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...