nature of modern human ill health, we need first to understand the IRS.
REAVEN BECOMES INTERESTED IN INSULIN INSENSITIVITY
Today, it is rather easier to distinguish between T1DM, T2DM, and IRS in affected patients. All one need do is measure blood insulin concentrations. If endogenous
(produced by the patient’s body) insulin is absent, the patient has T1DM; if insulin is present, the patient may have either T2DM or IRS.
But when Reaven began his work, the ability to effectively measure blood insulin concentrations was still new. It had only just been achieved by Rosalyn Yalow and
Solomon Berson in 1960. Working at the Veterans Administration (VA) hospital in the Bronx, New York, Yalow and Berson developed an immunoassay method to
accurately measure the tiny amounts of insulin in the blood (17). For this, Yalow was awarded the Nobel Prize in 1977.
Yalow and Berson wasted no time in showing that blood insulin concentrations were, on average, higher in persons with T2DM than in healthy subjects without the
disease. They concluded: “The tissues of the maturity-onset diabetic do not respond to his insulin as well as the tissues of the nondiabetic subject respond to his
insulin” (16). Thus, they confirmed Himsworth’s postulate from two decades earlier: that those with T2DM are “insulin insensitive.”

3. Yet, no one at that time understood exactly what constitutes “insulin insensitivity.” Reaven would devote the remainder of his working life to the explanation of this
phenomenon.
REAVEN’S INTEREST PIQUED BY ELEVATED BLOOD TRIGLYCERIDE
CONCENTRATIONS
Reaven began his research in the 1960s, at a time when Keys’ diet-heart and lipid hypotheses were gaining great traction globally. Reaven, (like most medical
doctors around the world then and now) was taught that an elevated blood cholesterol concentration “was considered the primary culprit in heart disease” (18, p.
47).
But what was Reaven to make of Margaret Albrink and Evelyn Man’s 1959 findings (19), which showed blood cholesterol concentrations appeared to be no higher in
those who had suffered heart attacks (many of whom had T2DM) than they were in normal patients without established heart disease (Figure 1)?
Figure 1: The distribution at different ages of blood cholesterol concentrations in persons without (normals) and those with diagnosed heart attack (acute myocardial
infarction) (coronaries). Note that the majority of coronaries have what were then considered normal blood cholesterol concentrations (below horizontal line at a
cholesterol concentration of 280 mg%). Reproduced from reference 19.
The usual response to such information is to ignore it, to pretend that it does not exist, as indeed has been the common practice for the past six decades. But clearly
Reaven was made of sterner stuff. He knew a paradox when he saw one, and his personality was such that the uncertainty revealed by this paradox would drive him
to examine that enigma until its truth was exposed.
Albrink and Man also reported that blood triglyceride concentrations were different in normal and coronary groups, and appeared to be higher in those with
established heart disease (Figure 2).

4. Figure 2: The distribution at different ages of blood triglyceride concentrations in persons without (normals) and those with (coronaries) diagnosed heart attack (acute
myocardial infarction). Note that the majority of normal subjects have normal blood triglyceride concentrations, whereas more than 50% of coronaries have elevated
blood triglyceride concentrations (above horizontal line at a triglyceride concentration of 8 mEq/L. Reproduced from reference 19.
When Albrink and Man plotted the distribution of these cholesterol and triglyceride concentrations in the two groups, there was much greater overlap in blood
cholesterol than in blood triglyceride concentrations (Figure 3), which suggests coronary patients and normal” were more similar in the blood cholesterol than in
their blood triglyceride concentrations. From this, Reaven could have drawn only one conclusion: that it cannot be differences in blood cholesterol concentrations
driving the greater prevalence of CHD in the coronary patients. He may indeed have wondered: Does the difference in blood triglyceride concentrations explains this
difference, and if so, why? This was the research question that would define his legacy.
Figure 3: Distribution of blood triglyceride (top) and blood cholesterol (bottom) concentrations in persons without (normals) and those with diagnosed heart attack
(acute myocardial infarction) (coronaries). Note that the overlap in these values in much greater for blood cholesterol than for blood triglyceride concentrations.
Reproduced from reference 19.
To further analyze the possible association of elevated blood triglyceride concentrations and development of CHD, the authors next compared the percentage of
persons with blood triglyceride concentrations higher than 5.5 mEq/L. As shown in Figure 4, the percentage with serum triglyceride concentrations above 5.5
mEq/L rose from about 5% in normal persons between ages 20 and 29 to >70% in those with coronary artery disease and to >85% in 12 subjects who had
experienced chest pain during exertion (angina) but who had not suffered a heart attack.

5. Figure 4: Percentage of cases below and above blood triglyceride concentrations of 5.5 mEq/L in persons without (normal) and those with diagnosed heart attack (acute
myocardial infarction) (coronary) and in persons with chest pain during exercise (angina). Note that the percentage with elevated blood triglyceride concentrations rises
from about 5% in 20- to 29-years-old normal subjects to above 85% in 12 subjects with angina. Note that the top and bottom extents of the vertical blocks show the % of
subjects with (top) and without (bottom) elevated blood triglyceride concentrations. Reproduced from reference 19.
These findings forced the following conclusion:
In summary, elevations of serum triglycerides above 5.5 mEq. per liter (about 160 mg.%) occurred in only 5% of normal young adults, in at most 30% of normal
men over 50, and, if the effects of acute illness were excluded, in 85% to 90% of patients with coronary artery disease. Few, if any, other lipid measurements which
have been reported effect such a clear-cut separation between the normal and coronary subjects.
And then Albrink and Man added the sentence that probably galvanized Reaven’s attention: “The present report suggests that an error in the metabolism of
triglycerides is the lipid abnormality operative in coronary artery disease.”
In their final studies (20, 21) the authors expanded on this theory that blood triglyceride concentrations are more likely to be elevated than are blood cholesterol
concentrations in persons with coronary artery disease. Thus, in their 1961 paper (20), they reported, “82 per cent of the patients of all ages with coronary artery
disease had high serum triglyceride concentrations.” In contrast, elevated serum cholesterol concentrations “in the absence of elevated triglyceride values
characterized only about 10 per cent of the normal population, 10 to 18 percent of the population of the patients with coronary artery disease under fifty years of
age, but virtually none of the patients over age fifty” (p. 11).
As a result, they concluded, “The serum triglyceride levels in this series appeared to provide a better separation between normal persons and patients with coronary
artery disease than the reported measurements of other serum lipids, and may provide the most accurate single indication yet available of the biochemical defect
recognizable in disease of the coronary arteries” (p. 15). They added, “There can be no doubt from the present data that the serum triglyceride concentration is more
closely associated with coronary heart disease than is the serum cholesterol concentration” (p. 17).
Only in the very recent past has the key insight of these pioneers — that elevated blood triglyceride concentrations are more effective (associational) predictors of
CHD risk than are blood cholesterol markers — begun to be appreciated. The reason for such reluctance is obvious: Whereas the targeted lowering of blood
cholesterol concentrations is a highly profitable billion-dollar industry, there are no drugs that effectively lower blood triglyceride concentrations. But there is one
simple, cheap and absolutely effective method of which, as I will reveal, these authors were already well aware.
Five years after Albrink and Man’s original publication, Peter Kuo at the Hospital of the University of Pennsylvania published his study of 286 persons with arterial
disease and known abnormalities of blood lipid (cholesterol, triglycerides, or both) concentrations (22). He showed that by far the commonest abnormality in 234
(81.8%) of these subjects was what he termed “carbohydrate-induced hyper(tri)glyceridemia.” In fact, he concluded that more than 90% of these patients had the
condition:
Although the majority of patients with atherosclerosis in this series were referred to us … (for the investigation) of hypercholesterolemia, only 8.4% were found to
have essential familial hypercholesterolemia. More than 90% were found to have carbohydrate-sensitive hyper(tri)glyceridemia with or without
hypercholesterolemia. Thus, it is reasonable to assume that with proper dietary preparation and appropriate laboratory studies, a high incidence of carbohydrate-
sensitive hyperglyceridemia could be demonstrated in persons with atherosclerosis. (22, p. 92)
Another key finding at about this time was made by Manuel Tzagournis and colleagues (23). They found that the majority of persons with premature CHD before age
49 had elevated blood triglyceride and fasting insulin concentrations, as well as abnormal glucose tolerance. All are markers of impaired insulin sensitivity. They
explain, “The high prevalence of abnormal glucose tolerance tests was unexpected because subjects with known clinical diabetes and elevated blood glucose levels
were deliberately excluded. This study also disclosed a significant positive correlation between fasting serum triglyceride concentrations and the magnitude of
glucose-induced insulin secretion as well as the level of serum cholesterol” (p. 1161).
The study by Tzagournis et al. advanced the finding of Kuo (22) because it suggested a link between carbohydrate-sensitive hypertriglyceridemia, insulin resistance,
and premature development of CHD, even in the absence of diagnosed T2DM.

6. Fast-forward to 1997 and the study by J. Michael Gaziano et al. (24), which found that persons in the highest quartile of blood triglyceride concentrations had a 16-
fold higher risk of heart attack than did the group with the lowest blood triglyceride concentrations. The authors could have been repeating the 1959 statement by
Albrink and Man when they concluded, “Elevated fasting triglyceride represents a useful marker for risk of coronary heart disease, particularly when HDL levels are
considered” (24, p. 2520).
More recently, in 2014, Maria-Agata Miselli and colleagues (25) reported their results from a study in which they followed 1,917 T2DM outpatients over 10 years to
evaluate predictors of long-term outcomes. They reported:
In conclusion, we found a direct association between mean triglycerides levels and long-term total mortality risk in older adult type 2 diabetic outpatients; the
relationship was significant even after taking into account for the effect of traditional cardiovascular risk factors and pharmacological treatments. This finding
suggests that more attention should be given to cardiovascular risk management in type 2 diabetic patients with high triglycerides levels.
The modern literature is now replete with scientific papers reporting precisely the same finding.
It is a pity that the pioneering observations of Albrink and Man have been ignored for so long while an alternate but false hypothesis has been promoted.
ANOTHER IMPORTANT OBSERVATION FROM ALBRINK AND MAN
In 1961, Albrink and Man reviewed the data they had collected in the previous 30 years since they began treating T2DM patients in 1931 (20, 21). During this time,
they learned that persons with T2DM are at increased risk of developing CHD (26). Importantly, during the course of their study, there had been a significant change
in the dietary advice given to all persons with diabetes, including those with T2DM.
Before the discovery of insulin in 1921, it was known that persons with insulin-sensitive T1DM could survive a little longer if they severely restricted their calorie
intake and ate a low-carbohydrate diet (27, 28). Thus, in the 1870s, William Morgan wrote, “A diabetic should exclude all saccharine and farinaceous materials from
his diet” (29, p. 159). He observed, “Theoretically, the Diabetic should be supplied pretty largely with FAT; and practically it is found that its effect is highly
beneficial” (p.162-3).
But the discovery of insulin allowed persons with T1DM to survive when they ate more calories, including more carbohydrate. The result was that, with time,
diabetologists began to prescribe diets with progressively higher carbohydrate contents, so that whereas in 1915 the typical diet for a T1DM patient would contain
only about 25 grams of carbohydrate per day, already by the 1940 this had increased to 172 grams/day (30, p. 62). Concurrently, diabetologists began to prescribe
higher carbohydrate diets also for those with T2DM.
Albrink, Man, and Paul Lavietes proposed that this dietary change had not been without one potentially worrying effect (21). In particular, they argued that this
change to a higher carbohydrate diet had produced an increase in average blood triglyceride concentrations in diabetic patients (Figure 5).
Figure 5: Blood triglyceride concentrations in two populations of patients with T2DM; the one studied from 1931 to 1939, when diets containing between 53 and 67% of
total calories as fat were prescribed for persons with T2DM, and the second from 1951 to 1961, when restrictions on dietary carbohydrate intake had been relaxed,
causing a reduction in fat intake percentages to about 40%. Note that the number of subjects with elevated blood triglyceride concentrations increased substantially
with this increase in carbohydrate intake. Reproduced from reference 21.
Since Albrink and Man were of the opinion that elevated blood triglyceride concentrations rather than higher blood cholesterol concentrations were the better
predictors of risk for developing CHD, they were bound to conclude the following:
At least in diabetic persons, the present study suggests that the increased coronary rate over the past 30 years has not been associated with any change in the serum
cholesterol, but rather with an increased triglyceride concentration, and the dietary change has been in the direction of lower fat and higher carbohydrate intake
rather than the higher fat reported for the country as a whole. Indeed starvation, rigorous caloric restriction, and stringent high fat, low carbohydrate diets were the

7. only form of therapy for diabetes prior to insulin. A similar diet, liberal in fat but low in carbohydrate, was carried over in the early part of the 1930’s when the
present study began, but in recent years fat intake has been reduced to that of the country as a whole and carbohydrate intake has been liberalized. Thus the rising
triglyceride concentration of diabetics is associated with the trend toward decreasing dietary fat and increasing carbohydrate intake. (21)
As if their first dramatic finding (debunking the lipid hypothesis) was not enough, Albrink and colleagues were now proposing a second theory that would also be
completely ignored in the teaching of cardiology and internal medicine, then and now. They proposed that the prescription of a higher carbohydrate diet to persons
with T2DM may cause their blood triglyceride concentrations to rise (Figure 5). According to their first controversial theory, this would have to mean that a higher
carbohydrate diet would place these persons at increased risk for CHD. Kuo, of course, later provided them with evidence that their theory was correct and a high-
carbohydrate diet does indeed elevate blood triglyceride levels.
Kuo noted that others (34, 35) had already observed that very high-carbohydrate diets (80%) could cause blood triglyceride concentrations to increase even in
healthy persons (34). But diets containing such large amounts of carbohydrate are unusual, so this finding is not of much practical significance.
Kuo’s next contribution (22, 36) was to establish that humans differ in their sensitivity to this carbohydrate-induced hypertriglyceridemia so that some would
develop hypertriglyceridemia with much lower carbohydrate intakes. He wrote:
The salient feature of a patient sensitivity to carbohydrate resides in his ability to develop hyper(tri)glyceridemia on an average American diet, estimated to supply
35% to 40% of total calories largely as refined carbohydrates … (so that) wide fluctuations of the serum triglyceride level in relation to carbohydrate intake is
another distinctive feature of carbohydrate-induced hyper(tri)glyceridemia. (22, pp.106-107)
To prove this causal relationship, he placed 64 patients with carbohydrate-sensitive hyper(tri)glyceridemia (CSHT) on a carbohydrate- and sugar-restricted diet for
between six and 30 months. The prescribed diet included four elements (22, p. 92):
1. Limit carbohydrate intake to 125 to 150 g/day.
2. Give complex carbohydrates in place of sugars, fruit juice, and sugar-containing foods. (Sucrose, lactose and fructose had to be totally eliminated from the
diet).
3. Restrict fats and oils with high short- and medium-chain fatty acid content (milk fat and coconut oil).
4. Reduce alcohol consumption.
A typical response to this dietary intervention in one such patient with CSHT is shown in Figure 6.
Figure 6: Changes in serum cholesterol, phospholipid, and triglyceride concentrations induced in one subject in response to a dietary change from a low-fat, high-
carbohydrate to a low-carbohydrate, high-fat diet with no added sugars at 12 months. Note that all three blood parameters fell on the low-carbohydrate diet and
remained low for the remaining 20 months of the study. Reproduced from reference 22.
Figure 7 shows the outcome in all 64 CSHT patients who followed the low-carbohydrate diet for an average of 16.6 months.

8. Figure 7: Changes in serum triglyceride, phospholipid, and cholesterol concentrations in 64 subjects with CSHT in response to a dietary change from a low-fat, high-
carbohydrate to a low-carbohydrate, high-fat diet with no added sugars at time zero. Note that all three blood parameters fell on the low-carbohydrate diet and
remained low for the remaining 16.6 months of the study. Reproduced from reference 22.
An interesting finding shown in Figure 7 is that the low-carbohydrate, no-sugar diet not only lowered blood triglyceride concentrations but also lowered blood
cholesterol concentrations.
Another important finding was that sugar and “starch” had quite different effects on blood triglyceride responses in persons with CSHT. Whereas ingesting the same
number of calories in the form of sugar substantially raised blood triglyceride concentrations, these concentrations fell steeply when the sugar was replaced with
“starch” (36).
WHAT WE KNEW IN THE 1960S
So what did we know in 1967 as a result of the research of Albrink, Man, and Kuo, and what have we since forgotten?
1. Blood triglyceride concentrations appear to be better predictors of the risk of CHD than blood cholesterol concentrations.
2. Blood triglyceride concentrations rise in response to carbohydrate ingestion.
3. Individuals differ in the extent to which their blood triglyceride concentrations rise in response to carbohydrate feeding.
4. The extent to which blood triglyceride concentrations rise with carbohydrate feeding is one of the best measures of that individual’s degree of insulin-
sensitivity/insulin-resistance. Hence, Kuo coined the term “carbohydrate-sensitive hyper(tri)glyceridemia” (CSHT).
5. Sugar (sucrose) produced a greater increase in blood triglyceride concentrations than did an equivalent amount of starch (36, 37). This effect was due to
the presence of fructose (in sucrose) and resulted from up-regulation of triglyceride synthesis in both liver and adipose tissue (37).
6. A carbohydrate-restricted diet lowers blood triglyceride concentrations and may also reduce blood cholesterol concentrations.
CONSEQUENCES OF THESE FINDINGS
All these findings were most inconvenient, as they were reported at the exact time Ancel Keys and the American Heart Association were beginning to demonize fat,
especially saturated fat, as the cause of CHD. Thus, the need arose to glorify carbohydrates, especially “whole” grains, as uniquely healthy.
To achieve this, any finding that carbohydrates may produce undesirable health consequences would have to be suppressed; six decades of the “health-washing” of
carbohydrates was about to begin in earnest.
A key component of this carbohydrate “health-washing” would have to be the absolute suppression of any mention that carbohydrate-sensitive
hypertriglyceridemia is a — perhaps the key driver of CHD.
This inconvenient fact would need to be hidden over the next 60 years as the false diet-heart and lipid hypotheses became the dominant paradigms directing the
teaching and conduct of medical professionals around the globe.

9. In the following column, we will continue to track Reaven’s journey toward discovering an alternate explanation for CHD.
This article was first published on the CrossFit website.
Professor T.D. Noakes (OMS, MBChB, MD, D.Sc., Ph.D.[hc], FACSM, [hon] FFSEM UK, [hon] FFSEM Ire) studied at the University of Cape Town (UCT), obtaining a
MBChB degree and an MD and DSc (Med) in Exercise Science. He is now an Emeritus Professor at UCT, following his retirement from the Research Unit of Exercise
Science and Sports Medicine. In 1995, he was a co-founder of the now-prestigious Sports Science Institute of South Africa (SSISA). He has been rated an A1 scientist
by the National Research Foundation of SA (NRF) for a second five-year term. In 2008, he received the Order of Mapungubwe, Silver, from the President of South
Africa for his “excellent contribution in the field of sports and the science of physical exercise.”
Noakes has published more than 750 scientific books and articles. He has been cited more than 16,000 times in scientific literature and has an H-index of 71. He has
won numerous awards over the years and made himself available on many editorial boards. He has authored many books, including Lore of Running (4th Edition),
considered to be the “bible” for runners; his autobiography, Challenging Beliefs: Memoirs of a Career; Waterlogged: The Serious Problem of Overhydration in
Endurance Sports (in 2012); and The Real Meal Revolution (in 2013).
Following the publication of the best-selling The Real Meal Revolution, he founded The Noakes Foundation, the focus of which is to support high quality research of
the low-carbohydrate, high-fat diet, especially for those with insulin resistance.
He is highly acclaimed in his field and, at age 67, still is physically active, taking part in races up to 21 km as well as regular CrossFit training.
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disease. Circulation 38(1968): 1156-1163.
24. Gaziano JM, Hennekens CH, O’Donnell CJ, et al. Fasting triglycerides, high-density lipoprotein, and risk of myocardial infarction. Circulation 96(1997): 2520-2525.
25. Miselli M-A, Nora ED, Passaro N, et al. Plasma triglycerides predict ten-years all-cause mortality in outpatients with type 2 diabetes mellitus: A longitudinal
observational study. Cardiov Diabetol. 13(2014): 135.
26. Root, HF, Bland EF, Gordon WH, et al. Coronary atherosclerosis in diabetes mellitus. JAMA 113(1939): 27-30.
27. Henderson G. Court of last appeal – the early history of the high-fat diet for diabetes. J Diabetes Metab. 7(2016): 8.
28. Westman EC, Yancy WS, Humphreys M. Dietary treatment of diabetes mellitus in the pre-insulin era (1914-1922). Perspectives Biol Med. 49(2006): 77-83.
29. Morgan W. Diabetes mellitus: Its history, chemistry, anatomy, pathology, physiology and treatment. London: The Homeopathic Publishing Company, 1877.
30. Joslin EP. A diabetic manual for the mutual use of doctor and patient. Philadelphia: Lea and Febiger, 1941.
31. Allen FM, Stillman E, Fitz R. Total dietary regulation in the treatment of diabetes. Monograph 11. Rockefeller Institute for Medical Research, 1919.
32. Rabinowitz IM. Experiences with a high carbohydrate low calorie diet for the treatment of diabetes mellitus. Can Med Assoc J. 23(1930): 489-498.
33. Somogyi M. Exacerbation of diabetes by excessive insulin action. Am J Med. 26(1959): 169-191.
34. Ahrens EH, Hirsch J, Oette K, et al. Carbohydrate-induced and fat-induced lipemia. Trans Assoc Am Physicians 74(1961): 134-146.
35. Hatch FT, Arell LL, Kendall FE. Effects of restriction of dietary fat and cholesterol upon serum lipids and lipoproteins in patients with hypertension. Am J
Med. 19(1955): 48-60.
36. Kuo PT, Bassett DR. Dietary sugar in the production of hyperglyceridemia. Ann Intern Med. 62(1965): 1199-1212.
37. Kuo PT, Feng L, Cohen NN, et al. Dietary carbohydrates in hyperlipemia (hyperglyceridemia); hepatic and adipose tissue lipogenic activities. Am J Clin
Nutr. 20(1967): 116-125.
IT’S THE INSULIN RESISTANCE, STUPID:
PART 2
ByProf. Timothy NoakesJuly 17, 2019
GERALD REAVEN SETS OUT TO DISCOVER WHAT INSULIN RESISTANCE
SYNDROME (IRS) IS
In the previous column (1), I explained that Gerald Reaven began his research of insulin resistance syndrome (IRS) because he wanted to understand what Harry
Himsworth meant when he proposed that the metabolic defect in the commoner form of diabetes is an insensitivity of the patient’s tissues to the actions of insulin
(2). In the process, Reaven discovered the work of Margaret Albrink and her colleagues (3), which showed that persons with coronary heart disease (CHD),
including those with Type 2 diabetes mellitus (T2DM), are rather more likely to have elevated blood triglyceride than blood cholesterol concentrations. This finding
ran contrary to the idea then gaining global credence: that elevated blood cholesterol concentrations are the singular cause of CHD. At the same time, Peter Kuo in
Philadelphia was showing that high-carbohydrate diets, especially those containing sucrose or fructose, caused an increase in blood triglyceride concentrations
(hypertriglyceridemia), particularly in those who are carbohydrate-sensitive (4). Thus, Kuo coined the term “carbohydrate-sensitive hypertriglyceridemia” (CSHT).
This led Reaven to ask the question: Why do carbohydrate-sensitive persons with insulin-resistant T2DM have elevated blood triglyceride concentrations?

11. WHY BLOOD TRIGLYCERIDE CONCENTRATIONS ARE ELEVATED IN PERSONS
WITH T2DM
Reaven began his research journey with the popular understanding of the day that T2DM is a key driver of arterial disease, especially of the coronary arteries, thus
leading to coronary heart disease (CHD). This was the concept that, I suspect, was then being taught at most of the world’s medical schools, but the next 60 years
would witness a radical change. Future generations instead would be taught Ancel Keys’ false lipid hypothesis, which holds that an elevated blood cholesterol
concentration is the only important blood (bio)chemical driver of CHD.
So when those with T2DM developed CHD, the explanation offered by the experts was as simple then as it is today: The main cause is elevated blood cholesterol
concentrations. The evidence Albrink and her colleagues presented to show blood triglyceride and not blood cholesterol concentrations were more likely to be
raised in persons with T2DM and CHD was simply ignored — and ultimately suppressed and then forgotten (as it is today).
This knowledge was forgotten even though other researchers (5-9) had come to exactly the same conclusion by the time Reaven and colleagues completed their
studies of the topic in 1994.
Reaven’s first important study, published in 1963 (10), evaluated carbohydrate metabolism in 41 patients with documented myocardial infarction (MI). He found
that carbohydrate metabolism was impaired in MI patients compared to controls — that is, MI patients were more insulin resistant. He also observed that MI
patients had higher serum triglyceride and cholesterol levels. He concluded, “The apparent presence of minimal abnormalities of carbohydrate metabolism in a
significant number of patients with arteriosclerotic heart disease warrants further consideration as a possible factor in the development of atherosclerosis” (10, p.
1013, my emphasis). He noted that four other studies had already recognized this relationship:
Although the number of patients from the infarction group with a positive glucose tolerance test seems quite high (41%), the existence of abnormal carbohydrate
metabolism in patients with atherosclerosis has been observed by Sohrade, Boehle and Bieglee (11), Waddell and Field (12), Sowton (13) and Wahlberg (14).
Although all these studies differed in the nature of the patients selected, composition of the control group, glucose tolerance test used, time tested after infarction,
and other factors, there is considerable degree of similarity between the results. (10, p. 1019)
Patients with higher blood triglyceride concentrations were more insulin resistant than controls, but Reaven was unable to demonstrate a clear link between higher
levels of insulin resistance and hypertriglyceridemia. Thus, the cause of hypertriglyceridemia in these MI patients was not established.
However, others were already showing that persons with hypertriglyceridemia were more likely to be resistant to the glucose-lowering effects of injected insulin
(15). That is, persons with hypertriglyceridemia required the injection of more insulin to lower their blood glucose concentrations.
Next, Reaven developed the methods to measure rates of liver triglyceride production (16). These rates were then measured in a range of persons with different
blood triglyceride concentrations. In a second study (17), a group of 33 clinic patients were fed a high-carbohydrate diet (85%) for three weeks, at the end of which,
29 subjects had markedly elevated blood triglyceride concentrations (>300 mg/dL; >3.4 mmol/L).
These studies showed a linear relationship between the rates of liver triglyceride production and the log of the blood (plasma) triglyceride concentrations (Figure 1;
left panel). They showed a similar linear relationship between plasma triglyceride concentrations and blood insulin concentrations.
Figure 1: The left panel shows a significant linear relationship between the rates of hepatic (liver) triglyceride production and the log of plasma (blood) triglyceride
concentrations. The right panel shows a significant relationship between plasma triglyceride and plasma insulin concentrations. Reproduced from reference 17.
Note that a healthy blood triglyceride concentration is below 88 mg/dL (1 mmol/L). Thus, the overwhelming majority of subjects in this study were markedly
hypertriglyceridemic.
Thus, the primary cause of hypertriglyceridemia in these studies appeared to be “carbohydrate-induced increases in hepatic triglyceride secretion rates” (17, p.
1765), which was in turn “highly correlated with the plasma insulin response produced by that diet” (p. 1766). Interestingly there was no relationship between
degree of obesity and the extent of this carbohydrate-induced hypertriglyceridemia.

12. A subsequent study seven years later (18) confirmed all these findings. It added the additional finding that the stable blood triglyceride concentrations in persons all
eating the same diet was predicted by differences in their levels of insulin resistance, which determined their insulin responses to carbohydrate ingestion. Once
again, obesity did not predict any of these relationships.
One of the forgotten gems from this 1974 paper is that the metabolic responses of subjects were measured when they ingested a diet that “attempts to approximate
the constituents of the average American diet” of that time. The diet comprised 43% carbohydrate and 42% fat (18, p. 552). In today’s language, that would be
described (incorrectly) as a low-carbohydrate, high-fat diet.
During this period, Reaven’s group also evaluated the effects on blood triglyceride concentrations of eating high- and low-carbohydrate diets (85% and 17%,
respectively) for between two and 10 weeks (19). As shown in Figure 2, blood triglyceride concentrations doubled on the high-carbohydrate diet, whereas blood
cholesterol and phospholipid values were less affected. Note that even on the 0%-carbohydrate diet, the majority of patients had quite markedly elevated blood
triglyceride concentrations, with only two subjects recording desirable values of <88 mg/dL (<1 mmol/L).
Figure 2: Comparison of blood triglyceride, cholesterol, and phospholipid concentrations in the same subjects when they ate either a high-fat, low-carbohydrate diet (left
panels) or a high-carbohydrate, low-fat diet (right panels) for 10 weeks. Note that blood triglyceride concentrations more than doubled on the high-carbohydrate, low-
fat diet, whereas the increases in blood cholesterol and phospholipid concentrations were more modest. Redrawn from data in Table 2, reference 19.
The study found that all measures of glucose and insulin responses to carbohydrate ingestion correlated “very well with triglyceride response” (p. 1652-3). Thus, the
authors explained, “The more abnormal the glucose tolerance test and the higher the accompanying rises in plasma insulin-like activity and immune-reactive
insulin, the greater the subsequent triglyceride rise on ingestion of a high carbohydrate diet” (p.1654). Once again, the indication was that the hypertriglyceridemic
response was related to the individual’s degree of insulin resistance.
The authors concluded, “The observed elevations of plasma glucose, insulin-like activity, and immunoreactive insulin correlated well with the magnitude of the
triglyceride response that resulted from the subsequent ingestion of the higher carbohydrate diet.” They therefore ultimately suggested, “Hyperinsulinemia, in the
presence of normal to moderately elevated levels of plasma glucose, may be an important cause of the enhanced hepatic triglyceride production that underlies
endogenous hypertriglyceridemia” (p. 1655).
As I described in the previous column (1), at precisely the same time, Kuo in Philadelphia was showing that “a high incidence of carbohydrate-sensitive
hyperglyceridemia could be demonstrated in persons with atherosclerosis” (4, p. 92).
So, already by 1967, Reaven’s research group had established the following:
1. When tested appropriately, a significant proportion of persons with coronary artery disease (atherosclerosis) have abnormalities in carbohydrate
metabolism.
2. The key abnormality appears to be elevated blood triglyceride concentrations due in part to higher levels of insulin resistance.
3. Higher blood triglyceride concentrations were due to higher rates of hepatic (liver) triglyceride production.
4. Higher rates of liver triglyceride production were due to higher blood insulin concentrations.
5. Blood triglyceride concentrations increased on a very high-carb, low-fat diet (85% and 0%, respectively).
6. Blood triglyceride concentrations were lower on a lower-carbohydrate, higher-fat diet (17% and 68%, respectively).
7. The response of blood triglyceride concentrations appeared to be explained by individual differences in carbohydrate tolerance (insulin resistance).
Most of the future work performed by Reaven and his group would be focused on the description of this condition (insulin resistance/carbohydrate intolerance) and
its role in causing the majority of our modern chronic “lifestyle” diseases. We will conclude this column with an analysis of his groups’ studies of the influence of diet,
in particular carbohydrate content, on hypertriglyceridemia and other markers of impaired carbohydrate metabolism.

13. THE ROLE OF LOW-CARBOHYDRATE DIETS IN THE MANAGEMENT OF T2DM
Over a seven-year period between 1987 and 1994, Reaven and his colleagues published three papers (20-23) that evaluated the effects of diets with different
carbohydrate contents on blood parameters, specifically in persons with T2DM.
Without exception, these studies showed that removing carbohydrates from the diet uniformly improved measures of metabolic health in those with T2DM.
Conversely, increasing the carbohydrate content of the diets produced uniformly detrimental effects.
In the first study, nine patients with T2DM followed diets with higher (60%) or lower (40%) carbohydrate contents for 15 days each (20). The authors made the
point that the 40%-carbohydrate diet was, at the time, reflective of what Americans were eating, whereas the 60%-carbohydrate diet was the diet promoted by the
American Diabetes Association (ADA) for persons with T2DM in order to produce a “fall in plasma low-density lipoprotein (LDL) cholesterol concentration and thus
a reduction in the risk of coronary heart disease” (p. 214).
But the authors noted there was no evidence that a 60%-carb diet was advisable. Instead, they cited a range of studies showing that in person with T2DM, a higher-
carbohydrate diet was known to cause “hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and reduced plasma HDL cholesterol concentrations (all of which)
have been identified as factors predisposing to the risk of coronary artery disease” (p. 214).
They warned: “Thus, there appears to be evidence that the dietary recommendations of the ADA may actually increase the risk (of) coronary artery disease in
patients with T2DM” (p. 214).
The important point is that Reaven was saying a diet that raised blood triglyceride concentrations would increase the risk of coronary artery disease, even if it
lowered the blood cholesterol concentrations.
The key findings were that eating the higher-carbohydrate diet produced the precise outcomes the authors believed to be detrimental, specifically “an increase in
fasting and postprandial triglyceride concentrations, a deterioration in glycemic control … and a fall in plasma HDL-cholesterol concentrations” (p. 216). Worse, “the
decrease in dietary fat intake associated with the 60 percent carbohydrate diet did not result in lower LDL cholesterol concentrations” (p. 216).
The authors concluded:
The 60 percent carbohydrate diet did not have the beneficial effect on LDL metabolism that was predicted and aggravated the defects in glucose, lipid and
lipoprotein metabolism that are characteristic of NIDDM (non-insulin-dependent diabetes mellitus or T2DM). Furthermore, it should be emphasized that these
untoward changes were noted despite the fact that the 60 percent carbohydrate diet contained almost twice as much (dietary) fiber. (p. 216-217)
Further, because of their interest in the triglyceride-raising effects of carbohydrates, they continued to focus their attention on what they then considered to be the
key question: What are the likely long-term health consequences of this carbohydrate-induced deterioration in glycemic control, the carbohydrate-induced
hypertriglyceridemia, and the carbohydrate-induced reduction in blood HDL-cholesterol concentrations?
They began by drawing attention to three studies (5-7) showing hypertriglyceridemia is a significant risk factor for CHD in patients with T2DM and noted: “It seems
inappropriate to dismiss the current findings on the presumption that elevated triglyceride concentrations in patients with NIDDM are of no clinical significance” (p.
218). In fact, all three studies showed plasma triglyceride concentrations were more important CHD risk factors than cholesterol (7, p. 351).
Next, they quoted a study (26) linking the degree of hyperglycemia and damage to small arteries (which would include the arteries supplying the retina and the
kidneys) and posed this question: “Even if the significance of this relationship is debated, could it be argued that the best diet for patients with NIDDM is one that
accentuates the magnitude of their hyperglycemia?” (p. 218)
Finally, they noted that even a small (carbohydrate-induced) reduction in blood HDL-cholesterol concentrations had been associated with “significantly increased
risk of coronary artery disease (27). Consequently, it seems to us that the burden of proof is on those who would argue that the effects of a 60 percent carbohydrate
diet on HDL cholesterol is of no clinical significance” (p. 218).
They finalized their conclusions with a challenge to the ADA:
These results document that low-fat (20%), high-carbohydrate (60%) diets, containing moderate amounts of sucrose, similar in composition to the
recommendations of the American Diabetes Association, have deleterious metabolic effects when consumed by patients with NIDDM for 15 days. Until it can be
shown that these untoward effects are evanescent, and that long-term ingestion of similar diets will result in beneficial metabolic changes, it seems prudent to avoid
the use of low-fat, high-carbohydrate diets containing moderate amounts of sucrose in patients with NIDDM. (20, p. 213)
The next study from this research group repeated a study identical to the previous study but increased the dietary intervention periods from 15 days to six weeks
(21). The findings were essentially identical and showed that persons with NIDDM do not “adapt” to the negative metabolic consequences of eating a low-fat, high-
carbohydrate diet.
Thus, the authors again concluded:
The results of this study indicate that high-carbohydrate diets lead to several changes in carbohydrate and lipid metabolism in patients with NIDDM that could lead
to an increased risk of coronary artery disease, and these effects persist for >6 weeks. Given these results, it seems reasonable to suggest that the routine
recommendation of low-fat high-carbohydrate diets for patients with NIDDM be reconsidered. (21, p. 94)
In their final study, published in 1994, the authors investigated the effects of the metabolic parameters of two different diets — the first high in carbohydrate (55%)
and moderate in fat (30%); the second lower in carbohydrate (40%) and higher in fat (45%), with the added fat coming from monounsaturated fatty acids (22).
Once again, the control diet was designed to match the ADA guidelines of the day.

14. And once again, the findings were identical to those of the other studies:
In NIDDM patients, high-carbohydrate diets compared with high-monounsaturated-fat diets caused persistent deterioration of glycemic control and accentuation of
hyperinsulinemia, as well as increased plasma triglyceride and very-low-density lipoprotein cholesterol levels, which may not be desirable. (22, p. 1421)
The authors again warned:
We conclude that high-carbohydrate diets in NIDDM patients may cause persistent increase in plasma triglyceride and VLDL cholesterol levels, hyperinsulinemia,
and deterioration in glycemic control; all of these metabolic changes may be deleterious and have the potential to accelerate atherosclerosis as well as
microangiopathy. … Diets with higher proportions of cis-monounsaturated fats may be advantageous in reducing the long-term complications, particularly heart
disease, in NIDDM patients. (p. 1427)
REAVEN FAILS TO ASK THE CRUCIAL QUESTION
So, the key point is that by 1994, Reaven and his group were on the brink of discovering the optimum treatment for the very condition — the insulin resistance
syndrome (IRS), including T2DM and what Reaven would call “Syndrome X” — that his remarkable research group would discover and define over the next 20
years.
The treatment they would have “discovered” was a very low-carbohydrate (5-10%) diet.
But they failed to ask the key question: If higher-carbohydrate diets (60%) induce an abnormal metabolic profile in those with IRS, whereas lower-carbohydrate
diets (40%) have a less damaging effect, what would happen if we lowered the carbohydrate content even lower. Say to below 20%? Or perhaps even below 10%?
Or as low as 5%?
The result was that between 1994 and when he passed away in 2018, Reaven would never promote a genuinely low-carbohydrate diet for the management of IRS,
T2DM, or Syndrome X.
Instead he would, in my opinion and as I describe in the next column, drop the dietary “ball.” On the edge of a stunning medical victory and with perhaps a real shot
at the Nobel Prize, he would snatch defeat right out of the jaws of victory.
By failing to ask the key question, he delayed by at least two decades the discovery that very low-carbohydrate diets (5-10%) can reverse the metabolic
consequences of IRS.
This article was first published on the CrossFit website.
Professor T.D. Noakes (OMS, MBChB, MD, D.Sc., Ph.D.[hc], FACSM, [hon] FFSEM UK, [hon] FFSEM Ire) studied at the University of Cape Town (UCT), obtaining a
MBChB degree and an MD and DSc (Med) in Exercise Science. He is now an Emeritus Professor at UCT, following his retirement from the Research Unit of Exercise
Science and Sports Medicine. In 1995, he was a co-founder of the now-prestigious Sports Science Institute of South Africa (SSISA). He has been rated an A1 scientist
by the National Research Foundation of SA (NRF) for a second five-year term. In 2008, he received the Order of Mapungubwe, Silver, from the President of South
Africa for his “excellent contribution in the field of sports and the science of physical exercise.”
Noakes has published more than 750 scientific books and articles. He has been cited more than 16,000 times in scientific literature and has an H-index of 71. He has
won numerous awards over the years and made himself available on many editorial boards. He has authored many books, including Lore of Running (4th Edition),
considered to be the “bible” for runners; his autobiography, Challenging Beliefs: Memoirs of a Career; Waterlogged: The Serious Problem of Overhydration in
Endurance Sports (in 2012); and The Real Meal Revolution (in 2013).
Following the publication of the best-selling The Real Meal Revolution, he founded The Noakes Foundation, the focus of which is to support high quality research of
the low-carbohydrate, high-fat diet, especially for those with insulin resistance.
He is highly acclaimed in his field and, at age 67, still is physically active, taking part in races up to 21 km as well as regular CrossFit training.

15. REFERENCES
1. Noakes TD. It’s the insulin resistance, stupid: Part 1. CrossFit.com. 7 July 2019. Available here.
2. Himsworth HP. Diabetes mellitus: Its differentiation into insulin sensitive and insulin insensitive types. Lancet 1(1936):127–130.
3. Albrink MJ, Man EB. Serum triglycerides in coronary artery disease. Arch Intern Med. 103(1959): 4-8; Albrink MJ, Lavietes PH, Man EB. Vascular disease and serum
lipids in diabetes mellitus: observations over thirty years (1931-1961). Ann Intern Med. 58(1963): 305-323. Albrink MJ, Meigs JW, Man EB. Serum lipids,
hypertension and coronary artery disease. Am J Med. 31(1961): 4-23.
4. Kuo PT. Hyperglyceridemia in coronary artery disease and its management. JAMA 201(1967): 87-94.
5. Santen RJ, Willis PW, Fajans SS. Arteriosclerosis in diabetes mellitus. Correlations with serum lipid levels, adiposity, and serum lipid levels. Arch Intern
Med. 130(1972): 833-843.
6. West KM, Ahuja MMS, Bennett PH, et al. The role of circulating glucose and triglyceride concentrations and their interaction with other “risk factors” as determinants
of arterial disease in nine diabetic population samples from the WHO multinational study. Diabetes Care 6(1983): 361-169.
7. Carlson LA, Bottiger LE, Ahfeldt PE. Risk factors for myocardial infarction in the Stockholm prospective study. A 14-year follow-up focussing on the role of plasma
triglycerides and cholesterol. Acta Med Scand. 206(1979): 351-360.
8. Fontbonne AM, Eschwege EM. Insulin and cardiovascular disease: Paris prospective study. Diabetes Care 14(1991): 461-469.
9. Fontbonne AM, Eschwege EM, Cambien F, et al. Hypertriglyceridemia as a risk factor of coronary heart disease mortality in subject with impaired glucose tolerance
or diabetes: Results from the 11-year follow-up of the Paris prospective study. Diabetologia 32(1989): 300-304.
10. Reaven G, Calciano A, Cody R, et al. Carbohydrate intolerance and hyperlipidemia in patients with myocardial infarction with known diabetes mellitus. J Clin
Endocrinol Metab. 23(1963):1013-1023.
11. Sohrade W, Boehle E, Bieglee R. Humoral changes in arteriosclerosis. Investigations on lipids, fatty acids, ketone bodies, pyruvic acid, lactic acid, and glucose in the
blood. Lancet 2(1960): 1409-1416.
12. Waddell WR, Field RA. Carbohydrate metabolism in atherosclerosis. Metabolism 9(1960): 800-806.
13. Sowton E. Cardiac infarction and the glucose tolerance test. Brit Med J. 1(1962): 85-87.
14. Wahlberg F. The intravenous glucose tolerance test in the atherosclerotic disease with special reference to obesity, hypertension, diabetic heredity and cholesterol
values. Acta Med Scand. 171(1962): 1-7.
15. Davidson PC, Albrink MJ. Insulin resistance in hyperglyceridemia. Metabolism 14(1965): 1059-1070.
16. Reaven GM, Hill DB, Gross RC, et al. Kinetics of triglyceride turnover of very low density lipoproteins of human plasma. J Clin Invest. 44(1965): 1826-1833.
17. Reaven GM, Lerner RL, Stern MP, et al. Role of insulin in endogenous hypertriglyceridemia. J Clin Invest. 46(1967): 1756-1767.
18. Olefsky JM, Farquhar JW, Reaven GM. Reappraisal of the role of insulin in hypertriglyceridemia. Am J Med. 57(1974): 551-560.
19. Farquhar JW, Frank A, Gross RC, et al. Glucose, insulin and triglyceride responses to high and low carbohydrate diets in man. J Clin Invest. 45(1966): 1648-1656.
20. Coulson AM, Hollenbeck CB, Swislocki ALM, et al. Deleterious metabolic effects of high-carbohydate, sucrose-containing diets in patients with non-insulin-dependent
diabetes mellitus. Am J Med. 82(1987): 213-220.
21. Coulson AM, Hollenbeck CB, Swislocki ALM, et al. Persistence of hypertriglyceridemic effects of low-fat high-carbohydrate diets in NIDDM patients. Diabetes
Care 12(1989): 94-101.
22. Garg A, Bantle JP, Henry RR, et al. Effects of varying carbohydrate content of diet in patients with non-insulin-dependent diabetes mellitus. JAMA 271(1994): 1421-
1428.
23. Albrink MJ. Dietary and drug treatment of hyperlipidemia in diabetes. Diabetes 23(1974): 913-918.
24. Goldberg RB. Lipid disorders in diabetes. Diabetes Care 4(1981): 561-572.
25. Reaven G, Strom TK, Fox B. Syndrome X. The Silent Killer. The new heart disease risk. New York: Simon and Schuster, 2001.
26. Bennett PH, Knowler WC, Pettit DJ. Longitudinal studies of the development of diabetes in the Pima Indian. In: Eschwege E, ed. Advances in diabetes
epidemiology. New York: Elsevier Biomedical Press,1982; 65-74.
27. Castelli WP, Doyle JT, Gordon T, et al. HDL cholesterol and other lipids in coronary heart disease. The cooperative lipoprotein phenotyping
study. Circulation 55(1977): 767-772.

16. IT’S THE INSULIN RESISTANCE, STUPID:
PART 3
ByProf. Timothy NoakesJuly 31, 2019
It is November 1963. The 33-year-old New York physician Dr. Robert Atkins, MD, is dissatisfied with his life — and his physical appearance. He reckons he has
gained 90 pounds in the 16 years since he graduated from high school in Dayton, Ohio. But his medical training at the University of Michigan and Cornell Medical
College has provided no answers to his persistent worry: How do I lose this excess weight (2)? He has already experimented with a number of different weight-loss
diets but without any lasting success. Always the outcome is the same: His willpower capitulates to ravenous hunger.
Then the unimaginable happens. At midday on November 22, 1963, President John F. Kennedy is assassinated in Dealey Plaza, Dallas, Texas. As he watches the story
unfold on national television, Atkins becomes deeply depressed. He decides that it is time to save his own life. He vows that his recovery must begin immediately. To
start, he must somehow find a way to lose his excess weight.
He begins with one rule: He will never again attempt any diet that makes him hungry — not even for a single day. He decides to devote himself to solving this
baffling riddle: How can one eat less without being perpetually hungry? His natural inclination is to search for answers in the medical literature, and he begins in the
medical school library.
His first discovery is the work of Garfield Duncan, MD (3-5). Duncan describes his use of total fasts lasting one to 15 days for the treatment of intractable obesity.
There, Atkins uncovers the first two clues: “Anorexia was the rule after the first day of fasting and paralleled the degree of hyperketonemia. A sense of well-being
was associated with the fast” (2, p. 309); “Ketonuria usually occurred on the first or second day of the fast and hyperketonemia was detectable on the second day
and increased as the fast progressed (3, p. 124-125). The sense of well-being and cheerfulness was surprisingly constant; anorexia was striking, notably after the
first day of the fast, but in many patients, hunger was not a complaint at any time. Several patients expressed a desire to continue the fast beyond 14 days; there was
a close relationship between hyperketonemia and the loss of appetite in every case (p. 126). The anorexia during total abstinence from food, Duncan writes, is
associated with and believed to be due to the hyperketonemia provoked by the fast (p. 126).
Atkins concludes that the development of ketosis explains the anorexia of fasting, but he knows fasting cannot be a long-term solution. He narrows his search to
discover a diet that will produce persistent ketosis while providing sufficient calories for sustained health.
His search takes him to a study published just eight months earlier by G.J. Azar and W.L. Bloom, two physicians from Atlanta, Georgia. In their article, entitled
“Similarities of carbohydrate deficiency and fasting. II. Ketones, nonesterified fatty acids, and nitrogen excretion” (6), Azar and Bloom note, “At a cellular level, the
major characteristic of fasting is limitation of available carbohydrate as an energy source. Since fat and protein are the energy sources in fasting, there should be
little difference in cellular metabolism whether the fat and protein come from endogenous or exogenous resources” (p. 92).
Azar and Bloom’s study reports that the low-carbohydrate diet “similar to the endogenous caloric mixture of fasting” produced a 10-fold increase in blood ketones
within the first 24 hours that continued until the subjects again ate carbohydrates. The authors conclude that the availability of dietary carbohydrate determines this
ketogenic response. In addition, they note, “The fat-sparing action of glucose in normal metabolism is out of proportion to its calorigenic capacity” (p. 341).
So, if fasting and low-carbohydrate diets have the same effects on human metabolism, and both produce significant ketosis, Atkins reasons that perhaps a
“carbohydrate-deficient” diet is the hunger-free, healthy eating plan for which he is searching.
Returning home, he decides to test the idea on himself: “He threw out the bread and donuts in his kitchen, instead filling the refrigerator with as much fresh shrimp
as he could hold. He followed the same routine when he wasn’t at home.”
“He lost twenty-eight pounds in six weeks. The rest is history” (2, p. 55).
ATKINS DISCOVERS THE WORK OF DRS. BLAKE DONALDSON AND ALFRED
PENNINGTON
Atkins’ subsequent academic search introduces him to the work of two other New York physicians, Drs. Blake F. Donaldson and Alfred Pennington, both of whom
had been promoting low-carbohydrate diets, Donaldson from as early as the 1920s.
As Gary Taubes, who carefully researched the topic, explains, Donaldson had been working with a group of “fat cardiacs” in New York (7). Frustrated at their
inability to lose weight when trying to eat less and exercise more, Donaldson seeks another explanation (1). By chance, he befriends a Canadian engineer who is

17. himself a friend of the Arctic explorer Vilhjalmur Stefansson, author of a series of books describing his life among the Arctic Inuit (8-12). After they meet in New York
City and Stefansson describes how the Inuit live on a purely carnivorous diet, Donaldson recalls wondering, “What was I worrying about? If Stefansson could get his
people (North American Europeans) to live that way, I certainly should have enough executive ability to get my patients to stick to a beautifully broiled sirloin and a
demitasse of black coffee” (1, p. 41).
Based on the meat-only diet Stefansson had eaten for a full year during the iconic laboratory study that included himself and fellow explorer Karsten Anderson (13),
Donaldson designs an identical diet of three meals a day, each of a half-pound of fatty meat, three parts fat to one part lean protein by calories. After cooking, this
would provide 18 ounces of lean meat with six ounces of attached fat per day (1). The Stefansson/Donaldson diet prohibits all sugar, flour, alcohol, and starches,
with the exception of a small portion of raw fruit or potato once a day.
According to Taubes (7), Donaldson claims to have treated about 17,000 patients over four decades, most of whom lost two to three pounds per week on the diet
without experiencing hunger. The only patients who failed to lose weight were those with a “bread addiction,” for which his advice was, “No breadstuff means any
kind of bread … . They must go out of your life, now and forever.” To diabetics, he admonished: “You are out of your mind when you take insulin in order to eat
Danish pastry.”
Donaldson does not publish any personal scientific research, preferring to speak only to audiences at the New York Hospital, where Pennington, a local internist,
hears him speak. Impressed, Pennington tests the diet on himself and soon begins prescribing it to his patients.
At the time, Pennington is employed as a company physician in the medical care division of E.I. du Pont de Nemours and Company. By 1948, the company is
becoming concerned about the rising incidence of heart attack among its employees; the target of the diet prescription is the prevention and reversal of obesity in
the hope that this will reduce heart-disease risk.
The original dietary intervention followed the standard for the day, which called for a reduction in portion size, calorie counting, limiting the amount of fat and
carbohydrate consumed in meals, and exercising more (7). The results of the original diet were predictable: None of those things worked, so instead Pennington and
his team decided to test Donaldson’s diet on their overweight executives.
In his first publications (14, 15), Pennington reports the outcomes in 20 Du Pont executives who have lost between nine and 54 pounds at an average rate of nearly
two pounds per week. Subjects ate a minimum of 2,400 calories.
“Notable was a lack of hunger between meals, increased physical activity and sense of well-being,” Pennington writes. Although carbohydrate intake was restricted
to no more than 80 calories (20 grams) at each meal, he notes that “in a few cases even this much carbohydrate prevented weight loss, though an ad-libitum
(unrestricted) intake of protein and fat, more exclusively, was successful” (14, p. 260).
Pennington subsequently writes extensively on what he learns from his clinical experience working with these patients (16-23). The model of obesity he develops
includes the following:
• Appetite is homeostatically regulated to ensure energy intake exactly matches energy expenditure. The mechanism can be affected by (i) altered
hormonal influences, as in hyperinsulinemia or through the action of the stress hormones; (ii) structural damage to the center (in the hypothalamus);
(iii) conscious overeating (“careless or perverted eating habits”).
• Alterations in “lipophilia,” which is the theory that obesity is the result of “increased fat storage in the body (and which is) presumed an active regulation
of the size of the adipose deposits, rather than the mere passive response to the balance between calorie intake and output” (18, p. 102, my emphasis). (This
concept is first described in the English scientific literature by Julius Bauer (24): “The adipose tissue is not merely a passive storing place for reserve fat,
but a living and active part of the body, with its own physiologic and pathologic processes” (p. 993). Lipophilia explains, for example, why hunger is
stimulated by weight loss and is only restrained when the adipose fat stores are again refilled.)
• Fat is stored in adipose tissue, not just from ingested fat but also from carbohydrate (22), and this later process is stimulated in the presence of insulin.
• The oxidation of fat is impaired in the obese, a consequence of a reduced capacity to fully oxidize carbohydrates. Instead, partial (glycolytic;
fermentation) carbohydrate metabolism causes blood pyruvic (and lactic) acid levels to rise. Higher pyruvic acid levels then inhibit fat oxidation in all
tissues, particularly in the muscles. Thus, pyruvic acid is a metabolic regulator, “stimulating fat formation and inhibiting fat oxidation” (18, p. 104).
• Since the obese have an impaired capacity to generate energy from both carbohydrate and fat, they will be continually hungry. As a result, “excessive fat
storage, or obesity, would be the cause of an increased appetite, rather than the result of it” (22, p. 71).
Pennington states his hypothesis in the following terms: “Obesity, in most cases, is a compensatory hypertrophy of the adipose tissues, providing for a greater
utilization of fat by an organism that suffers a defect in its ability to oxidize carbohydrate” (21, p. 68).
He concludes that if obesity is due to excessive fat storage (lipophilia) directed by the fat cells themselves, then caloric restriction is a non-specific therapy that acts
solely at the level of the appetite, reducing calorie consumption without addressing the disordered drive of the fat cells to store excessive amounts of fat. His solution
is to promote treatment “directed primarily toward mobilization of the adipose deposits,” which would allow the appetite “to regulate the intake of food needed to
supplement the mobilized fat in fulfilling the energy needs of the body.”
Since incomplete metabolism of carbohydrate is the key factor preventing fat utilization, “Limitation of dietary carbohydrate, specifically, as the chief source of
pyruvic acid makes possible a treatment of obesity without restriction of the total caloric intake” (22, p. 73). His experience with the Du Pont executives teaches him,
“The use of a diet allowing an ad libitum intake of protein and fat and restricting only carbohydrate appears to meet the qualifications of such a treatment” (18, p.
104).
The advantages of this approach include the following:
Restriction of carbohydrate, alone, appears to make possible the treatment of obesity on a calorically unrestricted diet composed chiefly of protein and fat. The
limiting factor on appetite, necessary to any treatment of obesity, appears to be provided by increased mobilization and utilization of fat, in conjunction with the
homeostatic forces which normally regulate the appetite. Ketogenesis appears to be a key factor in the increased utilization of fat. Treatment of obesity by this
method appears to avoid the decline in the metabolism encountered in treatment of caloric restriction. (19, p. 347).

18. Pennington also notes that some patients become hungry on the low-carbohydrate diet and need to “increase their fat intake” (23, p. 36). He writes: “Provided
carbohydrate is restricted sufficiently, there does not seem to be any need to restrict fat at all … . Although the emphasis has often been put on protein in
constructing diets for the obese, it seems that the emphasis should be put on fat as the major source of energy, with carbohydrate restricted to the degree
necessitated by the obesity defect, and ample protein allowed for its well-recognized benefits to health” (23, p.36).
Pennington’s ideas strengthen Atkins’ understanding that a low-carbohydrate diet that induces ketosis and reduces hunger without requiring significant caloric
restriction is the solution for his own weight problem — and perhaps for many others who have a similar problem.
Atkins is further encouraged by a recent publication showing that the Pennington diet reduces hunger and produces weight loss in the majority: “Our results do
show that satisfactory weight loss may be accomplished by a full caloric, low carbohydrate diet. The patients ingested protein and fat as desired. Careful attention
was paid to keeping carbohydrate intake to a minimum” (25, p. 1413).
The authors continue: “All the other methods of weight reduction mentioned earlier have been utilized by the author in the past. The diet discussed was found to be
the most satisfactory of all these methods in our hands. Weight reduction occurred dramatically with a rapid fall early and proceeding slowly but surely” (25,
p.1414).
Perhaps Atkins also reads the chairman’s address, presented by George L.Thorpe, MD, of Wichita, Kansas, at the 106th Annual Meeting of the American Medical
Association in New York on June 4, 1957 (26). There, Thorpe repeats the Pennington interpretation of how a low-carbohydrate diet induces weight loss in the obese:
“That the usual low-calorie diet is rarely successful is readily understood in the light of our present knowledge of carbohydrate and fat metabolism … (as) the
presence of carbohydrate suppresses the fat-mobilizing ability of the pituitary gland and increases the fat-depositing activity of insulin” (p.1364).
Thorpe says, “It is possible to lose weight without counting the calorie intake, without being weak, hungry, lethargic, irritable, and constipated. There is no magic or
mystery, no fancy rules to follow, and the entire program may be successfully conducted without radical change to one’s normal routine … but the key to long-term
success is the simple return to normal eating habits. Normal eating habits might be described in technical language as adhering to a high-protein, high-fat, low-
carbohydrate diet” (p. 1364).
Thorpe then describes how his own consumption of high-carbohydrate foods had caused him to develop a “personal problem of excess weight” and how, in trying to
solve this personal issue, he had discovered the low-carbohydrate diet promoted by Stefansson, Donaldson, and Pennington.
This information likely confirms to Atkins that the solution to his personal weight problem is the same as it was for Thorpe: a low-carbohydrate diet.
THE STUDIES OF KERWICK AND PAWAN
Atkins finds one final piece of evidence to further support his growing conviction that he has discovered a “cure” for obesity. Dr. A. Kerwick and Mr. G. L. S. Pawan
from Middlesex Hospital Medical School had also become disillusioned with the calories-in, calories-out model of human weight control (27-29). As they wrote, “If
deficiency of calories accounts for loss of weight, low calorie diets should induce the same rate of weight loss in the same patient, no matter what the composition of
the diet. Manifestly they do not do so” (29, p. 449).
A series of their studies shows that whereas subjects eating a low-calorie (1,000 cal), high-protein or high-fat diet for seven days lost substantial amounts of weight,
eating a high-carbohydrate diet resulted in little if any weight loss (28). They conclude, “An alteration in metabolism takes place (in those eating low-carbohydrate
diets)” (28, p. 161). This alteration in metabolism apparently explains the greater rates of weight loss in those eating low-carbohydrate diets.
We now know that Kerwick and Pawan’s conclusions are in error. Marjorie Yang and Theodore Van Itallie subsequently show that, in the short term, any differences
in absolute weight losses on isocaloric diets differing in their fat, protein, and carbohydrate contents can be explained entirely by much greater water losses on the
higher fat and protein diets (30). However, this applies only to short-duration studies of less than perhaps 14 days or so. The one fact established by these studies is
that high-carbohydrate diets promote fluid retention, most likely as a result of an insulin effect increasing water retention by the kidneys (31).
Fortunately, at the time, Atkins is unaware of this error.
THE ERIC WESTMAN, MD, CONNECTION
By the late 1960s, Atkins has converted his private medical practice to focus purely on weight loss using the low-carbohydrate diet. Although he treats tens of
thousands of patients during this period, he has little interest in documenting the results of his diet prescription on their health. He is happy to be surrounded by so
much clear evidence of success.
In 1997, Dr. Eric Westman, a physician practicing at the Duke University Medical Center in Durham, North Carolina, is becoming concerned that some of his patients
have chosen to follow what had by then become known as the Atkins Diet. In particular, he is worried that the high fat content of the diet will increase his patients’
blood cholesterol concentrations, placing them at risk of “artery clogging” and heart attacks. He is initially so skeptical of Atkins’ dietary advice that “he didn’t believe
Atkins actually had gone to medical school and earned his M.D.” (2, p. 167).
Yet Westman’s patients continue to show impressive weight loss. At their suggestion, he agrees to read Atkins’ first book (32). He remains puzzled about how Atkins
can claim success from a diet that conflicts with everything Westman has been taught in his medical training. He can’t understand how, first, his patients are losing
weight eating so much fat, and second, why their blood cholesterol concentrations don’t seem to be reaching dangerous levels.
When faced with such a paradox, the majority of physicians simply ignore it as if what they are seeing hasn’t really happened. But Westman is different. He writes to
Atkins, who invites him to come to New York to sit in on some patient consultations. Later, Westman recalls, “I was both surprised and impressed that he actually
had an office and was seeing patients. I had to see through the veneer of the book before I could actually start to believe the concept behind the diet” (2, p. 169).
By the end of his visit, Westman has convinced Atkins that he needs to fund rigorous scientific studies to prove to a growing body of medical skeptics that his diet is
safe and can successfully treat obesity and Type 2 diabetes mellitus (T2DM).

19. WESTMAN FINDS A LOW-CARBOHYDRATE DIET CAN PUT T2DM INTO
REMISSION
Westman uses Atkins’ funding to undertake a six-month pilot study of the effects of a low-carbohydrate (<25 g/day) diet “with no limit on caloric intake” on body
weight and blood lipid parameters in 51 overweight/obese healthy volunteers (33). The 41 subjects who adhere to the program lose an average of 9.0 kg (19.8 lb.)
and improve all their blood parameters, including lowering their total cholesterol and LDL-cholesterol concentrations. The authors conclude rather modestly, “A
very low carbohydrate diet program led to sustained weight loss during a 6-month period (without any adverse effects in the 41 subjects who completed the
program).”
The study leads to a larger study, this time with 120 subjects, 60 of whom follow a hypocaloric low-fat diet and the other 60 a low-carbohydrate diet for 24 weeks
(34). The study finds that “compared with a low-fat diet, a low-carbohydrate diet program had better participant retention and greater weight loss.” The authors
observe, “During active weight loss, serum triglyceride levels decreased more and high-density lipoprotein cholesterol levels increased more with the low-
carbohydrate than with the low-fat diet” (p. 769).
Predictably, when the same study is presented at the American Heart Association (AHA) meeting in November 2002, the Association feels compelled to issue a
media advisory that conveys its “concerns with the study” in the following terms:
• The study is very small, with only 120 total participants and just 60 on the high-fat, low-carbohydrate diet.
• This is a short-term study, following participants for just 6 months. There is no evidence provided by this study that the weight loss produced could be
maintained long term.
• There is no evidence provided by the study that the diet is effective long term in improving health.
• A high intake of saturated fats over time raises great concern about increased cardiovascular risk — the study did not follow participants long enough to
evaluate this.
• This study did not actually compare the Atkins diet with the current AHA dietary recommendations. (35)
The advisory concludes with a statement from Robert O. Bonow, MD, President of the AHA: “‘Bottom line, the American Heart Association says that people who want
to lose weight and keep it off need to make lifestyle changes for the long term — this means regular exercise and a balanced diet.”
Bonow adds, “People should not change their eating patterns based on one very small, short-term study. Instead, we hope that the public will continue to rely on the
guidance of organizations such as the American Heart Association which look at all the very best evidence before formulating recommendations.”
This advisory echoes some of the sentiments published in the Journal of the American Medical Association 29 years earlier in a highly critical review of Atkins’ first
book (36). The article is attributed to Philip L. White, D.Sc., Secretary of the American Medical Association Council on Food and Nutrition. White is not a trained
medical practitioner.
White’s relevant points include the following:
• “The low-carbohydrate diet approach to weight reduction is neither new nor innovative” (p. 1415).
• “If such diets are truly successful, why then, do they fade into obscurity within a relatively short period only to be resurrected some years later in slightly
different guise and under new sponsorship?” (p. 1415).
• “Moreover, despite the claims of universal and painless success for such diets, no nationwide decrease in obesity has been reported” (p. 1415).
• “Dietary carbohydrate, particularly sugar, is considered by some advocates to be a nutritional ‘poison’ that promotes ‘hypoglycemia’, diabetes,
atherosclerosis and, of course, obesity” (p. 1415).
• “… the weight reduction that occurs in obese subjects who are shifted to a low-carbohydrate diet seems to reflect their inability to adapt rapidly to the
marked change in dietary composition” (p. 1416).
• “There appears to be no inherent reason why body weight cannot be maintained on a diet devoid of carbohydrate if the other essential nutrients are
provided” (p. 1416). (Dr. White appears to have forgotten this is a discussion on diets for weight loss, not weight maintenance.)
• Many human populations remain lean “on diets extremely high in carbohydrate (by American standards) and correspondingly low in fat.” Thus, “there is
equally no inherent reason to associate a diet rich in carbohydrate with obesity” (p. 1416).
• Potential hazards of low-carbohydrate diets include hypercholesterolemia and hypertriglyceridemia (p.1416-1417). (White does not realize
hypertriglyceridemia is caused by high-carbohydrate diets in those with carbohydrate-sensitive hypertriglyceridemia, but he is right to note
hypertriglyceridemia is a risk factor for coronary heart disease).
• Other potential hazards include hyperuricemia, fatigue, and postural hypotension. (Note: Postural hypotension is a benign condition and indicates that
the diet is producing an overall reduction in blood pressure. This surely is good since high blood pressure is common and in most is described as
“essential hypertension.” In other words, medicine has no understanding of what is causing the hypertension, but if a low-carbohydrate diet causes
hypotension, could this not possibly be an indication of a possible mechanism for hypertension — high-carbohydrate diets in persons with insulin
resistance?)
• “The assertion that carbohydrates are the principal elements in foods that fatten is, at best, a half-truth” (p. 1417). White argues instead that higher rates
of dietary fat intake explain the high rates of obesity in North Americans: “Obesity is relatively rare in large areas of the world where the ‘hidden sugar’ of
rice starch comprises a very high proportion of the total daily food intake” (p. 1417).
• White concludes: “The ‘diet revolution’ is neither new nor revolutionary” (p. 1418). He argues the low-carb diet is simply a variant of a diet that has been
promoted for many years. The rationale used to promote the diet is “for the most part without scientific merit” (p. 1418). The unlimited intake of
saturated fat and cholesterol-rich foods may well increase “coronary artery disease and other clinical manifestations of atherosclerosis … particularly if
the diet is maintained over a prolonged period” (p. 1418). “Any grossly unbalanced diet, particularly one which interdicts the 45% of calories that is
usually consumed as carbohydrate, is likely to induce some anorexia if the subject is willing to persevere in following such a bizarre regimen” (p. 1419).
“Bizarre concepts of nutrition and dieting should not be promoted to the public as if they were established scientific principles” (p. 1419). “Patients
should counsel their patients as to the potentially harmful results that might occur because of the adherence to the ‘ketogenic diet’” (p. 1419). And
finally: “Observations on patients who suffer adverse effects from this regimen should be reported in the medical literature or elsewhere, just as in the
case of an adverse drug reaction” (p. 1419).

20. Important points missing from White’s critique include the following:
• He ignores evidence from North America that establishes a high-fat diet can manage T2DM (see subsequent discussion). He also ignores Pennington’s
work, which shows obesity can be effectively treated with this dietary intervention.
• He ignores opinions from Britain, especially the published work of John Yudkin, a former Professor of Nutrition and Dietetics at the University of London.
Unlike White, but like Pennington (and Atkins), Yudkin had actually studied the low-carbohydrate diet in real patients and become convinced of the
value of this diet for the management of obesity (37-41). Thus, Yudkin wrote in 1972: “I have no doubt that in practice the low-carbohydrate diet will be
found to be the most effective and, nutritionally, the most desirable for the management of obese patients” (41, p. 154). In the same article, he warned of
the danger of drawing conclusions from theoretical considerations rather than practical experience.
• White ignores the editorial by Thorpe, advocating the value of this diet in the same journal two decades earlier (26).
• He ignores Atkins’ extensive discussions of the role of carbohydrate intolerance (insulin resistance) in obesity and T2DM, as well as Atkins’ explanation
of why the high-fat diet works in persons with this condition. White, who is not a medical practitioner and has no personal experience in the treatment of
persons with obesity/T2DM, fails to appreciate that Atkins’ advocacy was for a diet that worked best for persons with carbohydrate intolerance/insulin
resistance.
• White’s errors are further underscored by the absence of reports in the medical literature of “adverse effects from the regimen” in the 46 years since he
made the plea that all such negative outcomes should be reported.
None of White’s misgivings deter Westman, who negotiates with Atkins to fund another trial, this time in persons with T2DM. The resulting study finds that 21
patients with T2DM who followed the diet for 16 weeks lost an average of 9 kg (19.8lbs), reduced their blood HbA1c values by 1.2% (Figure 1), and improved all
their blood markers, including reducing blood triglyceride concentrations by an average of 1.1 mmol/L (42). Seventeen of the 21 patients reduced or stopped using
anti-diabetic medications, indicating disease “remission” or perhaps even “reversal” in some.
Figure 1: Changes in glycated hemoglobin (HbA1c) concentrations in 21 patients with T2DM who ate a low-carbohydrate diet for 16 weeks. HbA1c concentrations are a
measure of the average 24-hour blood glucose concentrations over the previous three months. Values greater than 6.5% are considered diagnostic of T2DM. According to
this measurement, 14 of 21 (67%) patients put their T2DM into “remission” on this eating plan. Reproduced from reference 42.
Since an HbA1c below 6.5% is considered to be the upper end of the “normal” range, perhaps this is the first study in the modern literature showing “remission” or
“reversal” of T2DM while using nothing more than a dietary intervention. Importantly, there is no single report in the medical literature documenting T2DM
“remission” or “reversal” while following usual medical care including the prescription of insulin or other medications.
For historical completeness, it’s appropriate to mention that Leslie Newburg and colleagues at the University of Michigan began to use a high-fat, low-carbohydrate
diet to treat T2DM in the 1920s (43-49). It seems probable that among the 73 patients they reported in their first paper (43), some may have gone into “remission”
on the high-fat diet. Indeed, their second paper (44) shows a number of patients whose random blood glucose concentrations fall below 5.5 mmol/L (0.10%), as
does their third paper (45). The authors also argued that mortality in the group treated with this diet was no worse and might even have been slightly better than
that for similar patients treated with the low-fat, low-calorie diet then promoted at the Joslin clinic.
In 1973, J.R. Wall and colleagues also reported the use of a carbohydrate-restricted diet produced “good diabetic control on diet alone, in two-thirds of cases by the
time of the second visit — that is, within 2 to 3 weeks” (51, p. 578). The authors’ main focus was not on “reversal” of T2DM. Rather, they wished to determine
whether weight loss or carbohydrate restriction was the key to successful management of T2DM. They concluded that “control of diabetes in obese patients who
respond to diet alone is due to carbohydrate restriction rather than to weight loss” (p. 578).
These studies show that already in the 1920s, there were those who argued that a carbohydrate-restricted diet is beneficial for the management of T2DM.
Westman and his colleagues establish this as fact, and their study shows that on a carbohydrate-restricted diet, some T2DM patients do not require medications to
maintain good glucose control (42).
It takes another 13 years for a larger study to confirm these findings and bring the value of the low-carbohydrate diet for the management of T2DM to a much wider
audience.

21. THE STUDIES OF STEVEN PHINNEY AND JEFF VOLEK
Drs. Jeff Volek, Ph.D., and Stephen Phinney, MD, are two other scientists whose research was funded by the Atkins Foundation. They undertake a number of studies
of low-carbohydrate diets in different populations, ultimately focusing on changes in blood lipid profiles in those with metabolic syndrome (52-58).
The key difference between their work and Dr. Gerald Reaven’s is, for the reasons I will suggest in due course, that Reaven balks at studying truly low-carbohydrate
diets. Instead, Volek and Phinney choose to study properly low-carbohydrate diets (<50 g/day), and in the end, that makes all the difference.
Some of the most important findings from these studies are shown in Figure 2.
Figure 2: Changes in metabolic and other health markers in person with metabolic syndrome, randomized to either a high-carbohydrate (56%), low-fat (24%) diet or a
high-fat (59%), low-carbohydrate (12%) diet. Both diets were hypocaloric (~1,500 cal/day). Note that all variables show greater improvement on the low-carbohydrate
diet than the low-fat diet. Data from reference 54.
The evidence clearly shows that all variables improve to a greater extent on the low-carbohydrate diet. The greatest reductions are in blood triglyceride, insulin, and
saturated fatty acid concentrations, with a marked increase in blood HDL-cholesterol concentrations as well.
The authors conclude:
Restriction in dietary carbohydrate, even in the presence of high saturated fatty acids, decreases the availability of ligands (glucose, fructose, and insulin) that
activate lipogenic and inhibit fatty oxidation pathways. The relative importance of each transcriptional pathway is unclear, but the end result — increased fat
oxidation, decreased lipogenesis, and decreased secretion of very low-density lipoprotein — is a highly reliable outcome of a low-carbohydrate diet. (55, p. 309)
In their most recent study, Phinney and Volek find that these benefits can occur rapidly and are not dependent on weight loss (58). There, they conclude: “Overall,
this work highlights the importance of the dietary carbohydrate-to-fat ratio as a control element in Metabolic Syndrome expression and points to low carbohydrate
diets as being uniquely therapeutic independent of traditional concerns about dietary total and saturated fat intakes … . Based on these results, any long-term trials
in participants with Metabolic Syndrome should include low carbohydrate diets” (p. 11).
Phinney and Volek’s studies confirm and extend Reaven’s findings from between 1987 and 1994 (59), and address the impact of low-carbohydrate diets on the
metabolic profile and other health markers of persons with the metabolic syndrome.
Logically, Reaven’s group should have completed and published studies identical to these already by the turn of the last century. Why they did not is a mystery I will
explain subsequently.
SAMI INKINEN AND THE VIRTA HEALTH STUDY CONFIRM ATKINS IS CORRECT
Certain that the low-carbohydrate diet could correct the metabolic syndrome (55) and might even “reverse” T2DM in some individuals (41), some time around
2014, Phinney has the opportunity to speak to recently retired Sami Inkinen, who was planning to row across the Pacific from San Francisco to Honolulu on a
carbohydrate-free diet (60, 61). Phinney, together with Jeff Volek, wishes to repeat the Westman study (41) in a larger group. But Phinney and Volek need help, so
they ask Inkinen if he would be interested.
Inkinen agrees on one condition: that the study becomes part of a startup tech company, the ultimate goal of which is to “reverse diabetes in 100 million persons by
the year 2025.” And thus, the Virta Health company is founded.