Dr. Sandler's 50-Year-Old "How To Prevent Heart Attacks" Has Grown Weak with the Passage of Time

In the late 1950s, physician Dr. Benjamin Sandler published a monograph titled "How To Prevent Heart Attacks".  At the time of its publication, a debate was raging regarding the etiology of myocardial infarction (the medical term for "heart attack").  It was generally agreed upon that coronary atherosclerosis (hardening/thickening of the coronary arteries) and coronary thrombosis (blood clot formation) were somehow associated with myocardial infarction (MI) but there was no consensus regarding exactly how these conditions were pathophysiologically related.  Some believed that heart attacks occurred as a consequence of coronary thrombosis while others believed the opposite, that coronary thrombosis was a consequence of heart attacks.  The first few pages of this paper describe the controversy in more detail:  The Early History and Development of Thrombolysis in Acute Myocardial Infarction.

Dr. Sandler held the latter view.  He believed that a sharp and sudden fall in blood glucose, either relative or absolute, was the "immediate precipitating cause" of heart attacks.  Coronary thrombosis occurred in the aftermath, particularly in arteries more severely affected with atherosclerosis.  According to Dr. Sandler, the heart, like the brain, relies exclusively on glucose for energy production.  If blood glucose were to decrease rapidly, oxygen consumption by the heart would also decrease rapidly because the heart uses oxygen together with glucose to generate energy via aerobic respiration.  In other words, the heart has no need to take up a lot of oxygen when glucose availability is low.  A precipitous fall in glucose and oxygen uptake leads to the accumulation of lactic acid in heart muscle (myocardium) since glucose can now only be "burned" anaerobically (glucose => pyruvic acid => lactic acid).  The lactic acid build-up causes a portion of the heart muscle to go into a sustained cramp and the branch of the coronary artery passing through the cramped area will become kinked causing an obstruction of blood flow.  If the kinked coronary artery is particularly atherosclerotic and the cramp is significantly prolonged, a thrombus will form.  Otherwise, the sufferer will experience an MI with no thrombosis or even thrombosis with no MI.  Dr. Sandler recommended a diet low in carbohydrates because he believed consumption of sugar and starch resulted in the wild blood glucose swings which could lead to heart attacks.

Dr. Sandler based his theory on several facts/observations known at the time:

• Many people have coronary atherosclerosis yet only a relative few suffer recurrent chest pain (angina pectoris) and/or fall victim to a heart attack.  In fact, extensive atherosclerosis is found during autopsies in people who never suffered a heart attack.
• A heart attack can occur with or without coronary thrombosis, and coronary thrombosis can occur without a heart attack.
• Normal coronary arteries have been found on autopsy in individuals who experienced angina pectoris in life.
• Angina pectoris and heart attack pain come on suddenly and can wax and wane over hours, days, or even months, but coronary atherosclerotic lesions are relatively static; hence the condition of the arteries themselves can not adequately explain angina and heart attacks.  Unsteady blood sugar levels offer a much better explanation.  In Dr. Sandler's own words:

"The mechanism causing the chest pain and the eventual heart attack would thus have to be an exceedingly labile one that can come without warning, vary greatly in severity, and disappear spontaneously. Such a mechanism could very readily involve an essential nutrient to the heart muscle which is present in the blood stream, a biochemical dissolved in the blood which is capable of wide fluctuation in short periods of time from normal to abnormal range, and capable of embarrassing the heart muscle during such abnormal fluctuation. There is such a chemical in the blood, an essential nutrient for the heart muscle, essential for normal heart action, which must be available to the heart, every moment of life in order to permit the heart to beat around 70 times per minute, in the adult during rest, for every minute of life. This chemical is called the blood glucose or blood sugar."

First and foremost, Dr. Sandler’s theory relies heavily on his belief that the heart, like the brain*, utilizes only glucose for energy production.  It is now well-established that the heart also utilizes fatty acids, oftentimes as its main fuel source.  In fact, glucose is considered a secondary fuel source for the heart after the fetal and neonatal periods.  So the idea that the heart has an absolute requirement for an unwavering supply of glucose is likely incorrect.  A drop in glucose availability can be met by an increase in fatty acid oxidation if need be.

Fuel metabolism aside, Sandler's monograph really shows its age when discussing the role thrombosis plays in myocardial infarction. It is now accepted by the vast majority of the medical community that thrombus formation over "vulnerable" atherosclerotic plaque is the immediate precipitating cause of most heart attacks.  But it's certainly easy to see why Dr. Sandler and other like-minded individuals of his era doubted that coronary thrombosis caused myocardial infarcts.  Autopsy findings, from which most of the data concerning the etiology of MI came from at the time, were not very convincing; some studies found evidence of thrombi in as little as 21% of fatal myocardial infarctions.  However, post-mortem findings along with older autopsy and histology techniques can be unreliable in determining the role thrombus formation plays in heart attacks.  From The Elusive Clot: The Controversy over Coronary Thrombosis in Myocardial Infarction (I have bolded the arguments more applicable to the topic of this blog post):

"What were some of the factors that might have caused the under-reporting of coronary thrombosis in some of these studies?  1)- Studies that included patients dying within an hour of symptoms must surely have included patients with significant coronary narrowing precipitating fatal ventricular arrhythmias in the absence of an occluding thrombus.  2)- Inadequate serial sectioning, usually performed at 3mm to 5mm intervals along the coronary arteries may have missed some ultra-short occluding coronary thrombi in the range of only a millimeter in length.  3)- There was often difficulty in distinguishing older organized thrombi from other types of pathology in diseased arteries.  4)- The use of different criteria of what constituted an acute myocardial infarction resulted in the inclusion of some patients with minor myocardial or endocardial scarring that did not represent infarctions.  5)- Some investigators excluded "non-obstructive" thrombi, not realizing that these may have represented occluding thrombi that had been partially dissolved by intrinsic fibrinolytic mechanisms."

During the mid-1960s, several investigators claimed that their improved autopsy techniques showed that greater than 90% of fatal myocardial infarctions were associated with coronary thrombi, most of them totally occlusive.  This won some, but not all, over to the side of thrombosis being the immediate causative factor in the majority of MI's.  Many more became convinced in the late 1970s / early 1980s when it was shown that infusion of streptokinase, a drug capable of breaking down coronary thrombi, could restore coronary blood flow and improve patient outcome.  Another seminal study of this time period was that of Marcus DeWood and colleagues who, using coronary arteriography, demonstrated for the first time in live patients the commonality of coronary thrombosis in acute myocardial infarction.

Further study into the nature of atherosclerosis and thrombosis has revealed why a seemingly static atherosclerotic plaque can cause intermittent, unsteady chest pain, and why someone can have coronary atherosclerosis, yet no heart trouble.  The fact of the matter is, all atherosclerosis is not the same.  Some is relatively stable, meaning it builds up slowly over many years and is not prone to the rupturing which leads to thrombus formation.  This general category of atherosclerosis can lead to heart problems like stable angina or even MI but oftentimes it's essentially benign.  The atherosclerotic coronary arteries seen in the Masai of Africa are a good example of this.  However, a second general type of atherosclerosis, called vulnerable plaque because of its tendency to rupture, can cause the waxing and waning chest pain Dr. Sandler attributed to unstable blood glucose.  When thrombosis is triggered by vulnerable plaque rupture, the blood clot that forms can be broken down by "endogenous lysis" and then form again.  This transient lysis and formation of a coronary thrombus is responsible for the waxing and waning pain of unstable angina.  If the balance between the two states favors clot formation, then the resulting total occlusion will lead to MI if the lack of blood flow persists for a sufficient amount of time.  When Dr. Sandler suggested that unstable blood sugar provides a better explanation for the intermittent, "labile" pain of angina pectoris than the condition of the coronary arteries themselves, this information about the waxing and waning nature of coronary thrombi was not known.  From CORONARY DISEASE: The Pathophysiology of Acute Coronary Syndromes:

"It is difficult now to perceive why coronary thrombosis was regarded 25 years ago as an inconstant and irrelevant consequence of acute infarction rather than its prime cause. Once angiography was carried out soon after the onset of infarction, and it was realised that the subtending artery was totally blocked but spontaneously reopened with time in many cases (and that this reopening was accelerated by fibrinolytic treatment), thrombosis was seen as a major causal factor in occlusion. Suddenly the clinical world found thrombi to be both dynamic and important. Pathologists had thought thrombi were important but did not realise how dynamic they could be."

Although it's clear that Dr. Sandler's theory doesn't hold up exactly as written, is there any credence to it at all?  Moderate to severe hypoglycemia can increase certain aspects of heart function such as heart rate, peripheral systolic blood pressure, and myocardial contractility, so it can be argued that someone with a compromised heart could experience deleterious cardiac consequences if their blood sugar plummets.  There is a case report that features the experiences of a woman who sometimes has chest pain when she's hypoglycemic, but this is balanced by the case report of a man who experiences chest pain when he's hyperglycemic.  It's been shown that patients hospitalized with acute MI who experienced episodes of hypoglycemia had increased mortality compared to MI patients who did not experience hypoglycemia, but only if their hypoglycemia was spontaneous (not caused by insulin therapy).  MI patients whose hypoglycemic events were brought about by overly-aggressive insulin therapy had no increased mortality risk.  Spontaneous hypoglycemia is an indication of a more fragile metabolic state so it's not very surprising that it would be associated with an increased risk of death.  However, this does not mean hypoglycemia is the cause of the increased risk; the fact that there was no increased mortality in the insulin-induced hypoglycemic patients demonstrates that low blood sugar per se is probably not harmful.  This tells me that the case for hypoglycemia-induced angina and MI's is not particularly strong, although it may occur in certain individuals.

Why is all this important?  Myocardial infarction, unstable angina, etc. are not medically treated according to Dr. Sandler's ideas regarding unsteady blood sugar (although I have nothing against his dietary recommendations per se), but are treated as pathologies of the coronary arteries/thrombosis which science has made a very strong case for.  I think the harm may come from the fact that some people believe Sandler's theory is absolutely true; I've seen it around the internet.  The danger, IMHO, is that one of these people, when experiencing suspicious chest pain, may decide to treat themselves with diet or maybe even acutely with the proverbial glass of orange juice that diabetics are told to take when their blood sugar gets too low.  When it comes to myocardial infarction and related conditions, getting evaluated and treated quickly by licensed medical professionals is of the essence.  A few hours, even a few minutes, can mean the difference between life and death.


*Under “normal” mixed diet conditions, the brain essentially relies upon glucose exclusively. Under very low carbohydrate conditions, the brain relies more and more on ketones although it still has an absolute requirement for a small amount of glucose. However, the brain, unlike the heart, cannot directly utilize fatty acids for fuel.

In Defense of Glyceroneogenesis Researchers (not that they really need it)

A few days ago, Jimmy Moore aired an interview he did with Gary Taubes in which they discussed a myriad of topics.  Jimmy asked Gary if there was anything he would change in his book Good Calories, Bad Calories based on new information he had come across since its publication. Gary answered that he wished he hadn't stated that dietary carbohydrates were absolutely required to store fat in fat tissue because he has since learned that a process called glyceroneogenesis casts doubt on that assertion.  As someone who has written about glyceroneogenesis and low carb diets, I'm glad Taubes is spreading the word.

What I have a problem with is a comment left at Jimmy's site that comes across as biased against and dismissive of the scientists who elucidated glyceroneogenesis:

"I actually had a look again at one of the so called ‘studies’ explaining this Glyceroneogenesis process in this post:

http://adipo-insights.blogspot.com/2009/09/is-fable-of-unfettered-fat-burning.html

This study is basically flawed, even a layman like me can see things such as the fact that the test subjects were not keto-adapted and I believe that a total different set of rules apply for people who are not keto-adapted. There are some other flaws too, and I think at the end the basic biochemistry that Gary mentioned to in GCBC will carry more weight (take up a bigger part of a pie-chart of total processes) at the end."

I'm not sure what study this person is referring to since I didn't reference any study (i.e. primary research) concerning glyceroneogenesis, only two review papers, but the quotation marks around the word studies, as well as the term so called, indicates to me that this person believes that the glyceroneogenesis research to date is either worthless, corrupted, laughable, or some combination of the three.  I agree that keto-adaptation may affect the rate of glyceroneogenesis, but the fact that these researchers haven't examined that particular condition yet doesn't make their research "flawed".  These scientists are not trying to prove or disprove any low carbohydrate diet theory; they are trying to understand basic biochemistry.  And yes, glyceroneogenesis, although not well known, is a very important component of basic biochemistry because the ability to re-esterify fatty acids is critical to human metabolism.

I find it more than a bit ironic that an individual who appears to be an ardent fan of Taubes' Good Calories, Bad Calories would criticize the work of researchers who behave similarly to the "real" scientists lauded in the book.  In this article, Richard Hanson, Ph.D., one of the discoverers of the glyceroneogenic pathway, tells us how his and his colleagues' desire to answer an intriguing question, brought about by a scientific observation, led them on the journey to uncover glyceroneogenesis:

"By 1967 it had been well established that both pyruvate carboxylase and PEPCK-C were involved in hepatic and renal gluconeogenesis. So it was a real surprise that year when John Ballard and I found pyruvate carboxylase in adipose tissue, a tissue that did not make glucose. We proposed that pyruvate carboxylase played an anaplerotic role (i.e. it replenished citric acid cycle anions) during lipogenesis in adipose tissue, because citrate efflux from the mitochondria depletes intermediates of the citric acid cycle. This is similar to the function of the enzyme in the liver during gluconeogenesis. We came to the totally incorrect conclusion that there were both mitochondrial and cytosolic forms of the pyruvate carboxylase in adipose tissue. It turned out that it is easy to break mitochondria during their isolation from adipose tissue and thus release the enzyme. In the same year, John and I, together with Gilbert Leveille, reported that adipose tissue also contained PEPCK-C. What was this gluconeogenic enzyme doing in a tissue that does not make glucose?"

And the rest is scientific history.  Something tells me Gary would approve.

How the "Black Age" of Endocrinology May Be Affecting Your Understanding of Insulin Resistance & Obesity

If, on a Physiology exam, you were to answer that the primary action of insulin is to allow glucose entry into liver and muscle cells, you would probably be marked correct although the answer would be wrong!  The fact of the matter is, insulin is not required for glucose to enter cells.  During what is sometime referred to as the "black age" of Endocrinology (approximately from 1960 - 1980), scientists studying the actions of insulin using in vitro techniques with rodent tissues mistakenly assumed that their data mirrored what happens in living, breathing human beings.  It's now known, and has been for many years, that insulin's inhibitory effects on processes such as liver glycogenolysis and fat cell lipolysis are much stronger and more metabolically important than its excitatory effects on processes such as de novo lipogenesis and cellular glucose uptake.  Yet, despite this new knowledge, the old misconceptions about insulin still persist and have become dogma.  For an illuminating discussion of this topic, please see this article in the Journal of Endocrinology.

I think all would agree that understanding the true nature of insulin action is critical to understanding the development and progression of insulin resistance and obesity.  A common theory in the low-carb community, spurred in part by the book Good Calories, Bad Calories, is that insulin resistance develops first in the liver, progresses next in skeletal muscle before finally developing in fat cells.  This progression leads to obesity and ultimately, for those genetically unfortunate folks, to type 2 diabetes.  From page 393 of GCBC:

"…fat cells remain sensitive to insulin long after muscle cells become resistant to it. Once muscle cells become resistant to the insulin in the bloodstream, as Yalow and Berson explained, the fat cells have to remain sensitive to provide a place to store blood sugar, which would otherwise either accumulate to toxic levels or overflow into the urine and be lost to the body. As insulin levels rise, the storage of fat in the fat cells continues, long after the muscles become resistant to taking up any more glucose. Nonetheless, the pancreas may compensate for this insulin resistance, if it can, by secreting still more insulin. This will further elevate the level of insulin in the circulation and serve to increase further the storage of fat in the fat cells and the synthesis of carbohydrates from fat (note: I think it’s supposed to be ‘fat from carbohydrates’)."

There is some evidence to support this contention (most notably an experiment conducted by Ethan Sims which purported to show that fat tissue surgically removed at different time intervals from study subjects who were gaining weight from forced over-nutrition became progressively more insulin sensitive while muscle tissue did not), but the matter is far from settled.   A major problem I see with this hypothesis is that it is partially based on the incorrect notion that insulin (and by extension insulin sensitivity) is needed for muscle cells to take up glucose from the blood.  Human skeletal muscle in vivo can import glucose in the total absence of insulin.  Carefully designed studies have shown that type 1 diabetics, withdrawn from insulin for 24 hours, take up more glucose into their cells during the insulin depleted state than when they are re-administered insulin in the physiological range.  Knowing this, it's difficult for me to believe, at least without more concrete evidence, that insulin resistant muscles cannot take up a considerable amount of blood glucose and that this results in a physiologic imperative for fat cells to remain insulin sensitive in order to act as a "sink" for excess blood sugar.  Remember, the excitatory or stimulatory effects of insulin (of which cellular glucose uptake is one) are relatively unimportant.  Again, please read this article for clarification.

To be continued...

It’s ExASPerating!

To some in the low carb world, Acylation Stimulating Protein (ASP) is like the proverbial Gothic era crazy relative locked away in the never-to-be-entered part of the manor. They either try to forget about it or, if confronted with evidence of its existence, attempt to explain it away. ASP complicates the carbohydrate hypothesis of weight gain because it provides a mechanism whereby dietary fat can be stored without an increase in insulin. Briefly, fat cells produce ASP when they are exposed to chylomicrons (intestinally-derived packages of dietary fat). ASP up-regulates the enzyme diacylglycerol acyltransferase (DGAT) which catalyzes the final and committed step in triglyceride synthesis. Triglycerides are made from fatty acids liberated from chylomicrons by the enzyme lipoprotein lipase (LPL). ASP-directed triglyceride synthesis leads indirectly to an increase in LPL activity because increased triglyceride synthesis relieves product (i.e. fatty acid) inhibition of LPL. More LPL activity means more fatty acids will be available for triglyceride storage. ASP also inhibits the enzyme hormone sensitive lipase (HSL) resulting in decreased fat cell lipolysis, and it stimulates glucose uptake by fat cells which provides substrate for the glycerol backbone needed for triglyceride formation. All in all, it’s fairly straightforward and logical – you eat fat; your digestive system packages it into chylomicrons; the chylomicrons are transported via your blood circulation to your fat tissue; ASP is generated; ASP stimulates various biochemical mechanisms that allow you to store some amount of the fat for future use. It’s quite exquisite actually.

Individuals who don’t seem to want to give ASP a fair shake usually base their objections on two arguments:

• 1) - Chylomicrons, which stimulate ASP production, are only in the circulation for a relatively short period of time (usually less than ½ hour) so not much fat storage will take place.
• 2) - ASP levels don’t increase in the blood after study subjects consume fat so the in vitro studies showing chylomicron-stimulated ASP production don’t reflect what actually occurs in the human body.

Although these two statements contain facts, they don’t necessarily refute the ASP hypothesis of fat storage. As a counter to statement #1, it’s important to remember that chylomicrons themselves don’t promote fattening, ASP does. So does it really matter how long chylomicrons are in contact with fat tissue? Think of it this way: a few months ago I did something that many people can unfortunately relate to – I burned my hand while attempting to take something out of the oven. My hand was in contact with the hot surface for a fraction of a second, but for the next 24 hours, the injured area continued to get worse. It went from a barely visually discernible area to a mottled, ugly mess. In other words, destructive processes, mediated by various biochemicals, continued to damage the skin long after the initiating event. If somehow I had been able to halt the action of those biochemicals, much of the damage to my skin would not have taken place. Chylomicrons and ASP relate in much the same way. Although chylomicrons are exposed to fat cells for a relatively short time, it’s possible that the ASP produced from this exposure can remain for a much longer time prompting storage of fat. There is not a lot of research in this area, so until there are definitive answers, it’s premature to state that "this little pathway is very, very short-term".

As for statement #2, it’s important to keep in mind that when a molecule of ASP is synthesized, it acts upon the fat cell that produced it as well as neighboring cells. It does not need to leave the tissue space and enter the bloodstream to do this, unlike insulin which is produced by the pancreas and is then released into the general circulation to be transported to its target tissues all over the body. So is it really that big of a surprise that ASP levels do not rise in the peripheral blood after fat consumption? That’s not to say that ASP never enters the general circulation; if you were to have a blood sample taken from a vein in your arm, the sample would contain some amount of ASP. However, how and when ASP enters the bloodstream is controlled at the level of the microcirculation and the intricacies of this compartment are not completely understood. When looked at in action under magnification, one may see empty capillaries next to full ones, abrupt changes in blood flow direction, and other “strange” things not seen in the larger vessels of the macrocirculation. This is because the microcirculation (aka the nutritive circulation) is mainly concerned with allowing or not allowing molecule and fluid exchange between blood and cells, not with blood transportation per se. It seems that the actions of the microcirculation depend on the needs and functions of the cells close by as it has been shown that the microcirculation behaves differently in different tissues at different times. In my opinion, it is probable that ASP can be retained in the adipose tissue until it is no longer needed before being permitted to makes its way into the general circulation.  How long ASP "hangs out" in adipose tissue most likely varies according to an individual's unique metabolic state.  This could very well explain why ASP levels don’t rise in peripheral blood in a predictable manner after fat ingestion.  Of course, more research is needed to figure this all out.

In vitro experiments have shown that ASP levels rise to up to 150 times basal levels when fat cells are exposed to chylomicrons.  In contrast, insulin causes a 2 - 3 fold increase in ASP synthesis from fat cells.  These same experiments have demonstrated that ASP is the most potent in vitro stimulant of triglyceride synthesis in intact cells yet described, even more so than insulin.  Obviously more work needs to be done, but ASP may very well turn out to be a major player in fat storage and maintenance, at least for some people.  Let's not be so willing to dismiss it because it complicates a cherished dogma.  Rarely does anything good come out of that.

Glycero and Gluco Neogenesis: Related but Not Twins

I recently became aware of a blog posting by Dr. James Carlson that was inspired by my article Is the Fable of Unfettered Fat Burning Derailing Your Low Carb Diet?.  Dr. Carlson was asked by a Facebook follower to read the article and to elaborate on the "mechanism where your body can accumulate or at least not lose fat because of dietary protein intake".  I'm assuming the mechanism she is referring to is the biochemical pathway glyceroneogenesis which can use amino acids from dietary protein to synthesize the glycerol backbone necessary for triglyceride formation.  You can read Dr. Carlson's response here.  Although I may be mistaken, it seems Dr. Carlson is stating that glyceroneogenesis is simply gluconeogenesis with an additional step at the end.  Because that is not what glyceroneogenesis is and because my article was the impetus for the discussion, I feel the need to clarify.

Most people who follow low carb diets know what gluconeogenesis is: the creation of glucose from non-carbohydrate sources like lactate, glycerol, and glucogenic amino acids. Certain cells in the human body can only utilize glucose for fuel and gluconeogenesis is the process the body uses to make glucose when very little carbohydrate is coming in via one's diet. Gluconeogenesis takes place primarily in the liver and the resulting glucose is released into the bloodstream where it travels to the cells that need it. Again, I could be wrong, but it appears Dr. Carlson is stating that glyceroneogenesis  =  gluconeogenesis in the liver  +  glycerol 3-phosphate formation via glycolysis in fat cells. In other words, he believes glyceroneogenesis occurs when glucose formed in the liver from lactate, glycerol, or amino acids is taken up by fat cells and transformed into glycerol 3-phosphate, the glycerol backbone of a triglyceride molecule. Theoretically, this could happen but this process is not glyceroneogenesis. Glyceroneogenesis occurs in the fat cells themselves - no liver required. Glucogenic amino acids (or lactate) are taken up directly by fat cells and transformed into glycerol 3-phosphate by what would best be described as a truncated version of gluconeogenesis:

Although both (gluconeogenesis + glycolysis) and glyceroneogenesis can potentially provide the glycerol 3-phosphate necessary for triglyceride synthesis (aka body fat accumulation) on a low carb diet, I find glyceroneogenesis the more compelling candidate.  In general, only the amount of glucose needed for those cells that require it will be produced by gluconeogenesis.  And that requirement is not very much - I've seen references for as little as 40 grams of glucose per day during prolonged fasting or very low carb intake.  This glucose is consumed only by those cells that need it so that there is no "extra" for fat cells to use to make glycerol 3-phosphate.  Also, glycerol 3-phosphate synthesis from glucose occurs via glycolysis, and glycolysis is greatly reduced in fat cells during low carb intake.  Unlike glycolysis, glyceroneogenesis is up-regulated in fat cells during low carb intake.  The only major barrier to glyceroneogenesis when insulin is low is lack of substrate, but since many low carb dieters eat a good amount of protein, this scenario won't necessarily happen without conscious intervention.

Does this mean that reducing dietary protein is a good strategy for encouraging fat loss on a reduced carbohydrate diet?  In my opinion, it could work, but should only be attempted if fat loss has stalled for an appreciable amount of time or if one is gaining body fat.  Reducing protein intake is tricky - it has the potential to cause a loss of muscle mass which is something most of us don't want.  A good idea would be to calculate your individual protein need to see where you stand.  If you find that you are eating more protein than you need and you are not experiencing much in the way of fat loss success on a low carb diet, try reducing your protein intake a bit (or maybe more than a bit depending on how much you're eating).  Your body may be a pro-glyceroneogenesis machine and delivering less amino acid substrate to your fat cells may just do the trick.

Note:  the biochemical pathway diagrams in this article are technically correct but not complete.  In other words, I hope they help you understand the article but if you want to pass a biochemistry exam, don't study these diagrams or you will surely fail!  ;)

Is the Fable of Unfettered Fat Burning Derailing Your Low Carb Diet?

According to many low carb diet advocates, “carbohydrate drives insulin drives fat storage” is an elegantly uncomplicated yet scientifically unassailable summation of the diet’s weight loss rationale. To become lean, they assert, simply stop eating carbs in any appreciable amount; consuming carbohydrate prompts the pancreas to release the hormone insulin, and insulin is the primary promoter of body fat storage. No carbohydrate ingestion, no insulin response, no fat storage, end of story. There is no need to limit the amount of protein and fat you eat because they do not stimulate much of an insulin response (this is especially true of fat). So, as long as you forfeit sugary and starchy food, you will lose body fat and be immune to body fat gain regardless how much protein and fat you consume. To strengthen their assertion, low carb diet proponents often offer the following four points as proof that insulin, via carbohydrate ingestion, is the key physiological factor promoting body fat storage:


1) Insulin traps fat inside fat cells by down-regulating the action of Hormone-Sensitive Lipase (HSL), an enzyme that catalyzes the breakdown of triglycerides (the storage form of fat) into fatty acids. Whereas triglycerides cannot leave fat cells because they are too large, the smaller fatty acids can. They escape into the circulation and are now available to be “burned” to supply energy to other cells in the body. Because high blood sugar caused by carbohydrate intake elevates insulin, HSL will be switched off after a carb-rich meal, triglycerides will not be broken down into fatty acids, and fat will remain trapped in the fat cells. The opposite occurs during low insulin states such as fasting and low carb dieting: HSL action will not be inhibited, triglycerides will be broken down, and the resulting fatty acids will be free to leave the fat cells to be burned for energy.

2) Elevated insulin and blood sugar from carbohydrate ingestion are necessary for fat cells to make the molecule glycerol 3-phosphate. Glycerol 3-phosphate is an essential component of triglyceride synthesis. If fat cells cannot synthesize triglycerides, they cannot store fat. A more detailed explanation of this argument can be found here.

3) Carbohydrate intake causes a considerable increase in insulin that is not counteracted by a concurrent increase in glucagon, a pancreatic hormone that stimulates fat cells to release fat. Compared to carb intake, protein intake causes a much smaller increase in insulin as well as an increase in glucagon; this means that eating protein assists in burning body fat.

4) Untreated Type 1 diabetics, who produce essentially no insulin, cannot keep fat in their fat cells and consequently become emaciated. This phenomenon proves that insulin is the primary promoter of body fat storage and cannot be supplanted by any other physiological factor.

No doubt, the scientific arguments are very compelling, but are they accurate? Personal accounts abound on the internet of people stating that their low carb diets are yielding less than stellar results. Stalling after an initial loss of body fat, failing to lose much fat at all, or even gaining fat from the start have all been reported. If the low carb science is absolutely correct and if the diet is being followed properly, these experiences should be virtually impossible. So, that raises the question: are the low carb failures lying or are the low carb proponents wrong? Let’s take a more in-depth look at body fat metabolism and in particular the four points mentioned above, and then you can decide for yourself.


Point #1: Carbohydrate Consumption leads to Elevated Insulin leads to HSL Suppression leads to Trapped Fat.
Very true – elevated insulin, via carbohydrate intake, does indeed trap fat inside fat cells by suppressing the action of HSL. But that’s not the only mechanism the body has for entrapping fat. Take, for example, two studies done in the late 1990’s that showed that ingestion of a low carb/high fat meal or infusion of a pure fat load directly into the bloodstream resulted in almost no fat being released from fat cells (1, 2). The researchers, surprised by their results, stated “Intracellular lipolysis (the breakdown of triglycerides into fatty acids within fat cells) …was suppressed almost completely with both oral and intravenous fat load. Insulin is a major regulator of HSL activity, yet this showed only a slight increase after the oral lipid load and a gradual decrease during and after the intravenous load. It seems that suppression of HSL activity can occur without insulin.” The researchers also stated that their results “may reflect a novel mechanism for the regulation of fat storage.” A major contributor to this mechanism is certainly Acylation Stimulating Protein (ASP). ASP is a hormone made by fat cells primarily in response to consuming fat, and it does quite a nice job of trapping fat in fat cells without the aid of insulin (3).

Point #2: Glycerol 3-phosphate (G3P) synthesis is dependent upon carbohydrate intake, high insulin, and elevated blood sugar (glucose).
No, it isn’t. During prolonged fasting in humans, up to 40% of the fatty acids released from fat cells are taken up again and converted back into triglycerides in fat tissue (4). Triglyceride synthesis requires G3P. During fasting, fat cells cannot use glucose to produce G3P since glycolysis (the breaking down of glucose) is minimal in this state. Another source of G3P must be available. This is where a biological pathway called glyceroneogenesis comes into play. Glyceroneogenesis utilizes non-glucose substrates such as amino acids and lactate to synthesize G3P. The key glyceroneogenic enzyme, PEPCK-C, is up-regulated during fasting when both insulin and glucose are low (5). Because low insulin and low glucose are also consequences of low carb dieting, it’s not much of a jump to suggest that PEPCK-C will be up-regulated then as well. This can drive the production of G3P from amino acids supplied by dietary protein which in turn can allow the production of triglycerides from fatty acids supplied by dietary fat.

A few low carb proponents have acknowledged the existence of glyceroneogenesis, but state that it occurs at a rate not even worth mentioning. Apparently, they took what is known regarding the rate of glyceroneogenesis during the “normal” condition of mixed dietary intake and assumed that glyceroneogenesis is merely a minor metabolic pathway that doesn’t do much of anything under any condition, never considering that low carb dieting can (and does) change the equation.

#3: Protein Consumption leads to Elevated Glucagon leads to Fat Burning.
When I was in college some 20 years ago, my biochemistry text listed the hormone glucagon as one of a number of hormones having a major stimulatory effect on lipolysis. Perusing a more recent textbook however will reveal that glucagon has been dethroned. Glucagon’s association with lipolysis was just that – an association. Think about what occurs during fasting: insulin is low, glucagon is high, and a lot of fat is being liberated from fat cells and burned for energy. But that doesn’t necessarily mean that glucagon is causing the lipolysis; it may just be going along for the ride. In other words, correlation does not equal causation. When tested directly, it was found that glucagon in fact does not stimulate lipolysis in fat tissue (6, 7). Glucagon’s primary function is to maintain blood sugar levels by stimulating the liver to either release its stored glucose or to make glucose from substrates such as amino acids or glycerol. Why would protein consumption cause a rise in glucagon when carbohydrate and fat consumption do not? Dietary protein stimulates the pancreas to release insulin, sometimes to an even greater extent than carbohydrate (8). Because insulin decreases blood sugar, glucagon must be released at the same time to prevent blood sugar from getting too low.

All this being said, it's important to point out that eating protein can aid in fat loss and beneficial body composition changes in several ways unrelated to glucagon.  Of the three macronutrients, protein has the highest thermogenic (calorie-expending) effect.  And as I'm sure you know, not eating enough protein can have deleterious effects on muscle mass.


Point #4: Insulin is the primary regulator of body fat storage as evidenced by untreated type 1 diabetics.
Individuals who produce no insulin and do not receive it exogenously have an extremely difficult time storing body fat regardless of what or how much they eat. This is an undisputed fact. As mentioned earlier, ASP is a hormone that stimulates triglyceride synthesis and effectively traps fat in fat cells in an insulin-independent manner. If type 1 diabetics produce ASP in response to fat ingestion (and there’s no reason to think that they don’t), why can’t they store dietary fat after a mixed meal in spite of their lack of insulin? The answer can be found by looking at insulin’s effects on carbohydrate metabolism and the liver, not its direct effects on triglyceride synthesis and fat tissue. Insulin prompts the liver to synthesize glycogen from blood glucose and store it. The liver’s ability to store glycogen is critical because the body needs to have a readily available source of glucose to remedy any potential hypoglycemic episode: when blood sugar gets too low, glucagon causes the conversion of liver glycogen to glucose which is then released into the circulation. In the state of total insulin depletion however, the liver cannot store glycogen although it’s physiologically compelled to do so. In a futile attempt to fill the liver’s glycogen stores, muscle and fat tissue are catabolized to provide amino acids (from muscle protein) and glycerol (from fat cell triglyceride stores) as substrates for glycogen synthesis. The body is going to the extreme measure of wasting its muscle and fat tissue because maintaining stable blood glucose is exceedingly important to the brain’s functioning – and a liver with a well-maintained glycogen store is the body’s best defense against a hypoglycemic crisis. This demonstrates that total insulin deficiency causes extreme metabolic derangement. The wasting of muscle tissue and body fat to make glycogen in a desperate attempt to ward off low blood sugar during a time when blood sugar is abundant may not make sense, but the body is doing what it thinks is best – it’s just that the lack of insulin prevents it from having all the information it needs to make an informed decision, so to speak.

Like the liver, skeletal muscle requires the presence of insulin to store glycogen (10). Muscle glycogen is important because it supplies the muscles with the energy they need to perform anaerobically (lifting something heavy, sprinting away from an attacker, etc). If, after glycogen-depleting exercise, an individual fails to eat, his muscles will use amino acids from stored body protein as substrates for glycogen resynthesis (11). In other words, the muscles will consume some part of themselves until they are satisfactorily filled with glycogen. Now let's take this a step farther and consider what would happen to skeletal muscle under the condition of total insulin depletion: the muscles would have a very difficult time storing glycogen because the breaking down of glycogen (glycogenolysis) is essentially unrestrained. Because the glycogen stores are not filling up, muscle protein will continue to be catabolized to provide amino acids. Triglycerides in fat cells will also be catabolized to provide glycerol for glycogen synthesis. So, just as the liver will seek out any and all substrates to fill its glycogen stores when insulin is absent, skeletal muscles will do the same.


So, it appears that for untreated type 1 diabetics, insulin is indeed the primary regulator of body fat storage. ASP can synthesize and store fat as much as it's able; under the condition of complete insulin deficiency, the body will just steal it away from fat cells to get the precious glycerol it contains. But how does all this relate to insulin-producing people? Insulin, even in low amounts, allows the liver and muscles to store glycogen albeit in smaller amounts than when insulin is high. This moderate amount of glycogen is enough to prevent the massive fat (and muscle) tissue catabolism seen in type 1 diabetes. It also explains why ASP, without any insulin present, can cause fat cells in test tubes to make and store triglycerides, but why it can’t do the same in the human body: test tubes do not have livers and skeletal muscles desperately seeking large amounts of glycerol, but a human body lacking insulin does. The ability to produce insulin takes these glycerol-hungry tissues out of the equation, making both insulin and ASP potentially equally powerful promoters of body fat storage.  The extent to which insulin or ASP promotes body fat storage in an individual is largely genetically determined.


There are few things more frustrating than following a diet philosophy to a T yet failing to achieve the body fat reduction promised by the diet's promoters. If you experienced disappointing results while on a low carb diet, it's not because you are a physiological freak, it's because the mantra "carbohydrate drives insulin drives fat storage" is entirely too simplistic. The human body has the means to synthesize and store body fat when insulin is low. And if you follow a low carb diet yet fail to create a calorie deficit (9) that's exactly what it will do. For some individuals, low carb dieting offers an effortless method for achieving a calorie deficit mainly by appetite suppression. Others, however, must consciously restrict the number of calories they consume. The great thing about reduced carbohydrate diets (when compared to high carbohydrate diets) is that even while consciously limiting calories, people rarely get ravenously hungry. Periods of mild hunger are tolerable and in the grand scheme of things can be considered a part of the natural human condition (surely our Paleolithic ancestors experienced a growling stomach periodically). Although the notion of intentional calorie restriction is anathema to some low carb diet proponents because they firmly believe in the unfettered fat burning capability of a low insulin state, the physiology presented above clearly shows why some people have to consciously restrict the amount of food they eat. We are fortunate to live in a society where food is abundant and easy to obtain. Some of us have more of a "drive to eat" than others. Because our modern way of life doesn't force us to limit calories, we sometimes have to do it ourselves.


References
1) - Effects of an oral and intravenous fat load on adipose tissue and forearm lipid metabolism.
Evans K, Clark ML, Frayn KN.
Am J Physiol. 1999 Feb;276(2 Pt 1):E241-8.

2) - Peripheral fat metabolism during infusion of an exogenous triacylglycerol emulsion.
Samra JS, Giles SL, Summers LK, Evans RD, Arner P, Humphreys SM, Clark ML, Frayn KN.
Int J Obes Relat Metab Disord. 1998 Aug;22(8):806-12.

3) - Mechanisms involved in the regulation of free fatty acid release from isolated human fat cells by acylation-stimulating protein and insulin.
Van Harmelen V, Reynisdottir S, Cianflone K, Degerman E, Hoffstedt J, Nilsell K, Sniderman A, Arner P.
J Biol Chem. 1999 Jun 25;274(26):18243-51.

4) - Glyceroneogenesis and the triglyceride/fatty acid cycle.
Reshef L, Olswang Y, Cassuto H, Blum B, Croniger CM, Kalhan SC, Tilghman SM, Hanson RW.
J Biol Chem. 2003 Aug 15;278(33):30413-6.

5) - Fatty acid recycling in adipocytes: a role for glyceroneogenesis and phosphoenolpyruvate carboxykinase.
Forest C, Tordjman J, Glorian M, Duplus E, Chauvet G, Quette J, Beale EG, Antoine B.
Biochem Soc Trans. 2003 Dec;31(Pt 6):1125-9.

6) - Action of glucagon and glucagon-like peptide-1-(7-36) amide on lipolysis in human subcutaneous adipose tissue and skeletal muscle in vivo.
Bertin E, Arner P, Bolinder J, Hagström-Toft E.
J Clin Endocrinol Metab. 2001 Mar;86(3):1229-34.

7) - Physiological levels of glucagon do not influence lipolysis in abdominal adipose tissue as assessed by microdialysis.
Gravholt CH, Møller N, Jensen MD, Christiansen JS, Schmitz O.
J Clin Endocrinol Metab. 2001 May;86(5):2085-9.

8) - An insulin index of foods: the insulin demand generated by 1000-kJ portions of common foods.
Holt SH, Miller JC, Petocz P.
Am J Clin Nutr. 1997 Nov;66(5):1264-76.

9) - The Energy Balance Equation by Lyle McDonald
If you are one of those people who doesn't believe that it's necessary to create a caloric deficit in order to lose weight, this article will set you straight.

10) - Skeletal muscle glycogenolysis is more sensitive to insulin than is glucose transport/phosphorylation. Relation to the insulin-mediated inhibition of hepatic glucose production. Rossetti L, Hu M.
J Clin Invest. 1993 Dec;92(6):2963-74

11) - POST-EXERCISE MUSCLE GLYCOGEN REPLETION IN THE
EXTREME: EFFECT OF FOOD ABSENCE AND ACTIVE
RECOVERY.
Paul A. Fournier, Timothy J. Fairchild, Luis D. Ferreira and Lambert Bräu
Journal of Sports Science and Medicine (2004) 3, 139-146

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