Sedentary Physiology at Obesity Panacea

I want to direct attention to a thought-provoking series of articles at the Obesity Panacea blog.  The major argument being put forth is that participation in formal exercise may not be enough to overcome the negative health consequences of being a "couch potato" or "desk jockey".  Fascinating stuff!  Here is the first installment:  Sedentary Physiology Part I: Not Just the Lack of Physical Activity.

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.

Lifting Weights Makes Your Heart Unhappy Says Trainer-to-the-Stars Tracy Anderson

For those of you who don't know, Tracy Anderson is currently one of Hollywood's most in-demand fitness trainers for women. She promises that strict adherence to her special method of diet and exercise will result in a "teeny-tiny" feminine physique. She is most famous (or infamous) for stating that women should never lift more than 3 pounds because that will create bigger, bulkier arm muscles. Instead she recommends all women work their arms like this: Teeny-Tiny Arms Series. In addition to traditional weight lifting, Tracy has also railed against yoga, running, pilates, and just about any other form of exercise that is not the Tracy Anderson Method because they all can cause unsightly muscle growth. Of course, it can be argued that muscle growth is a perfectly natural adaptation to training, but Tracy could always counter with the argument that callus formation is a perfectly natural adaptation to friction but who wants big old nasty calluses all over their bodies? So there you have it.

If the whole "bulky, manly muscles" thing isn't enough to deter women from ever lifting anything much heavier than a can of soup again, Tracy has now revealed in her newly-released, thoroughly unreferenced book Tracy Anderson's 30-Day Method: The Weight-Loss Kick-Start that Makes Perfection Possible that weight lifting is downright unhealthy for your heart. On page 28 she writes: "...you're building muscles that are more prone to injury. You're tearing down your joints. You're destroying your structure. And your heart probably isn't happy about it." And before you think that yoga is safe, consider this pertinent piece of information again from page 28: "...too much Downward Dog can lead to vascular damage."

And on that note, I'm going to start getting my affairs in order. I've been lifting weights and practicing yoga for close to 20 years; a heart attack is surely around the corner! I just hope they make caskets big enough to accommodate my bulked-up corpse...

;~)

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.

Some Thoughts on VLDL, Carbs, & Insulin

A reader asked me to comment on the article below.  He recognized that the author was wrong when he wrote that LDL breaks down into VLDL and was wondering about the rest of the information in the article.  I decided to make my reply a separate post since there is much to discuss here. 

Question: What is VLDL cholesterol? Can it be harmful?

Answer:
from Thomas Behrenbeck, M.D.

Very-low-density lipoprotein (VLDL) cholesterol is a type of lipoprotein. Although you may hear about VLDL, your VLDL level usually isn't reported to you as a part of a routine cholesterol test.

There are several types of cholesterol, each made up of lipoproteins and fats. Each type of lipoprotein contains a mixture of cholesterol, protein and a type of fat (triglyceride), but in varying amounts.

Of the lipoprotein types, VLDL contains the highest amount of triglyceride. Because it contains a high level of triglyceride, having a high VLDL level means you may have an increased risk of coronary artery disease (CAD), which can lead to a heart attack or stroke.

There's no simple, direct way to measure VLDL cholesterol, which is why it's normally not mentioned during a routine cholesterol screening. VLDL cholesterol is usually estimated as a percentage of your triglyceride value. A normal VLDL cholesterol level is between 5 and 40 milligrams per deciliter.

So you can see from this why eating carbohydrates causes your VLDL to rise. VLDL is made up of mostly triglycerides, which require glycerol in order to be formed. The more glycerol present in your body, the more triglycerides your body will have to create. It's interesting that this particular type of triglyceride that effects the LDL is made in the liver.

As we learned in Taubes, when we eat food, it is broken down and all the various acids go to fat tissue first before being added to the bloodstream. So in terms of glycerol, this is added to the bloodstream and once the stream reaches adipose tissue, the glycerol undergoes the esterification process for passage in and out. Esterification is the formation and breakdown of triglycerides. These triglycerides are offered to every cell, muscle and tissue in the body as they travel through the blood stream. All of us should know that we can only have a small amount of sugar in our bloodstream at any point in time -- so this idea that we use all this sugar for energy is nonsensical to say the least.

Anyway, when it makes its rounds through the bloodstream and there are no takers, it goes to the liver where it is sent out on lipoproteins. This is the beginning of breaking the LDL down into VLDL which is a bad thing. This is why you have seen me write that the body sends sugar to one of 4 places in order to get rid of it, not for some beneficial purpose. It's true that our bodies require a steady amount of blood sugar, but this sugar is not that which is derived from eating carbohydrates, regardless of how similar it is in composition. The sugar you eat goes to fat. The liver produces the small amount that we require and anything beyond that requirement either goes to fat or degrades our cholesterol. Under ZC (zero carbohydrate) circumstances, our bodies are perfectly capable of making whatever sugar we require. We are not required to have any of this from our diet.

First I have to say that it is rather suspicious to me that an M.D. would have his "facts" so messed up.  Graduating from medical school certainly doesn't mean you know everything but this is BAD!  For what it's worth, I don't believe this person is really a physician.  An individual can present themselves any way they want on the Internet, and I believe we have ourselves a poser here.

It's difficult to discuss the article point by point since honestly I can't make heads nor tails of it, so I'm simply going to discuss some thoughts I have on VLDL, diet, and coronary artery disease as a whole.  The best way to begin is to explain briefly how VLDL are formed.  Their synthesis takes place in the liver where a molecule of apolipoprotein B-100 (apo B) forms a complex with phospholipids and cholesterol encasing a core of cholesteryl esters and triglycerides.  VLDL function primarily as carriers for triglycerides and as such contain many more triglycerides than cholesteryl esters.  VLDL enter the bloodstream and travel to various tissues, most notably fat tissue and muscle, where they are acted upon by the enzyme lipoprotein lipase (LPL) which releases some of the triglycerides so that they can be stored (in fat tissue) or used for energy production (in muscle).  As they lose their triglyceride cargo, VLDL become smaller and denser and eventually end up as LDL (low density lipoproteins).  This is a very simplified description; if you would like something much more in-depth, I suggest this article: Plasma Lipoproteins: Composition, Structure, and Biochemistry.

As for carbohydrate intake causing fasting VLDL to rise, it often does but this is not necessarily a harmful occurrence.  The amount of VLDL in the blood is the result of the rate of VLDL production together with the rate of VLDL clearance.  It is generally thought that an elevated VLDL level caused by increased production is harmful (or at least associated with harm) while an elevated VLDL level caused by decreased clearance is not.  It all comes down to insulin resistance.

It's often stated that insulin drives VLDL synthesis by the liver; this is a very misleading statement.  Believe it or not, insulin acutely inhibits liver VLDL production, particularly the large triglyceride-rich "bad" VLDL1.  This makes sense because after eating, triglycerides in chylomicrons would be competing for clearance with triglycerides in VLDL.  By slowing down production of VLDL, chylomicrons can be cleared from the circulation more efficiently.  Insulin slows down VLDL synthesis in several ways, the most obvious being via inhibition of fat cell lipolysis so that less fatty acids are delivered to the liver for triglyceride synthesis.  Insulin also exerts several direct effects on the liver itself such as increasing the degradation of apo B.  If an individual's fat cells (some experts assert that visceral fat cells are more important in this regard) and liver are resistant to the actions of insulin, it's easy to see why they would have an elevated VLDL concentration.  It's also interesting to speculate if elevated VLDL triglycerides may merely be a marker for insulin resistance and not harmful to the coronary arteries in and of themselves.  Consider people with the rare genetic condition called Fredrickson type V hyperlipidemia.  These individuals have extremely high VLDL and triglyceride concentrations due to decreased peripheral clearance caused by a deficiency of lipoprotein lipase.  Yet when their vascular endothelial function (an indication of coronary artery disease risk) was compared to subjects with normal triglyceride levels, no significant difference was found.  If VLDL triglycerides per se cause harm to the vascular endothelium, surely people with an average serum triglyceride concentration of 1914 mg/dl would exhibit some measurable degree of endothelial dysfunction over and above individuals with normal triglyceride levels.  Yet they don't appear to.  It's also important to note that Fredrickson type V hyperlipidemia does not seem to be associated with an increased risk of CAD.

Which brings us to the notion of moderately elevated VLDL being physiologically unremarkable when due to decreased peripheral clearance.  It has been shown that carbohydrate-induced hypertriglyceridemia is caused primarily by decreased clearance not increased production, assuming the person is insulin sensitive and the carbohydrates are mostly starches and not sugars.  It's been theorized that this reduction in VLDL triglyceride clearance "may reflect a homeostatically appropriate down-regulation of the LPL activity of skeletal muscle".  In other words, when one consumes a lot of carbohydrates especially without a lot fat, muscles will preferentially switch to using more glucose for fuel and therefore will not need to take up as much fat from the circulation, hence the reduction in skeletal muscle LPL activity.

How high can triglycerides go on a low sugar, high carbohydrate diet and still be considered "safe"?  In my opinion, a triglyceride concentration up to about 150 mg/dl is acceptable based on the fact that several CAD-free populations consuming their native high carbohydrate/low fat diets have such a level.  It's important to note however that the higher the carbohydrate-to-fat ratio, the higher the triglyceride concentration will generally be.  This means that a moderate amount of carbohydrates shouldn't lead to a 150 mg/dl triglyceride level if everything is working as it should.  That level of triglycerides on a moderate carbohydrate diet could indicate insulin resistance.

What this all means in the real world is this:  if an individual who has a fasting triglyceride concentration of 70 mg/dl on a standard Western diet (indicating that they are probably insulin sensitive) begins a high carb/low sugar/low fat diet (let's say 65% carbohydrate, 20% fat) and their triglyceride level elevates to 130 mg/dl, this is most likely a benign, totally appropriate change.  In this case, an elevation of triglycerides is most likely not a bad thing.

The Latest Low-Carb vs. Low-Fat Diet Study is Available Online for FREE!

The much talked about low-fat/low-carb diet comparison study published this month in the Annals of Internal Medicine can be found online for free.  As far as I know, it's not supposed to be free as several bloggers have stated that they had to purchase the full text version.  I've asked Stargazey at Low-Carb for You to confirm if this version is the same as the one she purchased.  She hasn't gotten back to me yet, but it sure appears to be a valid copy.  Here it is if you want to take a look at it:  Weight and Metabolic Outcomes After 2 Years on a Low-Carbohydrate Versus Low-Fat Diet.  Click on "Original Version (PDF)".  Here's a direct link to the PDF if for some reason the first link doesn't work:  http://www.annals.org/content/suppl/2010/08/03/153.3.147.DC2/0000605-201008030-00005-v1.pdf.

Happy Reading!

Nurse Claims She Was Reprimanded for Not Readily Giving Ice Cream to Diabetic Patient

Wow, I hope this story isn't true.

To give some background: for the last few years, there has been a big push by hospital administrators for staff to think of patients more like customers and to provide customer service along with health care. This goes beyond simply being polite and courteous; it entails ideas borrowed from the hospitality industry such as leaving a fancy note card in a patient's room after performing a service like drawing blood stating "Your phlebotomist today was Susan. I hope I exceeded your expectations and provided you with excellent care. Thank you for choosing City Hospital". The hospital will then give out questionnaires asking patients to rate their customer service experience and the hospital will use the results (if they're good of course) in advertising. I think they may even be required to report the results to some kind of governing body, but I could be wrong on that.

I was surfing the internet yesterday and happened upon a thread at allnurses.com titled Customer Service ... Yay or Nay?  In it, a nurse described a situation in which she was reprimanded by her superior for not providing good customer service because she was trying to discourage a diabetic patient from eating ice cream.  In her own words:

"I agree with everything said. I have worked in many aspects and in many settings of healthcare for 35 years. Most recently I've been an LPN for the last 12 years and I have found that the "customers" have finally completely burned me out. I am supposed to renew my license in the next 5 days and quite frankly I don't want to. If I am going to give people what they want with a smile instead of what they need with understanding and caring, then I'll flip burgers. I have ALWAYS greeted my patients (yes patients) with a smile, a caring hand on the shoulder if they allow and carefully explained what, why, and how. Lately I leave a bedside with confidence that while not pleased with their situation, they are comfortable with it. An hour later I'm being called into the charge nurse's office being chewed out for being mean and/or rude to the patient and/or the family! I did my nursing duty, I brought them that extra helping of ice cream with a teaching that this may not be their best choice for a diabetic and perhaps they would do better with the apple slices or sugar free cake I also brought along. But how rude of me to suggest such things! The "client" knows what is best for them, I'm told. I have seen nurses lose their jobs for consistently doing their job in just this way. I believe in doing everything and anything within the confines of the healthcare process to make a patient happy and comfortable but this customer satisfaction has come to a place where healthcare is no longer part of the process."

OK, maybe I'm just tired and not thinking straight, but isn't a nurse supposed to discourage a diabetic patient from eating a bunch of sugar?  She's not a waitress in a restaurant trying to ensure herself a hefty tip, she's a healthcare professional trying to see to her patient's best interest.  The patient may get annoyed but so what?  "I'm here to save your ass, not kiss it" is an old nursing adage.  Too bad this particular hospital's administrators seemed to have forgotten it.

Fat Fails First?

In my previous blog post, I explained what initially made me skeptical of the idea that insulin resistance develops first in the liver and skeletal muscles and last in fat tissue. Now I'd like to argue the opposite: that insulin resistance develops first in fat tissue and this leads, over time, to less insulin sensitivity in liver and muscle cells eventually resulting in the development of the metabolic syndrome.

Consider the fact that people with congenital generalized lipodystrophy, in whom fat cells are lacking from birth, typically develop components of the metabolic syndrome such as insulin resistance, non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes at a much earlier age and in more severe forms than do obese humans. This is believed to happen because a dearth of fat cells causes the body to have no "safe" place for excess fatty acids to be stored, and people with lipodystrophy tend to generate excess fatty acids because they cannot make much leptin, a major adipose-derived satiety hormone, and hence have a strong drive to eat. Some of the excess fatty acids will end up being stored in the liver and muscles as well as in other non-adipose tissues (aka lipotoxicity) resulting in decreased insulin sensitivity in these organs and the metabolic syndrome.

Obese humans, on the other hand, are not lacking fat cells so they can, and do, store a lot of excess fatty acids in their fat cells. I'm sure we've all known overweight or obese individuals who possess good health with no obvious signs of the metabolic syndrome - normal blood pressure, normal blood sugar, normal lipid profile, etc. These individuals will often bring these things up when a friend or family member urges them to lose weight - "All my blood tests are good and I'm not on any medication; my doctor says I'm healthy so I feel no urgent need to lose weight." And they may be able to go their entire lives without a hint of the metabolic syndrome if their fat cells maintain their insulin sensitivity. If they don't, these corpulent individuals will become, in essence, like a person with congenital generalized lipodystrophy: unable to store excess fatty acids in adipose tissue which will lead to lipotoxicity and metabolic syndrome. Unfortunately, the majority of obese individuals will develop metabolic problems related to their weight at some point in their lives.

It has been shown that many people's free fatty acid blood levels are elevated years before a diagnosis of type 2 diabetes (which is based solely on some measure of high blood sugar). In other words, blood sugar can remain within normal limits while fatty acid levels are soaring. Knowing that the inhibitory effects of insulin are the more physiologically important, this indicates that adipose tissue becomes resistant to insulin (resulting in increased free fatty acids via unrestrained fat cell lipolysis) before the liver does (resulting in increased blood sugar via unrestrained hepatic glucose production). 

It's also important to note that a class of diabetes drugs called thiazolidinediones (TZDs) lowers blood sugar primarily by increasing fatty acid uptake and storage in fat cells. By taking excess fatty acids out of the circulation, the liver becomes less affected by lipotoxicity and regains its sensitivity to insulin. Hepatic glucose production is restrained by insulin in a more normal fashion and blood glucose concentrations fall. 

Further, it has been demonstrated that serum free fatty acids are the main source of liver triglycerides in people with NAFLD; therefore, fat cell insulin resistance to lipolysis is likely a major contributor to fat accumulation in the liver.

Using the above information, the following scenario makes sense to me:

Chronic caloric surplus (possibly caused by a diet high in sugar and fat along with a sedentary lifestyle) causes fat tissue to expand to sequester toxic fatty acids that would otherwise damage organs. When fat tissue can no longer expand, it becomes resistant to insulin. This leads to increased fat cell lipolysis and elevated free fatty acids which leads to "ectopic" fat deposits in the liver and muscles. The liver and muscles then become resistant to insulin. This leads to increased hepatic glucose production with substrate partially supplied by amino acids coming from skeletal muscle because of increased proteolysis. The increase in blood sugar results in stimulation of insulin secretion from the pancreas. We now have chronic hyperinsulinemia and hyperglycemia - these conditions are associated with and possibly cause many of the problems linked with the metabolic syndrome like hypertension, coronary artery disease, kidney disease etc.

To be continued...

References

• From the metabolic syndrome to NAFLD or vice versa?
• Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity.

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...

This Just In: Carrying Matches in Your Breast Pocket Causes Lung Cancer!

Well, not really.  But I'd bet that if a study along these lines were conducted, a link would be found between carrying matches close to the chest and developing lung cancer.  Of course, the cause would not be the matches themselves, but what the matches are a marker for, namely cigarette smoking.  Although my example is pretty absurd and transparent, headlines similar to this sometimes appear in newspapers and on TV news programs.  If it's because the news writers truly don't understand the difference between correlation and causation or because they are more concerned with sensationalizing the news than with reporting the facts, I don't know.  But it's important to realize that popular media stories concerning new scientific research are not always accurate.  The illustration below sums it up nicely:

http://www.phdcomics.com/comics/archive.php?comicid=1174

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.

High Carb Intake After Intense Resistance Training Increases Inflammation

A study in this month's European Journal of Applied Physiology has shown that consuming a high carbohydrate diet soon after an intense weight training session results in more of an elevation of various inflammatory markers than does consuming a low carbohydrate diet.  I only have access to the abstract, so I do not know how the researchers defined the high carb and low carb diets, but I think it's safe to say that people may want to think twice about downing a high sugar "recovery" drink after a strength training session. 

Regardless of diet, moderate to intense exercise causes some degree of inflammation and oxidative stress.  It's been shown that the body produces endogenous anti-inflammatory and anti-oxidant factors to deal with these events.  And it's obvious that these factors do their jobs well since physical activity is almost always associated with beneficial effects on health and not with inflammatory diseases like atherosclerosis and type 2 diabetes.  But could a high-carbohydrate intake interfere with the body's natural defenses against exercise-induced physiological stress?  This study suggests that it very well could but more research needs to be done before we can say for sure.

Weight Gain: Protection Against Hyperthyroidism?

It’s been said that if an elephant’s metabolic rate were the same as that of a mouse, the elephant would spontaneously combust. This would happen because, although an elephant burns many more calories in total than does a mouse, a mouse burns many more calories per unit mass than does an elephant.  Burning calories leads to heat production. But because an elephant cannot dissipate heat nearly as easily as a mouse can, an elephant with a mouse’s metabolism would become so hot internally that, theoretically anyway, the animal would burst into flames.

Now, keep our unfortunate elephant in mind when reading the following statement: “If you eat 5,000 calories of only fat and protein, some protein will be converted by gluconeogenesis, some will go to building muscle, the fat will go to building hormones and cellular repair and the rest will be converted to heat by various metabolic processes and wasted.”

Like me, I’m sure you’ve read some version of the above belief a few times before – that is, the idea that all excess calories from fat and protein are dispelled from the body as heat when one is on a low carbohydrate diet. But as you can see from the theoretical elephant, creating heat is not always a good thing. Heat generated internally will raise core body temperature unless it is dissipated via the body’s surface area into the external surroundings. Maintenance of core temperature is something the body must regulate within a very narrow range by some combination of thermogenesis (heat creation) and heat dissipation/conservation. Too little heat generated and/or conserved will cause hypothermia and too much heat generated and/or conserved will cause hyperthermia. Both conditions can be fatal. Because animals have a limited body surface area from which to release heat, they cannot produce heat in an unrestrained manner without risking hyperthermia. These facts should call into question the assertion that all excess calories consumed on a low carb diet will be converted to heat and wasted. Note that I said all excess calories; it has been shown experimentally that humans can increase their energy expenditure (which creates heat) when overfed 1,000 calories a day so that many individuals will not gain as much weight as expected. The most “genetically lucky” individuals were able to increase their metabolisms to such an extent as to dissipate 600 of the extra 1,000 calories. So yes, some calories can be wasted as heat, but we must remember that thermogenesis does not occur in a haphazard manner and so we cannot assume that an unlimited amount of calories can be spent in heat production without some negative consequence arising.

Jules Hirsch and Theodore Van Itallie were thinking along these lines in 1973 when they penned a letter to the editor in The American Journal of Clinical Nutrition. They were critiquing a study done by Heinrich Kasper that purported to show that a normal weight adult individual (it’s not clear if the subject was male or female) gained no weight over a 10 day period of consuming 5,950 calories per day with most of the calories (4,988) coming from fat (corn oil). Kasper and colleagues conjectured that the lack of weight gain could be evidence of “luxus consumption” (heat creation as a means of wasting energy so that it will not be stored as fat) but when Hirsch and Van Itallie crunched the numbers, they showed just how potentially metabolically damaging disposing of 2,900 calories a day could be:

“If one were to accept the authors’ contention that “ . . .under a relatively low carbohydrate and protein intake, increasing amounts of fat produce an increase in the metabolic rate that becomes particularly marked if fats high in linoleic acid are given,” then the reader appears to be drawn into the following chain of calculations. A young man requires approximately 3,000 kcal/day, assuming a modest activity level. Approximately one-half of this amount is needed to support his basal metabolism (BMR). If, by consuming large quantities of corn oil, he then increases heat production sufficient to dispose of 2,900 (5,900 minus 3,000) additional calories, this “luxus consumption” would seem to require an elevation of the subject’s BMR by nearly 200% (on the average). Because patients with severe hyperthyroidism exhibit a BMR somewhat in excess of +50%, the data of Kasper et al. would call for this normal young subject to manifest a degree of hypermetabolism (24 hr/day) three- to fourfold greater than that associated with the most toxic form of Graves’ disease. It is perhaps not out of place to mention also that, for every degree (Fahrenheit) of temperature rise above normal, there is supposed to be an associated 8% increase in metabolic rate. In view of this fact, it seems inconceivable that the sensation of “heat over the entire body” reported by the subjects on a high corn oil intake could account for the almost 200% increase in BMR implied by the observations of Kasper et al.”

Using Hirsch’s and Van Itallie’s reasoning, let’s crunch the numbers on the subjects in the overfeeding study who were able to dispose of 600 extra calories per day. Since the subjects in this study were said to be sedentary (as opposed to modestly active), let’s bump their caloric requirement down to 2,500 calories/day. Assuming that about one-half of the total caloric requirement is needed to support basal metabolism, the subjects’ BMR would be approximately 1,250 calories/day. Wasting 600 calories per day would require an increase in BMR of a little less than 50%. Confounding the calculations is the fact that the subjects in the overfeeding experiment were gaining weight where as the subject in the Kasper study was not, but it’s interesting to speculate if a 50% elevation in BMR is the maximum increase the body will allow when trying to dispose of excess calories. Thyroid hormone is the primary regulator of thermogenesis; if the body wants to burn off excess calories, it must produce and release more thyroid hormone.  Too much thyroid hormone can have deleterious effects on health including coma and death.  According to Hirsch and Van Itallie, problems with severe hyperthyroidism begin when one's BMR increases above 50% of normal.  It appears some (lucky?) individuals can rev up their metabolisms to that point before they start storing fat.  Most of us however cannot and maybe that's not such a bad thing after all.

For a Better Understanding of the Thermodynamics of Living Organisms...

...check out this book:  Biological Thermodynamics by Donald T. Haynie.  All 440 pages are available free online.  For complete understanding of the topics discussed, the reader will need a certain knowledge base akin to an introductory undergraduate course in Biology/Biochemistry, so a well-read "lay" person should have little problem.  Happy Reading!

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!  ;)