[Author's note: this article is from the chapter by the same name from the book ESSENTIAL DIABETES LEADERSHIP. The DCCT is the most influential study to date investigating the use of insulin in the treatment of diabetes, but it is based upon a faulty assumption. DCCT stands for the Diabetes Control and Complications Trial, and this article details a metaphor. If you're not metaphorically-oriented, please feel free to skip to the last few paragraphs to find out why black holes are so fitting a metaphor for the DCCT.]
Friday, February 20, 2015
“I know that most men—not only those considered clever, but even those who are very clever and capable of understanding the most difficult scientific, mathematical, or philosophic, problems—can seldom discern even the simplest and most obvious truth if it be such as obliges them to admit the falsity of conclusions they have formed, perhaps with much difficulty—conclusions of which they are proud, which they have taught to others, and on which they have built their lives.”
LEO TOLSTOY, What is Art?, 1896
When a star runs out of nuclear fuel, it will collapse. If the core, or central region, of the star has a mass that is greater than three suns, no known nuclear forces can prevent the core from forming a deep gravitational warp in space called a black hole. A black hole is a dense, compact object whose gravitational pull is so strong that—within a certain distance of it—nothing can escape, not even light. Black holes are thought to result from the collapse of certain very massive stars at the ends of their evolution.
A black hole does not have a surface in the usual sense of the word. There is simply a region, or boundary, in space around a black hole beyond which we cannot see. This boundary is called the event horizon.
Anything that passes beyond the event horizon is doomed to be crushed as it descends ever deeper into the gravitational well of the black hole. No visible light, nor X-rays, nor any other form of electromagnetic radiation, nor any particle, no matter how energetic, can escape. The radius of the event horizon, proportional to the mass, is very small, only 30 kilometers for a non-spinning black hole with the mass of 10 Suns.
Can astronomers see a black hole? Not directly. The only way to find one is to use circumstantial evidence. Observations must imply that a sufficiently large amount of matter is compressed into a sufficiently small region of space so that no other explanation is possible. For stellar black holes, this means observing the orbital acceleration of a star as it orbits its unseen companion in a double or binary star system.
Searching for black holes is tricky business. One way to locate them has been to study X-ray binary systems. These systems consist of a visible star in close orbit around an invisible companion star which may be a neutron star or black hole. The companion star pulls gas away from the visible star.
As this gas forms a flattened disk, it swirls toward the companion. Friction caused by collisions between the particles in the gas heats them to extreme temperatures and they produce X-rays that flicker or vary in intensity within a second.
Many bright X-ray binary sources have been discovered in our galaxy and nearby galaxies. In about ten of these systems, the rapid orbital velocity of the visible star indicates that the unseen companion is a black hole. The X-rays in these objects are produced by particles very close to the event horizon. In less than a second after they give off their X-rays, they disappear beyond the event horizon.
However, not all the matter in the disk around a black hole is doomed to fall into the black hole. In many black hole systems, some of the gas escapes as a hot wind that is blown away from the disk at high speeds. Even more dramatic are the high-energy jets that radio and X-ray observations show exploding away from some stellar black holes. These jets can move at nearly the speed of light in tight beams and travel several light years before slowing down and fading away.
Do black holes grow when matter falls into them? Yes, the mass of the black hole increases by an amount equal to the amount of mass it captures. The radius of the event horizon also increases by about 3 kilometers for every solar mass that it swallows. A black hole in the center of a galaxy, where stars are densely packed, may grow to the mass of a billion Suns and become what is known as a supermassive black hole.
Recently Chandra* has found evidence that black holes with masses of about a thousand Suns can be formed in dense star clusters by processes that are not yet understood.
Kitty Ferguson, in her accessible book on black holes entitled Prisons of light: Black Holes, explains that a black hole is not the destiny of all suns:
“In the late 1920s, Subrahmanyan Chandrasekhar, a young Indian physicist then at the University of Cambridge, calculated that is a star’s mass is less than 1.4 times the mass of our sun, gravity will not be able to overpower this exclusion principle repulsion among the electrons. The star shrinks and becomes a white dwarf, but, because of the exclusion principle, it shrinks no further. That star will not become a black hole. We now call this mass of 1.4 solar masses the “Chandrasekhar limit.” Only in a star whose mass is more than the Chandrasekhar limit will gravity overcome the exclusion principle among the electrons and be the victor in this second competition.”
Supermassive black holes with the mass of many millions of stars are thought to lie at the center of most large galaxies. The evidence comes from optical and radio observations which show a sharp rise in the velocities of stars or gas clouds orbiting the centers of galaxies. High orbital velocities mean that something massive is creating a powerful gravitational field which is accelerating the stars. X-ray observations indicate that a large amount of energy is produced in the centers of many galaxies, presumably by the in-fall of matter into a black hole.
How could a supermassive black hole form in the center of a galaxy? One idea is that an individual star-like black hole forms and swallows up enormous amounts of matter over the course of millions of years to produce a supermassive black hole. Another possibility is that a cluster of starlike black holes forms and eventually merges into a single, supermassive black hole. Or, a single large gas cloud could collapse to form a supermassive black hole.
Recent research, including results from Chandra suggests that galaxies and their black holes do not grow steadily, but in fits and starts. In the beginning of a growth cycle, the galaxy and its central black hole are accumulating matter. The energy generated by the jets that accompany the growth of the supermassive black hole eventually brings the infall of matter and the growth of the galaxy to a halt. The activity around the central black hole then ceases because of the lack of a steady supply of matter, and the jets disappear. Millions of years later the hot gas around the galaxy cools and resumes falling into the galaxy, initiating a new season of growth.
Admittedly, this is a cursory introduction to the subject. If you are interested as much as I am in learning where, why, and how we are, let alone what else is out there, you would be best served by reviewing much more information.
A quick search on the Library of Congress returned 390 books written on black holes, and, surprisingly, only 9 on supermassive black holes. In addition to Kitty Ferguson’s book cited above, see Gravity’s Fatal Attraction: Black Holes in the Universe, by Mitchell Begelman and Martin Rees (New York: Scientific American Library, 1996). For a particularly good history underlying Chandrasekhar’s anticipation of the existence of black holes, and the clash of personalities at the time of his discoveries, see Empire of the Stars: Obsession, Friendship, and Betrayal in the Quest for Black Holes, by Arthur I. Miller (New York: Houghton Mifflin Company, 2005).
See also The Black Hole at the Center of our Galaxy, by Fulvio Melia (New Jersey: Princeton University Press, 2003). In addition, you could read any book by Stephen Hawking to gather a better understanding of our existence and that of black holes. These works include: A Brief History of Time (Tenth Anniversary Edition, New York: Bantam Books, 1996), Black Holes and Baby Universes and Other Essays (New York: Bantam Books, 1994) and The Theory of Everything: The Origin and Fate of the Universe (Beverly Hills, CA: New Millennium Press, 2002).
Two books worth mentioning that are not focused on black holes, but, nevertheless, are worth your reading time because they answer so many questions, and even propose others, are The Origins of the Future: Ten Questions for the Next Ten Years, by John Gribbin (New Haven, CT: Yale University Press, 2006), and Just Six Numbers: The Deep Forces that Shape the Universe, by Martin Rees (New York: Basic books, 2000). Both are written accessibly for the lay reader like me, and both do a good job of putting things—the universe—into perspective. That we exist at all is the result of some very fine tuning, and that the search for answers inevitably leads to more questions, ad infinitum.
And, of course, I cannot leave the subject of black holes and supermassive black holes without mentioning the 19,100,000 and 1,360,000 individual results, respectively, when performing a search on GOOGLE.
Having read my brief overview, and perhaps endeavored to read a few of the aforementioned cited books, you are now as much of an expert on black holes as I, and we are ready to develop a couple of metaphors, then apply our learning to find an optimal solution to our diabetes conundrum.
There are stellar black holes and supermassive black holes.
Stellar black holes in the realm of diabetes include the use of fiber and carbohydrates in the diet. Carbohydrates have typically been restricted in diabetes diets throughout the century, and only recently has it been such a controversial topic. For example, in “General Treatment of Diabetes,” (1970), written by D. A. Pyke, M.D., F.R.C.P., the author states:
“The only important recent advance in the dietary treatment of diabetes is that it has now been widely agreed that diets should be reckoned in 10 g. carbohydrate portions and that, except in the obese, fat and protein need not be restricted. Control of diabetes, even in the obese, is often achieved by carbohydrate restriction alone, before there is any weight reduction. Though it may be a useful encouragement to a fat patient to lose weight that this will control his diabetes, this is in fact seldom essential; the important measure is carbohydrate restriction.”
The above article is in sharp contrast to numerous biased articles written in the decades previous, and after, such as “Low-Fat Diet and Therapeutic Doses of Insulin in Diabetes Mellitus,” (1955), where the author, Inder Singh states assuredly that:
“There is no indication that healthy people taking a diet rich in carbohydrates are especially liable to diabetes; in fact numerous observations show improvement of carbohydrate tolerance following its greater intake.”
That conclusion was based on a study of 80 “insulin-sensitive” diabetics, but if you were to see the actual BG levels of those studied, you would be aghast at how high they were. Of the 80 people studied, 25 started with relatively normal BG levels, but the majority of them had starting BG levels over 125, with some in the 200, 300, and 400 mg/dL range, and one even starting at 600. By the end of the glucose tolerance test, that individual was at 1,000.
Clearly, the standards back in 1955 weren’t quite so high. Let us turn to 1976, however, when the high-carbohydrate diet was gaining some momentum. In “Beneficial Effects of a High Carbohydrate, High Fiber Diet on Hyperglycemic Diabetic Men,” (1976), the authors, Tae G. Kiehm, M.D., James W. Anderson, M.D., and Kyleen Ward, R.D., state the following:
“A “diabetic” diet is an essential feature in the treatment of diabetes and traditionally this diet has been restricted in carbohydrate. Although recently it has been recommended that the carbohydrate content of the diabetic diet be increased, no data are available that provide compelling evidence for increasing the carbohydrate content of the diabetic diet. However, several studies suggest that a high-carbohydrate may be beneficial in treating some patients. Because diets containing 75 to 85% of calories as carbohydrate have been associated with improved glucose metabolism of normal individuals and patients with mild diabetes, we have studied the therapeutic utility of a 75% carbohydrate diet in treating diabetic patients requiring either insulin or oral hypoglycemic agents.”
Here is a summary of that study:
“High carbohydrate diets rich in dietary fiber were fed to 13 hyperglycemic diabetic men; five men required 15 to 28 units of insulin per day, five men required sulfonylureas, and three men required 50 to 55 units of insulin. All 13 men were fed weight maintaining American Diabetic Association diets containing 43% of calories as carbohydrates for 1 week and then were fed 75% carbohydrate diets with 15 g. of crude dietary fiber for approximately 2 weeks. After 2 weeks on the 75% carbohydrate diet, sulfonylureas were discontinued in all five men, insulin was discontinued in four men and decreased from 28 to 15 units in 1 man from the group requiring less than 30 units per day. Fasting plasma glucose values were significantly lower (P<0.001)* in all 10 men. However, insulin requirements and fasting plasma glucose values were not changed in the three men requiring 40 to 55 units of insulin. Fasting serum cholesterol values were significantly (P<0.001) lower and mean fasting serum triglyceride values were 15% lower on the high carbohydrate diet than on the American Diabetic Association diet in these 13 men. Thus a high carbohydrate diet with generous amounts of fiber may be the treatment of choice of diabetic patients requiring sulfonylureas or less than 30 units of insulin per day.”
In “High-Carbohydrate Diets and Insulin-Dependent Diabetics,” (1979), by R W Simpson, J I Mann, J Eaton, R D Carter, and T D Hockaday, the authors concluded: “Thus several measures of carbohydrate and lipid metabolism appear to be more satisfactory when patients receive a HC [High-Carbohydrate] diet, which is an acceptable alternative to that still recommended to most insulin-requiring patients.”
In “A high Carbohydrate Leguminous Fibre Diet Improves All Aspects of Diabetic Control,” (1981), by Simpson HC, Simpson RW, Lousley S, Carter RD, Geekie M, Hockaday TD, and Mann JI, the authors concluded that “a diet high in complex carbohydrate and leguminous fibre improves all aspects of diabetic control, and continued use of a low carbohydrate diet no longer appears justified.”
In “Digestible Carbohydrate—an Independent Effect on Diabetic Control in Type 2 (Non-Insulin-Dependent) Diabetic Patients?” (1982), by H. C. R. Simpson, R. D. Carter, S. Lousley, and J. I. Mann, the authors stated that “Many studies have shown high carbohydrate, high fibre diets to benefit diabetic control, the improvement being attributed mainly to an effect of fibre,” without footnote identifying any of those studies. And they concluded “These results indicate that a diet rich in carbohydrate, but restricted in fibre, does not cause overall deterioration of diabetic control or lipid metabolism in stable Type 2 diabetic patients, and suggest that digestible carbohydrate has an effect on basal blood glucose independent of fibre.”
In “What Carbohydrate Foods Should Diabetics Eat?” (1984), by JI Mann, the author stated:
“…Epidemiological evidence suggested that the standard diabetic diet, low in carbohydrate and relatively high in fat, might actually increase the risk of cardiovascular disease, the most frequent cause of death among diabetics. Furthermore, several studies suggested that diets relatively high in fibre rich carbohydrate reduced hyperglycemia in diabetic patients. Though there remains some disagreement about the precise quantity of carbohydrate which should be included in the diabetic diet, the diabetic associations of many Western countries, including the United States, Britain, Canada, Australia, and Finland, have affirmed the importance in the management of diabetes and recommend an increase in unrefined carbohydrate (especially fibre rich carbohydrate) with a reduction in the fat intake.”
Further in the article, he asks two fundamental questions:
“Does this mean that wholemeal bread and potato should be eliminated from or at least discouraged in the diabetic diet, or that suitability of foods for the diabetic may in future be determined in the laboratory?
The answer to both questions must be no, at least in the light of present knowledge. Wholemeal bread and potatoes have formed a substantial part of several experimental diets which have over weeks or months shown an appreciable improvement in diabetic control.”
He concludes this article with the following statement, subtly insinuating that it’s not a diabetic’s diet that should drive the insulin use, but, rather, it’s the prescribed exogenous insulin use that should drive the diet:
“Finally, every commentary on dietary advice for diabetics should restate the most important principles: energy intake should be adjusted to maintain the ideal body weight and in the insulin dependent diabetic a regular meal pattern should be established to match the injected insulin.
But are these studies credible? Hardly. Dr. Uffe Ravnskov points out Jim Mann’s conflicts of interest in his latest book. He writes:
“All [these] studies were co-authored by Jim Mann, a professor in Human Nutrition and Medicine at the University of Otago, a WHO expert in nutrition and the main advisor for the Sugar Research Advisory Service (SRAS), an information service established in 2002 and funded by the New Zealand Sugar Company with the aim ‘to encourage appropriate use and enjoyment of sugar as part of a healthy and balanced diet.’ Jim Mann is also the main author of the European guidelines for the treatment and prevention of diabetic patients. But you will look in vain for any information about the author’s possible competing interests in that paper or in his other publications.”
We find more answers, especially those centered on what it means to be insulin resistant, in Gary Taubes’s discussion of geneticist James Neel, the thrifty-gene hypothesis creator that would later reject his own idea. Focused on what constitutes insulin resistance, Gary Taubes wrote that “Neel suggested three scenarios of these insulin-secretory responses that could constitute a pre-disposition to obesity and/or type 2 diabetes—each of which, he wrote, would be a physiological ‘response to the excessive glucose pulses that result from the refined carbohydrates/over-alimentation of many civilized diets.’” Of those three scenarios, one stands out as coming closest to reality:
“Here an appropriate amount of insulin is secreted in response to the “excessive glucose pulses” of a modern meal, and the response of the muscle cells to the insulin is also appropriate. The defect is in the relative sensitivity of muscle and fat cells to the insulin. The muscle cells become insulin-resistant in response to the “repeated high levels of insulinemia that result from excessive ingestion of highly refined carbohydrates and/or over-alimentation,” but the fat cells fail to compensate. They remain stubbornly sensitive to insulin. So, as Neel explained, the fat tissue accumulates more and more fat, but “mobilization of stored fat would be inhibited.” Now the accumulation of fat in the adipose tissue drives the vicious cycle.
This scenario is the most difficult to sort out clinically, because when these investigators measure insulin resistance in humans they invariably do so on a whole body level, which is all the existing technology allows. Any disparities between the responsiveness of fat and muscle tissue to insulin cannot be measured. This is critical, because for the past thirty-five years the American Diabetes Association has recommended that diabetics eat a diet relatively rich in carbohydrates based on the notion that this makes them more sensitive to insulin, at least temporarily, so the diet appears to ameliorate the diabetes. This effect was initially reported in 1971, by the University of Washington endocrinologists Edwin Bierman and John Brunzell, who then waged a lengthy and successful campaign to persuade the American Diabetes Association to recommend that diabetics eat more carbohydrates rather than less. If Neel’s third scenario is correct, however, a likely explanation for why carbohydrate-rich diets appear to facilitate blood-sugar control after meals is that they increase the insulin sensitivity of the fat cells specifically, while the muscle tissue remains insulin-resistant.”
Here might be the opportune time to tell the tale of James Van Gundia Neel (March 22, 1915 – February 1, 2000) and his refinement.
James Neel, a professor of Human Genetics at the University of Michigan Medical School, proposed the “thrifty genotype” hypothesis in 1962 in his paper “Diabetes Mellitus: A ‘Thrifty’ Genotype Rendered Detrimental by ‘Progress’?” Neel intended the paper to provoke further contemplation and research on the possible evolutionary and genetic causes of diabetes among populations that had only recently come into regular contact with Westerners.
The genetic paradox Neel sought to address was this: diabetes conferred a significant reproductive, and thus evolutionary, disadvantage to anyone who had it; yet the populations Neel studied had diabetes in such high frequencies that a genetic predisposition to develop diabetes seemed plausible. Neel sought to unravel the mystery of why genes that promote diabetes had not been naturally-selected out of the population's gene pool.
Neel proposed that a genetic predisposition to develop diabetes was adaptive to the feast and famine cycles of Paleolithic human existence, allowing humans to fatten rapidly and profoundly during times of feast in order that they might better survive during times of famine.
While Neel considered the “thrifty genotype” notion worth further investigation, he also proposed in 1962, yet did not develop until years later, a counter-hypothesis. namely that “this frequency of obesity and diabetes is a relatively recent phenomenon” in which case the question would become “what changes in the environment are responsible for the increase?”
In the decades following the publications of his first paper on the “thrifty genotype” hypothesis, Neel investigated the frequency of diabetes and, increasingly, obesity in a number of other populations, and, as a proper scientist, sought out observations that might disprove or discount his “thrifty gene” hypothesis.
Neel's further investigations cast doubt on the “thrifty genotype” hypothesis. If a propensity to develop diabetes were an evolutionary adaptation, then diabetes would have been a disease of long standing in those populations currently experiencing a high frequency of diabetes. However, Neel found no evidence of diabetes among these populations earlier in the century. And when he tested younger members of these populations for glucose intolerance—which might have indicated a predisposition for diabetes—he found none.
In 1989, Neel published a review of his further research based on the “thrifty genotype” hypothesis and in the Introduction noted the following: “The data on which that rather soft hypothesis was based has now largely collapsed.” However, this sentence clearly could only be applied to his original hypothesis, because later in the same paper where he continued to refine his concepts, Neel noted “...the concept of a “thrifty genotype” remains as viable as when first advanced...” He went on to advance that the thrifty genotype concept be thought of in the context of a “compromised” genotype that effects several other metabolically-related diseases.
This refinement is actually just a return by Neel to the alternative hypothesis to which he had alluded twenty years earlier—that modern, very-high levels of obesity and diabetes among formerly native populations were a relatively recent phenomenon most likely caused by changes in diet. Given that some “thrifty gene” populations, like the Inuit, experienced a rise in obesity and diabetes in conjunction with a reduction of the proportion of fat and protein in their diets, Neel surmised that the dietary causes of obesity and diabetes lay in carbohydrate consumption, “specifically the use of highly refined carbohydrate.”
The central premise of the thrifty gene hypothesis—that famines were common and severe enough to select for thrifty genes has been recently challenged. Many of the populations that later developed high rates of obesity and diabetes appeared to have no discernible history of famine or starvation (for example, Pacific Islanders whose “tropical-equatorial islands had luxuriant vegetation all year round and were surrounded by lukewarm waters full of fish.”). Moreover, one of the most significant problems for the “thrifty gene” idea is that it predicts that modern hunter gatherers should get fat in the periods between famines. Yet data on the body mass index of hunter-gatherer and subsistence agriculturalists clearly show that between famines they do not deposit large fat stores.
We return now to see that Gary Taubes provides the last word on carbohydrates when he states:
“It is not the case, despite public-health recommendations to the contrary, that carbohydrates are required in a healthy human diet. Most nutritionists still insist that a diet requires 120 to 130 grams of carbohydrates, because this is the amount of glucose that the brain and central nervous system will metabolize when the diet is carbohydrate rich. But what the brain uses and what it requires are two different things. Without carbohydrates in the diet, the brain and central nervous system will run on ketone bodies, converted from dietary fat and from the fatty acids released by the adipose tissue; on glycerol, also released from the fat tissue with the breakdown of triglycerides into free fatty acids; and on glucose, converted from the protein in the diet. Since a carbohydrate-restricted diet, unrestricted in calories, will, by definition, include considerable fat and protein, there will be no shortage of fuel for the brain. Indeed, this is likely to be the fuel mixture that our brains evolved to use, and our brains seem to run more efficiently on this fuel mixture than they do on glucose alone. (A good discussion of the rationale for a minimal amount of carbohydrates in the diet can be found in the 2002 Institute of Medicine [IOM] report, Dietary Reference Intakes. The IOM sets an “estimated average requirement” of a hundred grams of carbohydrates a day for adults, so that the brain can run exclusively on glucose, “without having to rely on a partial replacement of glucose by [ketone bodies].” It then sets the “recommended dietary allowance” at 130 grams to allow margin for error. But the IOM report also acknowledges that the brain will be fine without these carbohydrates, because it runs perfectly well on ketone bodies, glycerol, and the protein-derived glucose.)”
Let’s take a look at the IOM report:
“The lower limit of dietary carbohydrate compatible with life apparently is zero, provided that adequate amounts of protein and fat are consumed. However, the amount of dietary carbohydrate that provides for optimal health in humans is unknown. There are traditional populations that ingested a high fat, high protein diet containing only a minimal amount of carbohydrate for extended periods of time (Masai), and in some cases for a lifetime after infancy (Alaska and Greenland Natives, Inuits, and Pampas indigenous people) (Du Bois, 1928; Heinbecker, 1928). There was no apparent effect on health or longevity. Caucasians eating an essentially carbohydrate-free diet, resembling that of Greenland natives, for a year tolerated the diet quite well (Du Bois, 1928). However, a detailed modern comparison with populations ingesting the majority of food energy as carbohydrate has never been done.
It has been shown that rats and chickens grow and mature successfully on a carbohydrate-free diet (Brito et al., 1992; Renner and Elcombe, 1964), but only if adequate protein and glycerol from triacylglycerols are provided in the diet as substrates for gluconeogenesis. It has also been shown that rats grow and thrive on a 70 percent protein, carbohydrate-free diet (Gannon et al., 1985). Azar and Bloom (1963) also reported that nitrogen balance in adults ingesting a carbohydrate-free diet required the ingestion of 100 to 150 g of protein daily. This, plus the glycerol obtained from triacylglycerol in the diet, presumably supplied adequate substrate for gluconeogenesis and thus provided at least a minimal amount of completely oxidizable glucose.
The ability of humans to starve for weeks after endogenous glycogen supplies are essentially exhausted is also indicative of the ability of humans to survive without an exogenous supply of glucose or monosaccharides convertible to glucose in the liver (fructose and galactose). However, adaptation to a fat and protein fuel requires considerable metabolic adjustments.
The only cells that have an absolute requirement for glucose as an oxidizable fuel are those in the central nervous system (i.e., brain) and those cells that depend upon anaerobic glycolysis (i.e., the partial oxidation of glucose to produce lactate and alanine as a source of energy), such as red blood cells, white blood cells, and medulla of the kidney. The central nervous system can adapt to a dietary fat-derived fuel, at least in part (Cahill, 1970; Sokoloff, 1973). Also, the glycolyzing cells can obtain their complete energy needs from the indirect oxidation of fatty acids through the lactate and alanine-glucose cycles.
In the absence of dietary carbohydrate, de novo synthesis of glucose requires amino acids derived from the hydrolysis of endogenous or dietary protein or glycerol derived from fat. Therefore, the marginal amount of carbohydrate required in the diet in an energy-balanced state is conditional and dependent upon the remaining composition of the diet. Nevertheless, there may be subtle and unrecognized, untoward effects of a very low carbohydrate diet that may only be apparent when populations not genetically or traditionally adapted to this diet adopt it. This remains to be determined but is a reasonable expectation.
Of particular concern in a Western, urbanized society is the long-term consequences of a diet sufficiently low in carbohydrate such that it creates a chronically increased production of β-hydroxybutyric and acetoacetic acids (i.e., keto acids). The concern is that such a diet, deficient in water-soluble vitamins and some minerals, may result in bone mineral loss, may cause hypercholesterolemia, may increase the risk of urolithiasis (Vining, 1999), and may affect the development and function of the centra1 nervous system. It also may adversely affect an individual’s general sense of well being (Bloom and Azar, 1963), although in men starved for an extended period of time, encephalographic tracings remained unchanged and psychometric testing showed no deficits (Owen et al., 1967). It also may not provide for adequate stores of glycogen. The latter is required for hypoglycemic emergencies and for maximal short-term power production by muscles (Hultman et al., 1999).
EVIDENCE CONSIDERED FOR ESTIMATING THE AVERAGE REQUIREMENT FOR CARBOHYDRATE
The endogenous glucose production rate, and thus the utilization rate, depends on the duration of starvation. Glucose production has been determined in a number of laboratories using isotopically labeled glucose (Amiel et al., 1991; Arslanian and Kalhan, 1992; Bier et al., 1977; Denne and Kalhan, 1986; Kalhan et al., 1986; King et al., 1982; Patel and Kalhan, 1992). In overnight fasted adults (i.e., postabsorptive state), glucose production is approximately 2 to 2.5 mg/kg/min, or approximately 2.8 to 3.6 g/kg/d. In a 70-kg man, this represents approximately 210 to 270 g/d. In the postabsorptive state, approximately 50 percent of glucose production comes from glycogenolysis in liver and 50 percent from gluconeogenesis in the liver (Chandramouli et al., 1997; Landau et al., 1996).
The minimal amount of carbohydrate required, either from endogenous or exogenous sources, is determined by the brain’s requirement for glucose. The brain is the only true carbohydrate-dependent organ in that it oxidizes glucose completely to carbon dioxide and water. Normally, the brain uses glucose almost exclusively for its energy needs. The endogenous glucose production rate in a postabsorptive state correlates very well with the estimated size of the brain from birth to adult life. However, not all of the glucose produced is utilized by the brain (Bier et al., 1977; Felig, 1973). The requirement for glucose has been reported to be approximately 110 to 140 g/d in adults (Cahill et al., 1968).
Nevertheless, even the brain can adapt to a carbohydrate-free, energy-sufficient diet, or to starvation, by utilizing ketoacids for part of its fuel requirements. When glucose production or availability decreases below that required for the complete energy requirements for the brain, there is a rise in ketoacid production in the liver in order to provide the brain with an alternative fuel. This has been referred to as “ketosis.” Generally, this occurs in a starving person only after glycogen stores in the liver are reduced to a low concentration and the contribution of hepatic glycogenolysis is greatly reduced or absent (Cahill et al., 1968). It is associated with approximately a 20 to 50 percent decrease in circulating glucose and insulin concentration (Carlson et al., 1994; Owen et al., 1998; Streja et al., 1977). These are signals for adipose cells to increase lipolysis and release nonesterified fatty acids and glycerol into the circulation. The signal also is reinforced by an increase in circulating epinephrine, norepinephrine, glucagon, and growth hormone concentration (Carlson et al., 1994). The nonesterified fatty acids are removed by the liver and converted into ketoacids, which then diffuse out of the liver into the circulation. The increase in nonesterified fatty acids results in a concentration-dependent exponential increase in ketoacids (Hanson et al., 1965); glucagon facilitates this process (Mackrell and Sokal, 1969).
In an overnight fasted person, the circulating ketoacid concentration is very low, but with prolonged starvation the concentration increases dramatically and may exceed the molar concentration of glucose (Cahill, 1970; Streja et al., 1977). In individuals fully adapted to starvation, ketoacid oxidation can account for approximately 80 percent of the brain’s energy requirements (Cahill et al., 1973). Thus, only 22 to 28 g/d of glucose are required to fuel the brain. This is similar to the total glucose oxidation rate integrated over 24 hours determined by isotope-dilution studies in these starving individuals (Carlson et al., 1994; Owen et al., 1998).
Overall, the key to the metabolic adaptation to extended starvation is the rise in circulating nonesterified fatty acid concentrations and the large increase in ketoacid production. The glycerol released from the hydrolysis of triacylglycerols stored in fat cells becomes a significant source of substrate for gluconeogenesis, but the conversion of amino acids derived from protein catabolism into glucose is also an important source. Interestingly, in people who consumed a protein-free diet, total nitrogen excretion was reported to be in the range of 2.5 to 3.5 g/d (35 to 50 mg/kg), or the equivalent of 16 to 22 g of catabolized protein in a 70-kg man (Raguso et al., 1999). Thus, it is similar to that in starving individuals (3.7 g/d) (Owen et al., 1998). Overall, this represents the minimal amount of protein oxidized through gluconeogenic pathways (Du Bois, 1928). This amount of protein is considerably less than the Recommended Dietary Allowance (RDA) of 0.8 g/kg/d for adults with a normal body mass index (Chapter 10). For a 70-kg lean male, this equals 56 g/d of protein, which is greater than the estimated obligate daily loss in body protein from the shedding of cells, secretions, and other miscellaneous functions (approximately 6 to 8 g/d for a 70-kg man; see Chapter 10) and has been assumed to be due to inefficient utilization of amino acids for synthesis of replacement proteins and other amino acid-derived products (Gannon and Nuttall, 1999). In part, it also may represent the technical difficulty in determining a minimal daily protein requirement (see Chapter 10).
If 56 g/d of dietary protein is required for protein homeostasis, but the actual daily loss of protein is only approximately 7 g, then presumably the remaining difference (49 g) is metabolized and may be utilized for new glucose production. It has been determined that for ingested animal protein, approximately 0.56 g of glucose can be derived from every 1 g of protein ingested (Janney, 1915). Thus, from the 49 g of protein not directly utilized to replace loss of endogenous protein or not used for other synthetic processes, approximately 27 g (0.56 × 49) of glucose may be produced. In people on a protein-free diet or who are starving, the 16 to 22 g of catabolized protein could provide 10 to 14 g of glucose.
If the starving individual’s energy requirement is 1,800 kcal/d and 95 percent is supplied by fat oxidation either directly or indirectly through oxidation of ketoacids (Cahill et al., 1973), then fat oxidation represents 1,710 kcal/d, or 190 g based upon approximately 9 kcal/g fat. The glycerol content of a typical triacylglycerol is 10 percent by weight, or in this case 19 g of glycerol, which is equivalent to approximately 19 g of glucose. This, plus the amount of glucose potentially derived from protein, gives a total of approximately 30 to 34 g ([10 to 14] + 19). Thus, a combination of protein and fat utilization is required to supply the small amount of glucose still required by the brain in a person fully adapted to starvation. Presumably this also would be the obligatory glucose requirement in people adapted to a carbohydrate-free diet. Thus, the normal metabolic adaptation to a lack of dietary protein, as occurs in a starving person in whom the protein metabolized is in excess of that lost daily, is to provide the glucose required by the brain. Nevertheless, utilization of this amount of glucose by the brain is vitally important. Without it, function deteriorates dramatically, at least in the brain of rats (Sokoloff, 1973).
The required amount of glucose could be derived easily from ingested protein alone if the individual was ingesting a carbohydrate-free, but energy-adequate diet containing protein sufficient for nitrogen balance. However, ingested amounts of protein greater than 30 to 34 g/d would likely stimulate insulin secretion unless ingested in small amounts throughout a 24-hour period. For example, ingestion of 25 to 50 g of protein at a single time stimulates insulin secretion (Krezowski et al., 1986; Westphal et al., 1990), despite a lack of carbohydrate intake. This rise in insulin would result in a diminution in the release of fatty acids from adipose cells and as a consequence, reduce ketoacid formation and fatty acid oxidation. The ultimate effect would be to increase the requirement for glucose of the brain and other organs. Thus, the minimal amount of glucose irreversibly oxidized to carbon dioxide and water requires utilization of a finely balanced ratio of dietary fat and protein.
Azar and Bloom (1963) reported that 100 to 150 g/d of protein was necessary for maintenance of nitrogen balance. This amount of protein could typically provide amino acid substrate sufficient for the production of 56 to 84 g of glucose daily. However, daily infusion of 90 g of an amino acid mixture over 6 days to both postoperative and nonsurgical starving adults has been reported to reduce urinary nitrogen loss without a significant change in glucose or insulin concentration, but with a dramatic increase in ketoacids (Hoover et al., 1975). Thus, the issue becomes complex in nonstarving people.”
Let me repeat the words of Gary Taubes: “What the brain uses and what it requires are two different things. Without carbohydrates in the diet, the brain and central nervous system will run on ketone bodies, converted from dietary fat and from the fatty acids released by the adipose tissue; on glycerol, also released from the fat tissue with the breakdown of triglycerides into free fatty acids; and on glucose, converted from the protein in the diet. Since a carbohydrate-restricted diet, unrestricted in calories, will, by definition, include considerable fat and protein, there will be no shortage of fuel for the brain.”
There is no essential need for carbohydrates. Thus, any individual, group, or organization espousing the need for carbohydrates must be advancing their own agenda, or advancing the agenda of a third party, whether they know it—and benefit from it—or not. We’ll delve into that subject a little more later; for now, let’s complete the metaphors.
In a similar way, then, though created within a much shorter time span, the treatment—the galaxy—of diabetes has evolved around and upon the singularity of the DCCT, yes, our supermassive black hole.
We see the DCCT cited in nearly every reference book that advocates a specific diet available at the Santa Clara City Library. If I ever survey those 3,359 diabetes books at the Library of Congress, and publish my findings, I will be sure to include a section on reference books published after the DCCT concluded, at which time I will be able to say with certainty how many and what percentage cite the DCCT. My best guess from the evidence gathered to date—my hypothesis if you will—is that the number of reference books with specific sections detailing diabetes mellitus, advocating a low-fat diet, that cite the DCCT, approaches 100%.
The oldest reference book, with a section devoted to diabetes mellitus, in the reference section at Santa Clara City Library, which included a citation of the DCCT, was Family Medicine Principles & Practice, Fifth Edition (1998). That reference book states:
“One study showed, however, that early poor control despite later good control results in diabetes complications. The Diabetes Control and Complications Trial (DCCT) proved the profound impact of intensive therapy on reducing the risk of microvasular complications. Decades of questions about the glucose hypothesis are therefore finally answered, with the obvious recommendation that most individuals with type 1 diabetes mellitus be treated with intensive therapy.”
According to Rudolph's Pediatrics 21st Edition (2003):
“The goals of treatment of children with type 1 diabetes mellitus are as follows: 1. Stabilize blood level of glucose within a target range; 2. Avoid metabolic decompensation (diabetic ketoacidosis, severe hypoglycemia); 3. Ensure normal growth and development at both a physical and emotional level; 4. Prevent long-term complication of both hyperglycemia and hypoglycemia. The best means to achieve these goals have been established through several long-term studies involving adolescents and adults, most notably the Diabetes Control and Complications Trial (DCCT). This 9-year prospective multicenter trial compared outcomes among patients who underwent intensive treatment in an attempt to maintain euglycemia with outcomes among those treated in the conventional manner, in which the goal was clinical well-being. Patients in the intensive therapy group received three or more insulin injections per day or used an insulin pump; measured blood glucose several times a day; had monthly clinic visits with the health-care team and weekly follow-up telephone calls; and were encouraged to use a dynamic regimen with adjustments for variation in daily food intake and activities. Those in the conventional treatment group received one to two insulin injections per day, were seen in the clinic every several months, and followed a static daily insulin regimen. The study showed definitively that tighter glucose control reduces the risk of long-term complications of type 1 diabetes mellitus, decreases risk of development of microvascular complications, and slows progression of preexisting lesions 35 to 75%. The DCCT showed that any improvement in glucose control lowers the risk of long-term complications. Every 10% decrease in HbA1c is associated with a 40 to 45% lower risk of progression of retinopathy. Therefore, even if the stated target range is not achieved, any incremental decrease in blood glucose value decreases the risk of future microvascular disease.”
In Cecil Textbook of Medicine 22nd Edition (2004):
“The benefits achieved by intensive control in the DCCT were not without risk. Weight gain was more common, and most importantly, the frequency of severe hyperglycemia (including episodes in some patients) was three-fold higher in the intensive care group. In many cases, such episodes occurred without classic warning symptoms, often while the patient was asleep. Thus, in some patients, the risks of intensive therapy may outweigh the benefits; possibly included are patients with advanced complications, young children, and patients who are unable or unwilling to participate in their management (e.g., self-monitoring of blood glucose). Such individuals are likely to benefit from less aggressive therapy designed to moderately lower glucose levels without the risk of hypoglycemia. It is noteworthy that despite the higher rate of hypoglycemia, intensive therapy in the DCCT had no detectable long-term effects on cognitive function.”
In Harrison’s Principles of Internal Medicine, 17th Edition (2008):
“The DCCT demonstrated that improvement of glycemic control reduced nonproliferative and proliferative retinopathy (47% reduction), microalbuminuria (39% reduction), clinical nephropathy (54% reduction), and neuropathy (60% reduction). Improved glycemic control also slowed the progression of early diabetic complications.”
In Williams Textbook of Endocrinology, Tenth Edition (2003):
“On the basis of these results, the authors of the study [the DCCT] recommended that most patients with type 1 diabetes be treated with an intensive treatment regimen under the close supervision of a health-care team consisting of a physician, nurses, nutritionist, and behavioral and exercise specialists as needed.”
Additionally, according to the International Textbook of Diabetes Mellitus (2004):
“It was not until 1993 that definitive proof for the value of good glycemic control was established. The landmark Diabetes Control and Complications Trial (DCCT) study showed that the microvascular complications of diabetes could be delayed or avoided by good glycemic control, which required intensive insulin therapy.”
This idea is again validated in Joslin’s Diabetes Mellitus (2005):
“Joslin and his early associates became identified with the conservative viewpoint that “good” control delayed or prevented microvascular complications, particularly in type 1 diabetes. This position inaugurated an intense nationwide 30-year debate that only ended in 1993 with the publication of the results of the Diabetes Control and Complications Trial, which clearly supported Joslin’s claim.”
In the most recent reference book, Lange 2009 Current Medical Diagnosis & Treatment (2009), after summarizing the DCCT, the writers conclude:
“The general consensus of the ADA is that intensive insulin therapy associated with comprehensive self-management training should become standard therapy in patients with type 1 diabetes mellitus after the age of puberty. Exceptions include those with advanced renal disease and the elderly, since in those groups the detrimental risks of hypoglycemia outweigh the benefits of tight glycemic control.”
The far-reaching influence of the DCCT puts it at the center of the diabetes treatment galaxy. Let’s now take a closer look at the study and its design.
The Diabetes Control and Complications Trial was launched by the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) in 1981 when requests for proposals were issued for clinical centers and a central Data Coordinating Center. In early 1982 the Biostatistics Center of the George Washington University was awarded the contract to serve as the Coordinating Center. In addition, 29 clinical centers in the United States and Canada, and 8 central laboratories and units participated in the trial. The Coordinating Center contract spanned the period 1982-1998. The complete study group is listed in the Appendix to the principal publication of study results in the New England Journal of Medicine.
Since the discovery of insulin in 1921, the medical community debated the glucose hypothesis that the marked elevation of blood glucose, hyperglycemia, associated with diabetes mellitus, was responsible for the development and progression of the microvascular complications of type 1 diabetes: retinopathy leading to blindness, nephropathy leading to end-stage kidney disease, and neuropathy leading to loss of sensation, ulceration and amputation. The DCCT was designed to definitively answer whether a program of intensive therapy aimed at near normal levels of glycemia, when compared to conventional therapy aimed at maintenance of clinical well being, would affect the risk of onset and progression of these complications.
During the period 1983-1989, 1441 subjects were enrolled in the study, half the subjects assigned at random to intensive therapy and half to conventional therapy. All subjects were scheduled to be followed until the fall of 1993. However, the dramatic beneficial results of the trial lead to its termination one year early. The results were presented at the June, 1993, meeting of the American Diabetes Association and the initial principal results paper appeared in the New England Journal of Medicine in September of that year. The risks of the microvascular complications over the average of 6.5 years of follow-up were reduced by 26-63% with intensive versus conventional therapy. Intensive therapy, however, was associated with an excess weight gain of about 1 kg per year greater than that with conventional therapy, and a 3-fold greater risk of episodes of hypoglycemia where patients experience seizures and/or loss of consciousness, compared to conventional therapy.
Subsequent extensive statistical epidemiologic investigations showed that the risk of development of microvascular complications was principally determined by the lifetime exposure to hyperglycemia. However, the risk of hypoglycemia was weakly related to the level of glycemia, and more strongly related to intensive versus conventional therapy. All totaled, 57 papers have been published that present the various methods and results of the DCCT. The complete DCCT bibliography has been included in Appendix D.
The Harvard Health Letter named the DCCT the number one advance in medicine during 1993. In 1994, the DCCT Research Group was awarded the Charles H. Best Medal for distinguished service in the cause for diabetes, named for the co-founder of insulin, given by the American Diabetes Association. The DCCT has been used to set standards of care for diabetes mellitus worldwide.
After the close of the DCCT, the NIDDK launched the study of the Epidemiology of Diabetes Interventions and Complications (EDIC), for which the Biostatistics Center also serves as the Data Coordinating Center. Under the EDIC, the original DCCT cohort is being followed to assess the development of significant microvascular disease and the development of cardiovascular and other macrovascular diseases.
A more detailed examination of the DCCT shows that the improvements in the intensive therapy group were found with only a modest reduction in hemoglobin A1c. The mean hemoglobin A1c for the intensive therapy group was 7.1%, corresponding to a mean serum glucose level of 155 mg/dL. The DCCT intensive therapy protocol included a daily carbohydrate intake of 230 grams, self-monitoring of glucose levels at least four times daily, four daily insulin injections, monthly clinical visits, and a diet and exercise plan. Despite the extensive monitoring effort, the intensive therapy cohort had a threefold increase of severe hypoglycemic events compared with the standard therapy cohort. Accordingly, subjects following the intensive therapy had a reduction in long-term complications, but this benefit was tempered by an increased risk of severe hypoglycemic reactions.
In the minds of those that led, supported, financed, and judged the DCCT, not to mention those that decided to include it as the basis for treatment in fixed reference media, the DCCT proved that an intensive treatment of insulin is the best way to treat type 1 diabetes. Case closed.
But isn’t there one important question left to consider? I think you can see where this is going.
What was the diet used in both the conventional and intensive treatments?
To answer that question, as we surely must, we have to take a look at a document explaining how the trial was designed. Such a document exists. We can answer the question of what diets were used by reading through “The Diabetes Control and Complications Trial (DCCT) Design and Methodologic Considerations for the Feasibility Phase,” first published in Diabetes, in 1986.
Here is the diet fed to those participants of the standard (also known as the conventional) treatment group:
“A balanced diet containing sufficient calories and other nutrients to maintain weight at 90-120% of ideal and normal growth and development in adolescents. The diet consists of approximately 45-55% of the calories as carbohydrate, no more than 30% as fat, cholesterol content of <600 mg/day, and a P/S ratio of approximately 1.0 [P/S ratio is the ratio between polyunsaturated and saturated fatty acids]. An individual meal plan is provided for each subject that includes daily snacks and emphasizes consistency and regularity of caloric and carbohydrate intake.”
And here is the diet fed to those participants of the experimental (also known as the intensive) treatment:
“A balanced diet as in the standard treatment group.”
Stop to think about that for a moment. The same diet of approximately 45-55% of the calories as carbohydrates were fed to both the control group and the intensively treated group. True, keeping diets similar to test the effects of an independent variable—in this case insulin—is an indicator of a closely controlled study; but, the conclusion reached—that is, complications and risk are reduced by intensive insulin treatment—assumes you’re eating carbohydrates as a major potion of your diet. This study does not provide us with any new, actionable information, as we’ve known through observation for more than a century that diabetes is the relative inability of the body to effectively oxidize carbohydrates, albeit words such as “oxidize,” and “carbohydrate,” weren’t always used. And that we need to normalize our glucose levels if we want to reduce the risk of complications and shortened lifespan. This study really reminds type 1s that if prescribed bolus insulin, due to their consumption of carbohydrates, they should take enough—follow their prescription—to keep their blood sugar within normal range. And this enlightenment came at the expense of mostly tax-payer dollars, at a price of about $169 million.
Let me add an analogy here for clarification. Remember the old “Off!” TV commercials? “Off!” is a name-brand mosquito repellent, and in the TV commercial, they showed two bare arms, each connected to a live human, of course, being placed consecutively into a long, glass container full of hungry mosquitoes. The first arm, which can be thought of as the experimental arm, is sprayed with a generous amount of “Off!,” and the second, which can be thought of as the control arm, has not been sprayed with anything. Not surprisingly, the first arm, the one sprayed with “Off!,” suffered fewer, if any, mosquito bites than that of the bare arm. This analogy can be related to diabetes in that the mosquito bites represent the complications, and the “Off!” represents the insulin. Carbohydrates are equivalent to the actual sticking of the arm into the mosquito-filled glass container.
I’m sure you’re ahead of my discussion here; clearly it would be ideal to simply not be sticking your arm into a container full of hungry mosquitoes. This solution seems even more obvious than extricating a truck from an overpass by deflating its tires. Yes, “Off!” would come in handy if you’re hiking in the woods; an activity to be enjoyed while on vacation or a pretty weekend day, but it’s not something done often. Similarly, doesn’t it make sense to, at a minimum, reduce your intake of carbohydrates?
So, this study’s result is simply a monumental example of inherent bias. The study itself was done well, the statistics are correct, there was no bias during the literature review of the study question, during selection of the study sample, during measurement of exposure or outcome, during analysis of the data, during the interpretation of the analysis, or even during the publication of the analysis. There was no selection bias, information bias, or confounding bias.
Further, there was no bandwagon effect, base rate fallacy, bias blind spot, choice-supportive bias, confirmation bias, congruence bias, conservatism bias, contrast effect, distinction bias, endowment effect, expectation bias, extreme aversion, focusing effect, framing, hyperbolic discounting, illusion of control, impact bias, irrational escalation, loss aversion, mere exposure effect, moral credential effect, need for closure, neglect of probability, omission bias, outcome bias, planning fallacy, post-purchase rationalization, pseudocertainty effect, reactance, selective perception, Von Restorff effect, wishful thinking, or zero-risk bias. There were no biases in probability and belief, social biases or memory errors.
No, what we have here is just good, old fashioned, simple bias. The study was set up to not include a group that didn’t raise their blood sugar to begin with by not eating carbohydrates.*
The bias to not add a group of test subjects that simply didn’t eat carbohydrates could be thought of as a strain of “not invented here,” a sociological phenomenon manifested as an unwillingness to adopt an idea because it originates from another culture, i.e., the practice of natural medicine. Sociologically, it could also stem from a status-quo bias, the tendency for people to like things to stay relatively the same.
Again, it only makes sense to, at a minimum, reduce your intake of carbohydrates. And a growing number of physicians would agree, including Daniel F. O’Neill, Eric C. Westman, M.D., M.H.S., and Richard K. Bernstein, M.D. In “The Effects of a Low-Carbohydrate Regimen on Glycemic Control and Serum Lipids in Diabetes Mellitus,” (2003), the above authors state:
“These DCCT findings suggest that normal glycemic control (hemoglobin A1c of 4.0-6.0%) is not possible even with intensive treatment, unless there is some other way to improve glycemic control without increasing the risk of hypoglycemia. Recent preliminary studies have suggested that reduction of daily carbohydrate intake leads to improved glycemic control. One study over a 19-month period found that diabetics who increased their daily carbohydrate consumption from 38% (206.3 g/day) carbohydrate to 45.4% (241.4 g/day) carbohydrate had an increase in mean hemoglobin A1c from 9.4% to 11.2%. Another study with a cross-over design involving 28 type II diabetics found an increase in hemoglobin A1c from 7.8% to 9.2% after increasing dietary carbohydrate from 25% to 55% of the daily intake. A third clinical series including type II diabetics who reduced their daily carbohydrate consumption to 100 g/day obtained a mean hemoglobin A1c of 6.9%. Therefore a growing number of studies suggest that carbohydrate restriction can lead to better glycemic control.”
Interestingly, the authors of the above study also noted that prior to the discovery of insulin, Elliot P. Joslin recommended a low-carbohydrate diet as a treatment for diabetes mellitus.
In “Dietary Carbohydrate Restriction in Type 2 Diabetes Mellitus and Metabolic Syndrome: Time for a Critical Appraisal,” (2008), written by a host of renowned doctors, researchers and diabetologists including Anthony Accurso, Richard K. Bernstein, Annika Dahlqvist, Boris Draznin, Richard D. Feinman, Eugene J. Fine, Amy Gleed, David B. Jacobs, Gabriel Larson, Robert H. Lustig, Anssi H. Manninen, Samy I. McFarlane, Katharine Morrison, Jørgen Vesti Nielsen, Uffe Ravnskov, Karl S. Roth, Ricardo Silvestre, James R. Sowers, Ralf Sundberg, Jeff S. Volek, Eric C. Westman, Richard J. Wood, Jay Wortman, and Mary C. Vernon, the authors state:
“Current nutritional approaches to metabolic syndrome and type 2 diabetes generally rely on reductions in dietary fat. The success of such approaches has been limited and therapy more generally relies on pharmacology. The argument is made that a re-evaluation of the role of carbohydrate restriction, the historical and intuitive approach to the problem, may provide an alternative and possibly superior dietary strategy. The rationale is that carbohydrate restriction improves glycemic control and reduces insulin fluctuations which are primary targets. Experiments are summarized showing that carbohydrate-restricted diets are at least as effective for weight loss as low-fat diets and that substitution of fat for carbohydrate is generally beneficial for risk of cardiovascular disease. These beneficial effects of carbohydrate restriction do not require weight loss. Finally, the point is reiterated that carbohydrate restriction improves all of the features of metabolic syndrome.”
In the same article, the authors amplify their position:
“The epidemic of diabetes continues unabated, and impassioned calls for better treatment and prevention strategies are common features of scientific conferences. While it is generally acknowledged that total dietary carbohydrate is the major factor in glycemic control, strategies based on reduction of dietary carbohydrate have received little support. The American Diabetes Association, for example, has traditionally recommend against low carbohydrate diets (less than 130 g/day); while the most recent guidelines admit such diets as an alternative approach to weight loss, they continue to emphasize concerns and downplay benefits. Similarly, the Diabetes and Nutrition Study Group of the European Association for the Study of Diabetes reported “no justification for the recommendation of very low carbohydrate diets in persons with diabetes.” We feel, however, that there is ample evidence to warrant an alternative perspective and that diets based on carbohydrate restriction should be re-evaluated in light of current understanding of the underlying biochemistry and available clinical data.”
If you’re scratching your head at this point, you’re not alone. At some point in nearly every type 1 diabetic’s life, this thought—“Hmmm, I’m eating carbohydrates and taking bolus insulin, what would happen if I didn’t eat carbohydrates? Could I stop taking insulin?”—permeates the brain. It did for me early in my treatment. So, why not just stop eating carbohydrates, and, more importantly, why is it that the DCCT is so influential, resulting in treatments throughout the globe based upon carbohydrates and insulin?
To answer these two important questions, we might start by trying to figure out who is most negatively affected by restricting carbohydrates in a diabetic’s diet. Not the diabetic, ironically. No, if we stop eating carbohydrates, and thus reduce our intake of exogenous insulin, it is the pharmaceutical companies that will sell less insulin, diminishing demand for all the complimentary insulin goods such as insulin delivery devices (syringes, pumps & pens), lancets, test strips, blood sugar meters, batteries, test kit carrying cases, glucose tabs, ketone test strips, alcohol wipes, et al. And, of course, we’ll visit our health-care providers less often. The myriad carbohydrate manufacturers and marketers will find reduced demand for their products too, though, they can manufacture and market something else in a capital driven economy.
Too, if we stop eating carbohydrates, reducing our intake of exogenous insulin, we may even live a little longer.
So why does the DCCT continue to influence health-care providers on a near-global basis?
One explanation is termed “déformation professionnelle,” a French phrase, meaning a tendency to look at things from the point of view of one's own profession, forgetting the broader perspective. It is a pun on the expression “formation professionnelle,” meaning “professional training.” The implication is that all, or most, professional training results to some extent in a distortion of the way the professional views the world.
A better explanation is what Richard Dawkins terms a “meme.” “Dawkins himself used the analogy to illustrate how natural selection pertains to anything that can replicate, not just DNA,” as Steven Pinker describes in How the Mind Works. According to Dawkins:
“I think that a new kind of replicator has recently emerged on this very planet. It is staring us in the face. It is still in its infancy, still drifting clumsily about in its primeval soup, but already it is achieving evolutionary change at a rate that leaves the old gene panting far behind.
The new soup is the soup of human culture. We need a name for the new replicator, a noun that conveys the idea of a unit of cultural transmission, or a unit of imitation. ‘Mimeme’ comes from a suitable Greek root, but I want a monosyllable that sounds a bit like ‛gene’. I hope my classicist friends will forgive me if I abbreviate mimeme to meme. If it is any consolation, it could alternatively be thought of as being related to ‛memory’, or to the French word même. It should be pronounced to rhyme with ‛cream’.
Examples of memes are tunes, ideas, catch-phrases, clothes fashions, ways of making pots or of building arches. Just as genes propagate themselves in the gene pool by leaping from body to body via sperm or eggs, so memes propagate themselves in the meme pool by leaping from brain to brain via a process which, in the broad sense, can be called imitation. If a scientist hears, or reads about, a good idea, he passes it on to his colleagues and students. He mentions it in his articles and his lectures. If the idea catches on, it can be said to propagate itself, spreading from brain to brain. As my colleague N. K. Humphrey neatly summed up an earlier draft of this chapter: ‛…memes should be regarded as living structures, not just metaphorically but technically. When you plant a fertile meme in my mind you literally parasitize my brain, turning it into a vehicle for the meme’s propagation in just the way that a virus may parasitize the genetic mechanism of a host cell. And this isn’t just a way of talking—the meme for, say, “belief in life after death” is actually realized physically, millions of times over, as a structure in the nervous systems of individual men the world over.’”
Commenting on Dawkins and memes, Steven Pinker said:
“Richard Dawkins has drawn the clearest analogy between the selection of genes and the selection of bits of culture, which he dubbed memes. Memes such as tunes, ideas, and stories spread from brain to brain and sometimes mutate in the transmission. New features of a meme that make its recipients more likely to retain and disseminate it, such as being catchy, seductive, funny, or irrefutable, will lead to the meme’s becoming more common in the meme pool. In subsequent rounds of retelling, the most spreadworthy memes will spread the most and will eventually take over the population. Ideas will therefore evolve to become better adapted to spreading themselves. Note that we are talking about ideas evolving to become more spreadable, not people evolving to become more knowledgeable.”
So we see carbohydrates, fiber, the DCCT, black holes, supermassive black holes, wearing a baseball cap backward, et al., ad infinitum, all in a new light. These are all memes, all replicators, each fighting for their own permanence, through replication, in an otherwise impermanent universe. Viruses, bacterium, animals, plants, fungi, names, forms, ideas, melodies, processes, fashion, games, methods, madness: memes all.
Now, whether some of them are good, bad, or indifferent, who knows, depending, of course, on who or what is the protagonist. Well, pardon my speciesism, and kingdomism for that matter, but I do believe we are not here to serve the interests of carbohydrates, or those whose interests include carbohydrates. While we are not the center of the universe, it is in our own best interest to, well, work in our own best interest.
How we deal with some of these competing memes may pose a bit of a dilemma, something we will solve by book’s end. For now, though, having learned how we came to be where we are, let’s develop and implement our optimal solution…
* Since its launch on July 23, 1999, the Chandra X-ray Observatory has been NASA’s flagship mission for X-ray astronomy, taking its place in the fleet of “Great Observatories.” NASA’s premier X-ray observatory was named the Chandra X-ray Observatory in honor of the late Indian-American Nobel laureate, Subrahmanyan Chandrasekhar. Known to the world as Chandra, which means “moon” or “luminous” in Sanskrit, born October 19, 1910 in Lahore, died August 21, 1995, in Chicago, was widely regarded as one of the foremost astrophysicists of the twentieth century. Chandra was an Indian born American astrophysicist, a Nobel laureate in physics along with William Alfred Fowler for their work in the theoretical structure and evolution of stars, and nephew of Indian Nobel Laureate Sir C. V. Raman. Chandrasekhar served on the University of Chicago faculty from 1937 until his death. He became a naturalized citizen of the United States in 1953. Abridged biography courtesy of Wikipedia, available online at: http://en.wikipedia.org/wiki/Subrahmanyan_Chandrasekhar. Retrieved on 2/22/09.
* In statistical hypothesis testing, the p-value is the probability of obtaining a result at least as extreme as the one that was actually observed, assuming chance alone. In this case, P<0.001 means that the odds of the results happening by chance alone are 0.1%.
* In addition to refraining from carbohydrate consumption, type 1s should inject an optimal amount of basal insulin, also known as long-acting insulin, once or twice in a 24 hour period, to keep blood sugar stable throughout the day and offset the inevitable rise in BG caused by the dawn phenomenon.
 See http://chandra.harvard.edu/xray_sources/blackholes_stellar.html. Retrieved on 1/19/09.
 See Ibid.
 See Ibid.
 See Ibid.
 See Ibid.
 See Ibid.
 See Ibid.
 See Ibid.
 See Ibid.
 See Ibid.
 Ferguson, Kitty. Prisons of light: Black Holes. NY: Cambridge University Press, 1996, page 15.
 See http://chandra.harvard.edu/xray_sources/blackholes_sm.html. Retrieved on 1/19/09.
 See Ibid.
 See Ibid.
 For a good, authorized biography of Stephen Hawking, see Stephen Hawking: Quest for a Theory of the Universe, by Kitty Ferguson (New York: Franklin Watts, 1991). Kitty Ferguson is a remarkable person, receiving both a bachelor’s and master’s from the Julliard School. For many years she was a successful professional musician, conducting and performing oratorio, early music and chamber music, before renewing her lifelong interest in physics and cosmology by auditing graduate lectures and seminars at the Department of Applied Mathematics and Theoretical Physics at Cambridge University.
 See “General Treatment of Diabetes,” D. A. Pyke, Br Med J. 1970 Aug 1;3(5717):269. Available online at http://www.ncbi.nlm.nih.gov/pubmed/5448803. Retrieved on 3/7/09.
 Singh, Inder. “Low-Fat Diet and Therapeutic Doses of Insulin in Diabetes Mellitus.” Lancet, 1955, Feb 26; 268(6861): p. 422.
 Ibid, p. 423.
 Kinsell, L.W. “The Diabetic Diet.” In: Diabetes Mellitus: Diagnosis and Treatment, edited by G.J. Hamwi and T.S. Danowski. New York, American Diabetic Association, 1967, vol. II, pp. 97-99. See also Pyke, D.A. General Treatment of Diabetes. Brit. Med. J. 3: 268, 1970.
 Bierman, E.L., M.J. Albrink, R.A. Arky, W.E. Conner, et al. “Special Report. Principles of Nutrition and Dietary Recommendations for Patients with Diabetes Mellitus.” Diabetes. 20: 633, 1971.
 Singh, Inder. “Low-Fat Diet and Therapeutic Doses of Insulin in Diabetes Mellitus.” Lancet. 1955, Feb 26; 268(6861): p. 422. Anderson, J.W. “Influence of High Carbohydrate Diets on Glucose Tolerance of Normal and Diabetic Men.” Proc. Int. Sugar Res. Symposium. Washington, D.C., March, 1974. Kempner, W., R.L. Peschel and C. Schlayer. “Effect of Rice Diet on Diabetes Mellitus Associated with Vascular Disease.” Postgrad. Med. 24: 359, 1958. Brunzell. J.D., R.L. Lerner, W.R. Hazzard, D. Porte, Jr., et al. “Improved Glucose Tolerance with High Carbohydrate Feeding in Mild Diabetes.” N. Engl. J. Med. 284: 521, 1971. Brunzell, J.D., R.L. Lerner, D. Porte, Jr., and E.L. Bierman. “Effect of a Fat Free, High Carbohydrate Diet on Diabetic Subjects with Fasting hyperglycemia. Diabetes. 23: 138, 1974.
 Tae G. Kiehm, M.D., James W. Anderson, M.D., and Kyleen Ward, R.D. “Beneficial Effects of a High Carbohydrate, High Fiber Diet on Hyperglycemic Diabetic Men,” Am. J. Clin. Nutr. 29: 1976, p. 895.
 See “High-carbohydrate diets and insulin-dependent diabetics,” by R W Simpson, J I Mann, J Eaton, R D Carter, and T D Hockaday, Br Med J. 1979 September 1; 2(6189): 523–525. Available online at http://www.pubmedcentral.nih.gov/pagerender.fcgi?artid=1596170&pageindex=1#page. Retrieved on 5/3/09.
 In a randomised cross-over study 18 nondependent (NIDDM) and 9 insulin-dependent (IDDM) diabetics were put on to a high carbohydrate diet containing leguminous fibre (HL) for 6 weeks, and also a standard low carbohydrate diet (LC) for 6 weeks. During two identical 24 hour metabolic profiles mean preprandial and mean 2 hour postprandial blood glucoses were significantly lower on HL in both groups, as were also several overall measures of diabetic control, including the degree of glycosuria. Total cholesterol was reduced significantly on HL in both groups, and the HDL/LDL cholesterol ratio increased significantly on HL in the NIDDM group.
See “A high carbohydrate leguminous fibre diet improves all aspects of diabetic control,” by Simpson HC, Simpson RW, Lousley S, Carter RD, Geekie M, Hockaday TD, and Mann JI. Lancet. 1981 Jan 3;1(8210):1-5. Available online at http://www.ncbi.nlm.nih.gov/pubmed/6109047. Retrieved on 5/3/09.
 This study investigated the possible beneficial effects of the digestible carbohydrate component. A diet rich in carbohydrate was compared with a traditional low carbohydrate diet in 10 Type 2 (non-insulin-dependent) diabetic patients, using a crossover design; both diets contained < 20 g dietary fibre/day. During 24-h metabolic profiles carried out after 4 weeks on each diet, the mean basal plasma glucose (mean of 03.00, 05.00 and 07.00 h values) was 5.3 mmol/l on the high carbohydrate diet and 5.9 mmol/l on the low carbohydrate diet (p < 0.05), despite the 2-h postprandial glucose (mean of three main meals) being higher on the high carbohydrate diet than on the low carbohydrate diet (8.7 versus 7.3 mmol/1, p < 0.01). Overall diabetic control was the same throughout the study, as judged by a mean 24-h plasma glucose of 6.7 mmol/1 on the high carbohydrate and 6.6 mmol/1 on the low carbohydrate diet, and haemoglobin Alc percentage of 8.3 on both diets. Mean cholesterol was 4.55 mmol/1 on both diets and fasting plasma triglyceride was 2.83 mmol/l on the high carbohydrate and 2.55 mmol/1 on the low carbohydrate diet (p = NS).
See “Digestible Carbohydrate—an Independent Effect on Diabetic Control in Type 2 (Non-Insulin-Dependent) Diabetic Patients?” by H. C. R. Simpson, R. D. Carter, S. Lousley, and J. I. Mann. Diabetologia (1982) 23:235-239. Available online at http://www.springerlink.com/content/x272687026872634/fulltext.pdf. Retrieved on 5/3/09.
 “What carbohydrate foods should diabetics eat?” by J I Mann. Br Med J (Clin Res Ed). 1984 April 7; 288(6423): 1025. Available online at http://www.pubmedcentral.nih.gov/pagerender.fcgi?artid=1442616&pageindex=1#page. Retrieved on 5/3/09.
 See Ravnskov, Uffe. Fat and Cholesterol are Good for You! What Really Causes Heart Disease, Sweden: GB Publishing, 2009, page 76.
 Taubes, Gary. Good Calories, Bad Calories. First Anchor Books Edition. New York: Anchor Books, 2008, page 395.
 Ibid, pages 395-396.
 This tale is adapted from the Wikipedia article entitled “Thrifty Gene hypothesis,” available online at http://en.wikipedia.org/wiki/Thrifty_gene_hypothesis. Retrieved on 3/8/09.
 Neel JV (1962). “Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”?” Am. J. Hum. Genet. 14: 360. PMID 13937884. Available online at http://www.ncbi.nlm.nih.gov/pubmed/13937884. Retrieved on 3/8/09.
 Ibid, p.359
 Ibid, p.355
 Ibid, p.353
 Neel, J.V. 1982. “The Thrifty Genotype Revisited.” In: The Genetics of Diabetes Mellitus, ed. J. Kobberling and R. Tattersall. New York: Academic Press, 293-93.
 Speilman, R.S., S.S. Fajans, J.V. Neel, S. Pek, J.C. Floyd, and W.J. Oliver. 1982. “Glucose Tolerance in Two Unacculturated Indian Tribes of Brazil.” Diabetologia. Aug.;23(2):90-93.
 Neel, J.V. 1989. “Update to ‘The Study of Natural Selection in Primitive and Civilized Human Populations.’” Human Biology. Oct.-Dec.;61(5-6):811-23.
 Neel, J.V. 1999. “The ‘Thrifty Genotype’ in 1998.” Nutrition Reviews May; 57(5, pt.2):S2-9.
 Speakman JR (2007). “A nonadaptive scenario explaining the genetic predisposition to obesity: the “predation release” hypothesis.” Cell Metab. 6 (1): 5–12; doi: 10.1016/j.cmet.2007.06.004. PMID 17618852. Available online at http://www.ncbi.nlm.nih.gov/pubmed/17618852. Retrieved on 3/8/09.
 Baschetti R (1998). “Diabetes epidemic in newly westernized populations: is it due to thrifty genes or to genetically unknown foods?” J R Soc Med. 91 (12): 622–625. See also Lee, R.B. 1968. “What Hunters Do for a Living, or, How to Make Out on Scarce Resources.” In: Lee and Devores, eds. 1968.
 Speakman JR (2007). “A nonadaptive scenario explaining the genetic predisposition to obesity: the “predation release” hypothesis.” Cell Metab. 6 (1): 5–12; doi: 10.1016/j.cmet.2007.06.004. PMID 17618852. Available online at http://www.ncbi.nlm.nih.gov/pubmed/17618852. Retrieved on 3/8/09.
 Taubes, Gary. Good Calories, Bad Calories. First Anchor Books Edition. New York: Anchor Books, 2008, page 456.
 Reprinted with permission from the National Academies Press, Copyright 2005, National Academy of Sciences, “Dietary Carbohydrates: Sugars and Starches,” in Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients) (2005). Food and Nutrition Board, 2005, pages 275-279. License number 2241560984249. Available online at http://www.nap.edu/catalog.php?record_id=10490. Retrieved on 3/7/09. Established in 1970 under the charter of the National Academy of Sciences, the Institute of Medicine (http://www.iom.edu/) provides independent, objective, evidence-based advice to policymakers, health professionals, the private sector, and the public. The mission of the Institute of Medicine embraces the health of people everywhere.
 Taubes, Gary. Good Calories, Bad Calories. First Anchor Books Edition. New York: Anchor Books, 2008, page 456.
 Family Medicine Principles & Practice, Fifth Edition. Editor: Robert B. Taylor. Springer-Verlag, 1998, page 1067.
 Rudolph's Pediatrics 21st Edition. Edited by Colin D. Rudolph, Abraham M. Rudolph, Margaret K. Hostetter, George Lister, Norman J. Siegel. McGraw-Hill, Medical Publishing Division, 2003, page 2123.
 Cecil Textbook of Medicine 22nd Edition. Edited by Lee Goldman, MD, and Dennis Ausiello, MD. Saunders, an imprint of Elsevier, 2004, pages 1432-1433.
 Harrison’s Principles of Internal Medicine, 17th Edition. Edited by Anthony S. Fauci, MD, et al. McGraw-Hill Medical, 2008, page 2286.
 Williams Textbook of Endocrinology, Tenth Edition. P. Reed Larsen, MD, FACP, FRCP, Henry M. Kronenber, MD, Shlomo Melmed, MD, and Kenneth S. Polansky, MD. Saunders, an imprint of Elsevier, 2003, page 1496.
 International Textbook of Diabetes Mellitus. Editors-in-chief: R.A. Defronzo, E. Ferrannini, H. Keen, and P. Zimmet. John Wiley & Sons, Ltd., 2004, page 1067.
 Joslin’s Diabetes Mellitus. Edited by C. Ronald Kahn, Gordon C. Weir, George L. King, Alan M. Jacobson, Alan C. Moses, Robert J. Smith. Lippincott Williams & Wilkin & The Joslin Diabetes Center. Page 2.
 Lange 2009 Current Medical Diagnosis & Treatment. Edited by Stephen J. McPhee, MD, Maxine A. Papadakis, MD, and Lawrence M. Tierney, Jr., MD, Senior Editor. McGraw-Hill Medical, 2009, pages 1059-1060.
 See the Biostatistics Center of the George Washington University website, available online at http://www.bsc.gwu.edu/bsc/studies/dcct.html. Retrieved on 1/19/09.
 See Ibid.
 The DCCT Research Group (1993). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The New England Journal of Medicine329: 977-986.
 The DCCT Research Group (1995). Adverse events and their association with treatment regimens in the Diabetes Control and Complications Trial. Diabetes Care18: 1415-1427.
 The DCCT Research Group (1995). The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes44: 968-983. See also The DCCT Research Group (1996). The absence of a glycemic threshold for the development of long-term complication: the perspective of the Diabetes Control and Complications Trial. Diabetes45: 1289-1298.
 The DCCT Research Group (1997). Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes45: 271-286.
 See the Biostatistics Center of the George Washington University website, available online at http://www.bsc.gwu.edu/bsc/studies/dcct.html. Retrieved on 1/19/09.
 See Ibid.
 Diabetes Control and Complications Trial (DCCT). N Engl J Med 1993;329:977-986.
 “The Diabetes Control and Complications Trial (DCCT) Design and Methodologic Considerations for the Feasibility Phase,” Diabetes 1986; 35:534.
 The DCCT was supported under cooperative agreements and a research contract with the Division of Diabetes, Endocrinology, and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases and by the National Heart, Lung, and Blood Institute, the National Eye Institute, the National Center for Research Resources, and various corporate sponsors listed in Diabetes Care 1987;10:1-19). In addition, the Epidemiology of Diabetes Intervention and Complications (EDIC) ongoing funding was $58 million. See the National Institutes of Health Fact Sheet online at http://www.aimbe.org/assets/84_nihresearchintowhatworksb.pdf. Retrieved on 4/11/09.
 For a particularly enlightening article explaining how claimed research findings may often be simply accurate measures of the prevailing bias, see Ioannidis JPA (2005) Why Most Published Research Findings Are False. PLoS Med 2(8): e124; doi: 10.1371/journal.pmed.0020124. Available online at http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0020124. Retrieved on 3/24/09.
 For a good discussion of all the different types of cognitive bias, see the Wikipedia article “List of Cognitive Biases” online at http://en.wikipedia.org/wiki/List_of_cognitive_biases. Retrieved on 3/22/09.
 McCullough DK, Mitchell RD, Ambler J, et al. A prospective comparison of “conventional” and high-carbohydrate/high-fibre/low-fat diets in adults with type 1 diabetes. Diabetologia 1985;28:208-212.
 Gutierrez M, Akhavan M, et al. Utility of a short-term 25% carbohydrate diet on improving glycemic control in type II diabetes mellitus. J Am Coll Nutr 1998;17:595-600.
 Hays JH, et al. Abstract presented at the 81st Annual Meeting of the Endocrine Society, 1999.
 O’Neill DF, Westman EC, Bernstein RK. The effects of a low-carbohydrate regimen on glycemic control and serum lipids in diabetes mellitus. Metabolic Syndrome and Related Disorders. Volume 1, number 4, 2003, p. 291-298.
 See Osler W, McCrae T. The Principle and Practice of Medicine. New York: D. Appleton and Company, 1923. Op Cit. O’Neill (2003).
 See “Dietary carbohydrate restriction in type 2 diabetes mellitus and metabolic syndrome: time for a critical appraisal,” by Anthony Accurso, Richard K Bernstein, Annika Dahlqvist, Boris Draznin, Richard D Feinman, Eugene J Fine, Amy Gleed, David B Jacobs, Gabriel Larson, Robert H Lustig, Anssi H Manninen, Samy I McFarlane, Katharine Morrison, Jørgen Vesti Nielsen, Uffe Ravnskov, Karl S Roth, Ricardo Silvestre, James R Sowers, Ralf Sundberg,, Jeff S Volek, Eric C Westman, Richard J Wood, Jay Wortman, and Mary C Vernon. Nutrition & Metabolism 2008, 5:9; doi: 10.1186/1743-7075-5-9. Available online at http://www.nutritionandmetabolism.com/content/5/1/9#B29. Retrieved on 5/8/09.
For another good review of low-carbohydrate diets in the treatment of diabetes, as reprinted in my previous book Thrive With Diabetes, see Surender K Arora and Samy I McFarlane. “The Case for Low Carbohydrate Diets in Diabetes Management.” Nutr Metab (Lond). 2005; 2: 16. Published online July 14, 2005; doi: 10.1186/1743-7075-2-16. Available online at http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1188071. Retrieved on 3/14/08.
 See “Dietary carbohydrate restriction in type 2 diabetes mellitus and metabolic syndrome: time for a critical appraisal,” by Anthony Accurso, Richard K Bernstein, Annika Dahlqvist, Boris Draznin, Richard D Feinman, Eugene J Fine, Amy Gleed, David B Jacobs, Gabriel Larson, Robert H Lustig, Anssi H Manninen, Samy I McFarlane, Katharine Morrison, Jørgen Vesti Nielsen, Uffe Ravnskov, Karl S Roth, Ricardo Silvestre, James R Sowers, Ralf Sundberg, Jeff S Volek, Eric C Westman, Richard J Wood, Jay Wortman, and Mary C Vernon. Nutrition & Metabolism 2008, 5:9; doi: 10.1186/1743-7075-5-9. Available online at http://www.nutritionandmetabolism.com/content/5/1/9#B29. Retrieved on 5/8/09.
 For a good, brief history detailing three other possible attributions of the word “meme” see “A Note on the Origin of ‘Memes’/’Mnemes,’” by John Laurent, School of Science, Griffith University, available online at http://cfpm.org/jom-emit/1999/vol3/laurent_j.html. Retrieved on 4/9/09.
For a comprehensive list of Mimetics publications on the web including those of Susan Blackmore, Richard Dawkins, Daniel Dennett, Liane Gabora, Derek Gatherer, Francis Heylighen, Aaron Lynch, and Paul Marsden, et al., compiled by Dave Gross, see http://users.lycaeum.org/~sputnik/Memetics/. Retrieved on 4/9/09.
For a compelling short video replete with written transcript, see “Dan Dennett on Dangerous Memes,” on TED.com, recorded February, 2002, in Monterey, CA, (video duration: 15:39), online at http://blog.ted.com/2007/07/dan_dennett_on_2.php. Retrieved on 4/9/09.
See also Dennett, Daniel C. Darwin’s Dangerous Idea: Evolution and the Meanings of Life. New York: Simon & Schuster Paperbacks, 1995,
For further resources, see also the Wikipedia article “Meme” online at http://en.wikipedia.org/wiki/Meme. Retrieved on 4/9/09.
 Pinker, Steven. How the Mind Works. New York: W.W. Norton & Company, 1997, page 208.
 Dawkins, Richard. The Selfish Gene. New York: Oxford University Press, 30th Anniversary Edition, 2006, page 192.
 Pinker, Steven. How the Mind Works. New York: W.W. Norton & Company, 1997, page 208.