Small LDL particles and increased HbA1c--An evil duo

Small LDL particles are triggered by consumption of carbohydrates. Eat more "healthy whole grains," for instance, and small LDL particles skyrocket.

Increased hemoglobin A1c, HbA1c, a reflection of the last 60-90 days' blood sugars, is likewise a reflection of carbohydrate consumption. The greater the carbohydrate consumption and/or carbohydrate intolerance, the greater the HbA1c. Most regard a HbA1c of 6.5% or greater diabetes; values of 5.7-6.4% pre-diabetes. However, note that any value of 5.0% or more signifies that the process of glycation is occurring at a faster than normal rate. Recall that endogenous glycation, i.e., glucose modification of proteins, ensues whenever blood sugars increase over the normal range of 90 mg/dl (equivalent to HbA1c of 4.7-5.0%). Glycation is the fundamental process that leads to cataracts, arthritis, and atherosclerosis.

Put the two together--increased quantity of small LDL particles along with HbA1c of 5.0% or higher--and you have a powerful formula for heart disease and coronary plaque growth. This is because small LDL particles are not just smaller; they also have a unique conformation that exposes a (lysine residue-bearing) portion of the apoprotein B molecule contained within that makes small LDL particles uniquely glycation-prone. Compared to large LDL particles, small LDL particles are 8-fold more prone to glycation.

So glycated small LDL particles are present when HbA1c is increased above 5.0%. Small, glycated LDL particles are poorly recognized by the liver receptor that ordinarily picks up and disposes LDL particles, unlike large LDL particles, meaning small LDL particles "live" much longer in the bloodstream, providing more opportunityt to do its evil handiwork. Curiously, small LDL particles are avidly taken up by inflammatory white blood cells that can live in the walls of arteries, where they are oxidized--"glycoxidized"--and add to coronary atherosclerotic plaque.

The key is therefore to tackle both small LDL particles and HbA1c.

In his most recent Vitamin D Council Newsletter (reprinted in its entirety below, minus clickable links, as Dr. Cannell apparently lost his webmaster and this issue of the newsletter is therefore not posted on the Vitamin D Council website; if you would like to either donate money to the Vitamin D Council or pitch in with help with his website, go to www.vitamindcouncil.com), Dr. John Cannell once again enlightens us with some new insights into vitamin D and its enormous role in health. In this issue, he discusses the role of vitamin D in people diagnosed with cancer (treatment, not prevention).

While cancer is not our focus on the Heart Scan Blog, Dr. Cannell's always insightful comments provide some helpful thoughts for our management of vitamin D doses and blood levels.

Dr. Cannell cites a recent study from vitamin D research expert, Dr. Bruce Hollis:

In the first study of its kind, Professor Bruce Hollis of the Medical University of South Carolina gave all of us something to think about. He asked and answered a simple question: How much vitamin D do you have to take to normalize the metabolism of vitamin D?

Remember, unlike other steroid hormones, vitamin D has very unusual metabolism in most modern humans, called first-order, mass action, kinetics. All this means is that the more vitamin D you take, the higher the 25(OH)D level in your blood, and the higher the 25(OH)D level in your blood, the higher the levels of activated vitamin D in your tissues. No other steroid hormone in the body behaves like this. Think about it: would you like your estrogen level to be dependent on how much cholesterol you ate? Or your cortisol level? (I'd ask the same about testosterone levels but I know men well enough not to ask.) No, the body must tightly regulate powerful steroid hormones through substrate inhibition, that is, if an enzyme turns A into B, when the body has enough B, B inhibits the enzyme and so limits its own production.

Not so with vitamin D, at least at modern human vitamin D levels. Professor Reinhold Vieth was the first to write about this and Vieth's Chapter 61 in Feldman, Pike, and Glorieux's wonderful textbook, Vitamin D (Elsevier, 2005, second edition), is a great reason to buy the textbook or have your library do so. (I'm glad to see Amazon is out of stock of the new ones (someone must be reading about vitamin D) but you can still buy used editions.)

Why would the kinetics of vitamin D be different from all other steroids? Maybe they are not, Hollis reasoned, like Vieth before him. Maybe vitamin D levels are so low in modern humans that its metabolic system is on full blast all the time in an attempt to give the body all the vitamin D metabolites it craves. So Hollis asked, Is vitamin D's metabolism different in populations in the upper end of 25(OH)D levels (a population of sun-exposed people and a group of women prescribed 7,000 IU per day)? Note, the Hollis study is free on Medline, you can download the entire paper on the right hand of the PubMed page below.

Hollis BW, et al. Circulating vitamin D3 and 25-hydroxyvitamin D in humans: An important tool to define adequate nutritional vitamin D status. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):631-634.

If you look at the two graphs, Figures 1 and 2 of Hollis' paper, you find vitamin D's kinetics can be normalized, made just like all other steroid hormones in the body, but you have to get enough sunshine or take enough vitamin D to get your 25(OH)D level above 50 ng/ml, and 60 ng/ml would be better. Then your body starts to store cholecalciferol in the body without much further increase in 25(OH)D levels. The reaction becomes saturable. This is a remarkable discovery and it implies levels of 30 and 40 ng/ml are usually not sufficient. It also implies actual vitamin D levels (cholecalciferol levels), not just 25(OH)D levels, may be useful in diagnosing and treating deficiency. Note, that not all of the sun-exposed individuals or women prescribed 7,000 IU/day achieved such levels. That's because the sun-exposed individuals were tested after an Hawaiian winter and because prescribing and taking are two different things.

In answer to the question, "How much vitamin D should someone with cancer take?," Dr. Cannell advises:
"Take enough to get your 25(OH)D level above 60 ng/ml, summer and winter." In doing so, you will have normalized the kinetics of vitamin D and stored the parent compound, cholecalciferol, in your tissues. In the absence of sunshine, you need to take about 1,000 IU/day per 30 pounds of body weight to do this. A 150 pound cancer patient may need to take 5,000 IU per day, a 210 pound cancer patient about 7,000 IU per day, all this in the absence of sunlight.

Dr. Cannell, no stranger to the resisitance among many practicing physicians unaware of the expanding and robust literature on vitamin D, advises people with cancer that:
In the end, if you have cancer and your physician won't do a risk/benefit analysis, do it yourself. The risk side of that equation is easy. Both Quest Diagnostics and Lab-Corp, the two largest reference labs in the USA, report the upper limit of 25(OH)D normal is 100 ng/ml and toxic is above 150 ng/ml, so 60 ng/ml is well below both. The reason levels up to 100 ng/ml are published normals is because there is no credible evidence in the literature that levels of 100 ng/ml do any harm and because sun worshipers often have such levels. (If you don't believe me, go to the beach in the summer for one month, sunbath every day for 30 minutes on each side in your bathing suit, and go home and have a 25(OH)D level.) By getting your level above 60 ng/ml, all you are doing is getting your levels into the mid to upper range of laboratory reference normals. Little or no risk.

For readers wishing to read the entire text of Dr. Cannell's newsletter, it is reprinted below:

The Vitamin D Newsletter
January, 2008

The January newsletter is coming early as I will be out of touch for awhile. If you remember, the last newsletter was on preventing cancer, not treating it. Below is a sampling of the tragic emails the last newsletter generated:

"Dr. Cannell, I was just diagnosed with breast cancer, how much vitamin D should I take?"

"My mother has colon cancer, how much vitamin D should she take?"

"I've had prostate cancer for four years, is there any reason to think vitamin D would help?"

"Dr. Cannell, my son has leukemia, should I give him vitamin D?"

It's one thing to talk about evidence vitamin D may prevent cancer but something quite different to discuss evidence vitamin D might help treat cancer. I used to think the answers to all the above questions were the same. Like anyone else, people with cancer should be screened for vitamin D deficiency and be treated if deficiency is present. Simple. However, it's not that simple. The real questions are, What are reasonable 25-hydroxy-vitamin D [25(OH)D] levels for someone with a life-threatening cancer? How much vitamin D do they need to take to obtain such levels? Is there any evidence, of any kind, that vitamin D will help treat cancer? The risk/benefit analysis of taking vitamin D is quite different if you are in perfect health than if your life, or your child's life, is on the line.

Remember, unlike cancer prevention, not one human randomized controlled trial exists showing vitamin D has a treatment effect on cancer. By treatment effect, I mean prolongs the lives of cancer patients. However, as I cited in my last newsletter, Dr. Philippe Autier of the International Agency for Research on Cancer, and Dr. Sara Gandini of the European Institute of Oncology, performed a meta-analysis of 14 randomized controlled trials showing even low doses of vitamin D extend life but they looked at all-cause mortality, not just cancer (Arch Intern Med. 2007;167(16):1730-1737). However, some epidemiological studies indirectly address the treatment issue and are quite remarkable. The first are a series of discoveries by Professor Johan Moan, Department of Physics at the University of Oslo, with Dr. Alina Porojnicu as the lead author on most of the papers.

Moan J, et al. Colon cancer: Prognosis for different latitudes, age groups and seasons in Norway. J Photochem Photobiol B. 2007 Sep 19

Lagunova Z, et al. Prostate cancer survival is dependent on season of diagnosis. Prostate. 2007 Sep 1;67(12):1362-70.

Porojnicu AC, et al. Changes in risk of death from breast cancer with season and latitude: sun exposure and breast cancer survival in Norway. Breast Cancer Res Treat. 2007 May;102(3):323-8.

Porojnicu A, et al. Season of diagnosis is a predictor of cancer survival. Sun-induced vitamin D may be involved: a possible role of sun-induced Vitamin D. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):675-8.

Porojnicu AC, et al. Season of diagnosis is a prognostic factor in Hodgkin's lymphoma: a possible role of sun-induced vitamin D. Br J Cancer. 2005 Sep 5;93(5):571-4.

Porojnicu AC, et al. Seasonal and geographical variations in lung cancer prognosis in Norway. Does Vitamin D from the sun play a role? Lung Cancer. 2007 Mar;55(3):263-70.

What Professor Moan's group discovered, repeatedly, is quite simple, whether it be cancer of the breast, colon, prostate, lung, or a lymphoma. You live longer if your cancer is diagnosed in the summer. And it is not just Moan's group who has found this. A huge English study recently confirmed Moan's discovery.

Lim HS, et al. Cancer survival is dependent on season of diagnosis and sunlight exposure. Int J Cancer. 2006 Oct 1;119(7):1530-6.

What do these studies mean? Something about summer has a treatment effect on cancer. Whatever it is, you live longer if you are diagnosed in the summer but die sooner if you are diagnosed in the winter. What could it be about summer? Exercise? Fresh air? Melatonin? Sunlight? Pretty girls? Remember, these patients already had cancer. Whatever it is about summer, it is not a preventative effect that Professor Moan discovered, it is a treatment effect. Something about summer prolongs the life of cancer patients.

Dr. Ying Zhou, a research fellow, working with Professor David Christiani at the Harvard School of Public Health, went one step further. The stuffy Harvard researchers assumed summer worked its magic, not by pretty girls, but by summer sunlight making vitamin D. So they looked at total vitamin D input, from both sun and diet, to see if high vitamin D input improved the survival of cancer patients. Yes, indeed, remarkably. They found that early stage lung cancer patients with the highest vitamin D input (from summer season and high intake from diet) lived almost three times longer than patients with the lowest input (winter season and low intake from diet). Three times longer is a huge treatment effect, a treatment effect that most conventional cancer treatment methods would die for.

Zhou W, Vitamin D is associated with improved survival in early-stage non-small cell lung cancer patients. Cancer Epidemiol Biomarkers Prev. 2005 Oct;14(10):2303-9.

And that's not all, Marianne Berwick and her colleagues, at the New Mexico Cancer Institute, found malignant melanoma patients with evidence of continued sun exposure had a 60% mortality reduction compared to patients who did not. That implies a robust treatment effect from sunlight.

Berwick M, et al. Sun exposure and mortality from melanoma. J Natl Cancer Inst. 2005 Feb 2;97(3):195-9.

I will not list the thousands of animal studies that indicate vitamin D has a treatment effect on cancer as almost all of them studied activated vitamin D or its analogs, drugs that bypass normal regulatory mechanisms, cannot get autocrine quantities of the hormone into the cell, and that often cause hypercalcemia. However, Michael Holick's group found that simple vitamin D deficiency made cancers grow faster in mice. That is, vitamin D has a cancer treatment effect in vitamin D deficient mice. Professor Gary Schwartz, at Wake Forest, recently reviewed the reasons to think that vitamin D may have a treatment effect in cancer.

Tangpricha V, et al. Vitamin D deficiency enhances the growth of MC-26 colon cancer xenografts in Balb/c mice. J Nutr. 2005 Oct;135(10):2350-4.

Schwartz GG, Skinner HG. Vitamin D status and cancer: new insights. Curr Opin Clin Nutr Metab Care. 2007 Jan;10(1):6-11.

Finally, one human interventional study exists. In 2005, in an open trial, Professor Reinhold Vieth and his colleagues found just 2,000 IU of vitamin D per day had a positive effect on PSA levels in men with prostate cancer.

Woo TC, et al. Pilot study: potential role of vitamin D (Cholecalciferol) in patients with PSA relapse after definitive therapy. Nutr Cancer. 2005;51(1):32-6.

So we come back to the crucial question. If you have cancer, how much vitamin D should you take, or, more precisely, what 25(OH)D level should you maintain? We don't know. You can correctly say that definitive studies have not been done and, incorrectly, conclude physicians treating cancer patients should do nothing. I say incorrectly because standards of medical practice have always demanded that doctors make reasonable decisions based on what is currently known, doing a risk/benefit analysis along the way to decide what is best for their patients based on what is known today. If a patient has a potentially fatal cancer, the doctor cannot dismiss a relatively benign potential treatment modality just because definitive studies have not been done, and passively watch his patient die. Standards of care require doctors consider what is known now, using information currently available, perform a risk/benefit analysis, and then act in the best interest of their patient.

Luckily, such doctors recently obtained some guidance. In the first study of its kind, Professor Bruce Hollis of the Medical University of South Carolina gave all of us something to think about. He asked and answered a simple question: How much vitamin D do you have to take to normalize the metabolism of vitamin D?

Remember, unlike other steroid hormones, vitamin D has very unusual metabolism in most modern humans, called first-order, mass action, kinetics. All this means is that the more vitamin D you take, the higher the 25(OH)D level in your blood, and the higher the 25(OH)D level in your blood, the higher the levels of activated vitamin D in your tissues. No other steroid hormone in the body behaves like this. Think about it, would you like your estrogen level to be dependent on how much cholesterol you ate? Or your cortisol level? (I'd ask the same about testosterone levels but I know men well enough not to ask.) No, the body must tightly regulate powerful steroid hormones through substrate inhibition, that is, if an enzyme turns A into B, when the body has enough B, B inhibits the enzyme and so limits its own production.

Not so with vitamin D, at least at modern human vitamin D levels. Professor Reinhold Vieth was the first to write about this and Vieth's Chapter 61 in Feldman, Pike, and Glorieux's wonderful textbook, Vitamin D (Elsevier, 2005, second edition), is a great reason to buy the textbook or have your library do so. [ I'm glad to see Amazon is out of stock of the new ones (someone must be reading about vitamin D) but you can still buy used editions.)

Why would the kinetics of vitamin D be different from all other steroids? Maybe they are not, Hollis reasoned, like Vieth before him. Maybe vitamin D levels are so low in modern humans that its metabolic system is on full blast all the time in an attempt to give the body all the vitamin D metabolites it craves. So Hollis asked, Is vitamin D's metabolism different in populations in the upper end of 25(OH)D levels (a population of sun-exposed people and a group of women prescribed 7,000 IU per day)? Note, the Hollis study is free on Medline, you can download the entire paper on the right hand of the PubMed page below.

Hollis BW, et al. Circulating vitamin D3 and 25-hydroxyvitamin D in humans: An important tool to define adequate nutritional vitamin D status. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):631-4.

If you look at the two graphs, Figures 1 and 2 of Hollis' paper, you find vitamin D's kinetics can be normalized, made just like all other steroid hormones in the body, but you have to get enough sunshine or take enough vitamin D to get your 25(OH)D level above 50 ng/ml, and 60 ng/ml would be better. Then your body starts to store cholecalciferol in the body without much further increase in 25(OH)D levels. The reaction becomes saturable. This is a remarkable discovery and it implies levels of 30 and 40 ng/ml are usually not sufficient. It also implies actual vitamin D levels (cholecalciferol levels), not just 25(OH)D levels, may be useful in diagnosing and treating deficiency. Note, that not all of the sun-exposed individuals or women prescribed 7,000 IU/day achieved such levels. That's because the sun-exposed individuals were tested after an Hawaiian winter and because prescribing and taking are two different things.

So my answer to "How much should I take if I have cancer?" is "Take enough to get your 25(OH)D level above 60 ng/ml, summer and winter." In doing so, you will have normalized the kinetics of vitamin D and stored the parent compound, cholecalciferol, in your tissues. In the absence of sunshine, you need to take about 1,000 IU/day per 30 pounds of body weight to do this. A 150 pound cancer patient may need to take 5,000 IU per day, a 210 pound cancer patient about 7,000 IU per day, all this in the absence of sunlight. And this may not be enough; cancer patients may use it up faster (increased metabolic clearance) and children may do the same due to their young and vital enzymes. Or you may need less, because you get more sun than you think, more from your diet, or because you are taking a modern medicine that interferes with the metabolism of vitamin D. An even easier way to do it is go to a sun tanning booth every day and obtain and keep a dark, full-body, tan. Then you don't have to worry about blood levels but I'd get one anyway, just to be sure it was above 60 ng/ml.

Given what Hollis discovered, given the well-known potent anti-cancer properties of activated vitamin D, given epidemiological evidence that summer extends the life of cancer patients, given a meta-analysis of randomized controlled trials showed that vitamin D prolongs life, given animal data that simple vitamin D has a treatment effect on cancer, and given a patient with a life-threatening cancer, what would a reasonable physician do? Simply let their patient die while muttering something about the lack of randomized controlled trials?

No, they would simply check a 25(OH)D level every month and advise cancer patients to take enough vitamin D or frequent sun tanning parlors enough to keep their level above 60 ng/ml. Toxicity does not start until levels reach 150 ng/ml but if you take more than 2,000 IU per day have your doctor order a blood calcium every month or two along with the 25(OH)D. Both you and he will feel better and because if you have cancer, you are probably taking lots of other drugs and little is known about how modern drugs interact with vitamin D metabolism. By getting your level above 60 ng/ml, all you are doing is getting your level to where most lifeguards' levels are at the end of summer, to levels our ancestors had when they lived in the sun, to levels regular users of sun-tan parlors levels achieve, and most importantly, to levels where vitamin D's pharmacokinetics are normalized.

In the end, if you have cancer and your physician won't do a risk/benefit analysis, do it yourself. The risk side of that equation is easy. Both Quest Diagnostics and Lab-Corp, the two largest reference labs in the USA, report the upper limit of 25(OH)D normal is 100 ng/ml and toxic is above 150 ng/ml, so 60 ng/ml is well below both. The reason levels up to 100 ng/ml are published normals is because there is no credible evidence in the literature that levels of 100 ng/ml do any harm and because sun worshipers often have such levels. (If you don't believe me, go to the beach in the summer for one month, sunbath every day for 30 minutes on each side in your bathing suit, and go home and have a 25(OH)D level.) By getting your level above 60 ng/ml, all you are doing is getting your levels into the mid to upper range of laboratory reference normals. Little or no risk.

What are the potential benefits? It probably depends on a number of things. Did your cancer cells retain the enzyme that activates vitamin D? Many do. Did your cancer cells retain the vitamin D receptor? Many do. If your cancer cells get more substrate [25(OH)D], will that substrate induce the cancer cells to make more vitamin D receptors or more of the activating enzyme? Some cancer cells do both. In practical terms, vitamin D is theoretically more likely to help your cancer the earlier you start taking it. However, no one knows. Certainly there is no reason, other than bad medicine, for cancer patients to die vitamin D deficient. Unfortunately, most do.

Tangpricha V, et al. Prevalence of vitamin D deficiency in patients attending an outpatient cancer care clinic in Boston. Endocr Pract. 2004 May-Jun;10(3):292-3.

Plant AS, Tisman G. Frequency of combined deficiencies of vitamin D and holotranscobalamin in cancer patients. Nutr Cancer. 2006;56(2):143-8.

It is very important that readers understand I am not suggesting vitamin D cures cancer or that it replace standard cancer treatment. Oncologists perform miracles every day. Do what they say. The only exception is vitamin D. If your oncologist tells you not to take vitamin D, ask him three questions. 1) How do you convert ng/mls to nmol/Ls? How many IU in a nonogram? 3) How do you spell "cholecalciferol?" If he doesn't know how to measure it, weigh it, or spell it, chances are he doesn't know much about it.

All of the epidemiological and animal studies in the literature suggest cancer patients will prolong their lives if they take vitamin D. I can't find any studies that indicate otherwise. However, none of the suggestive studies are randomized controlled interventional trials; they are all epidemiological or animal studies, or, in the case of Vieth's, an open human study. However, if you have cancer, or your child does, do you want to wait the decades it will take for the American Cancer Society to fund randomized controlled trials using the proper dose of vitamin D? Chances are you, or your child, will not be around to see the results.

John Cannell, MD
The Vitamin D Council
9100 San Gregorio Road
Atascadero, CA 93422

This is a periodic newsletter from the Vitamin D Council, a non-profit trying to end the epidemic of vitamin D deficiency. If you don't want to get the newsletter, please hit reply and let us know. This newsletter is not copyrighted. Please reproduce it and post it on Internet sites. Remember, we are a non-profit and rely on donations to publish our newsletter and maintain our website. Send your tax-deductible contributions to:

The Vitamin D Council
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Atascadero, CA 93422

PS: The Vitamin D Council lost our webmaster. If you want to donate your time to a good cause, know all about maintaining websites, are interesting in keeping up with the latest press about vitamin D, and are willing to do so for free, please hit reply and let me know. We currently have $405.52 in our bank account so we cannot pay you now but may be able to pay you in the future.

Linda
10/30/2011 4:00:13 PM |

What do you consider to be ideal cholesterol readings? I am about to visit a new doctor, a D.O., and I am sure she is going to insist on blood tests for cholesterol plus stress testing, etc. My thyroid TSH was 2.70, but she is already showing reluctance to prescribe any thyroid meds. It is going to be a battle.

John Lorscheider
10/30/2011 4:32:57 PM |

And it is not just about the wheat either. Itâ€™s all carbs. Fructose, oats, rice, pasta, potatoes and certain fruits, etc. all drive up HbA1c and small LDL. Just for a reality check I bought a can of and made a bowl of â€œproperly preparedâ€ Scottish oatmeal yesterday according to Nourishing Traditions. Those are the minimally processed chewy steel cut oats soaked with warm water and kefir overnight and served with butter and cream. Yeah, they were good alright, but my fasting BG was 88 and one-hour PP was 158. A fast 5-mile run and it was back down to 84. The container is in the garbage can now. This morning was two pasture raised eggs and bacon with Â½ cup of blueberries and Greek yogurt. Fasting BG 89 and one-hour PP was 88. My HbA1c went from 5.8 to 5.1 in less than a year and hope to get below 5.0 soon. The stubborn small LDL percentage dropped during same time period but still have a way to go in that regard.

Buddy
10/30/2011 8:12:20 PM |

I'm not completely sold on HbA1C < 6.0% being a useful metric for anything but populations.  The problem is that the current HbA1C tests do not control for erythrocyte age and I see wide variations among piers on simialr  grain free lowish carb healthy diets.

There has been much more research on this effect as it pertains to diabetics that have falsely low HbA1c:  http://www.ncbi.nlm.nih.gov/pubmed/9773739
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581997/

There is some evidence out there that it works the other way as well, and it makes intuitive sense that the lower inflammation and oxidation associated  with a healthy diet would increase erythrocyte longevity.

Of course observational studies about any topic (small LDL or HbA1c) are always to be taken with a grain of salt.

Rosanne
10/30/2011 8:30:42 PM |

I wonder if you have ever experienced with any of you patients  what is going on with my husband?  He has very few small LDL particles, at least according to a VAP test - he is type A with lots of large, fluffy LDL.  But his HbA1c is 6.1.  His fasting glucose is 80, 1 hour post-prandial it's 1685, triglycerides are 60.  This is all on a grain-free, very low-carb Paleo diet.  Do you have any clue what is causing the HbA1c to be elevated?  Could it be anything besides carbs?  He gets lots of exercise and is very fit and lean.

Some have suggested that too much protein can also cause elevated HbA1c, due to gluconeogenisis causing higher levels of glucose.  But why would the body make more glucose than it needs?  And why would that excess glucose not show up in his fasting and post-prandial glucose numbers?

Is there any other factor, besides blood glucose, that can contribute to elevated HbA1c?  No doctor yet has been able to answer this question for us.

Rosanne
10/30/2011 8:32:55 PM |

Sorry for the typo, his 1 hour post-prandial glucose is 85.

Dr. William Davis
10/30/2011 9:08:02 PM |

The most common explanation, Rosanne, is that the HbA1c can stay high long after blood sugars have come under control.

It may be due to the extended longevity of RBCs that occurs in the setting of low-carbohydrate diets that allow a previously high HbA1c to stay high for an extended period.

There's also the possibility of a hemoglobin variant that allows this.

I would put more stock in the blood glucose values by fingerstick than the HbA1c.

arlene
10/31/2011 12:42:56 AM |

Thank you for explaining this. I just had my blood work done for the first time since quitting wheat and going low carb in April. Since I've lost a lot of weight, and a lot on my waist, I am very curious to see what my numbers are. This will help me compare the important stats. What is an ideal HbA1c?

pjnoir
10/31/2011 7:37:40 PM |

I can't go near oatmeal, steel cut or any other type. Its just eggs and avocados for breakfast these days with a lot of Asparagus in the spring with my yolks. Oatmeal has been banished for good.

Bob Sparkes
10/31/2011 10:46:27 PM |

Your article discuses how the combination of small LDL particles and high blood sugar
results in plaque. Is the article cited below by University of Washington at St. Louis useful here? The article points out the role of low Vitamin D in plaque formation with LDL and high blood sugar. Or am I confusing two separate mechanisms in plaque formation.

http://news.wustl.edu/news/Pages/14489.aspx

Dr. William Davis
11/1/2011 2:01:29 AM |

Hi, Bob--

Yes, I believe it is two unrelated mechanisms. However, this is a fascinating finding to tell us why people do so well from a heart standpoint when we correct vitamin D deficiency.

Dr. William Davis
11/1/2011 2:01:45 AM |

Smart move, Pj!

Dr. William Davis
11/1/2011 2:03:57 AM |

Hi, Arlene--

We aim for 5.0% or less.

learn chinese
11/1/2011 4:05:55 AM |

Thank you for explaining the topic. i learn more about Small LDL. great post.

Jeanne
11/1/2011 5:36:29 AM |

Dr. D,
Can this be related to the lysine- arginine balance in the body? Would taking arginine supplements affect the amount of lysine residue causing problems in any way? Just thinking out loud ...

Thanks!

Jeanne

Amit
11/1/2011 8:01:31 AM |

HI Doctor Davis,

I know its not the right place, but I could not find your email.

I read "wheat belly", it was revolutionary for me, and I am persuaded it can bring much relieve to many ailments.

I also wrote several posts about this issue on my health blog (in Hebrew) based on your book and your Blog.

Thank you for the great service you are offering in your work!

Amit.
Israel.

Janis
11/1/2011 2:40:01 PM |

Hello Dr. Davis,
I'm new to your blog. Just finished reading Wheat Belly. Excellent book! I also listened to the podcast with Robb Wolf. That's how I heard about you. Not to get off topic (didn't know how else to contact you) and this is probably a silly question, but would like clarification if you could help. I've been purchasing the 85% Lindt chocolate bars until you mentioned that you eat the 90%. I read the label and it said that it is pressed with alkali. You mentioned to avoid this process as it removes the healthful flavonoids. By saying "pressed" is that a different process? The chocolate was very good, but I want to make sure I'm getting the healthful flavonoids, especially when we don't eat too many sweets. Thank you so much for your time.

Might-o'chondri-AL
11/1/2011 6:44:50 PM |

Hi Dr.,
I am confused how to reconcile HbA1c details from J Am Coll Nutrition 2005, Vol.24(1):22-29
"Dietary Carbohydrate and Glycated Protein in the Blood in Non-Diabetic Subjects"
http://www.jacn.org/content/24/1/22.full
(and their relevant references no. 10 - 19 & 34-39 )

Rosanne
11/1/2011 7:15:17 PM |

This has been going on for 2 1/2 years and in fact, the longer he has been low-carb Paleo, the higher the HbA1c has gotten. When he started, it was 5.5 and has slowly
crept up to the 6.1 reading.
Thanks for the mention of the hemoglobin variant, I guess that's must be it. Can we stop worrying about the HbA1c since his glucose values are so good?

STG
11/1/2011 7:34:13 PM |

Dr. Davis:
What do you you think of Jenny Ruhl's advocacy of the 5% club at Blood Sugar 101? Your guidelines appear to be more aligned with Dr. Bernstein's and Dr. Ron Rosedale's? Do you think that all individuals ( including prediabetics, daibetics and glucose intolerant ) should strive for a HbA1c below 5%?

Dr. William Davis
11/2/2011 1:36:45 AM |

HI, STG--

That is precisely what I aim for, also: HbA1c of 5.0% or less. At that level, metabolic consequences of blood sugar essentially disappear. This is, of course, at variance with conventional guidelines.

Dr. William Davis
11/2/2011 1:37:19 AM |

That would be my vote. Ask your doctor, also, about fructosamine, another sugar markers.

Dr. William Davis
11/2/2011 1:39:24 AM |

Hi, Might--

Were you referring to their conclusion about polyunsaturates?

Dr. William Davis
11/2/2011 1:42:08 AM |

My bar says "processed" so, yes, the flavonoid content can be expected to be reduced in this bar. The best way to get a full dose of cocoa flavonoids is in undutched cocoa powder.

I still think you can enjoy your dark chocolate, but you just might not expect full benefit from this particular bar.

Dr. William Davis
11/2/2011 1:44:08 AM |

Thank you, Amit!

What is the wheat situation in Israel? Is it pushed there as much as it is here by official agencies and food companies?

Dr. William Davis
11/2/2011 1:44:43 AM |

Sorry, Jeanne, I don't believe the answer is known.

Might-o'chondri-AL
11/2/2011 3:35:43 AM |

Hi Dr. D.,
Authors in this report say glycated protein & HbA1c do not interact  with blood glucose in same way (ref #17) and that it is glycated albumen rather than glycated hemoglobin that is very senstitve to blood glucose levels (ref # 18,19); especially since 60% HgA1c is genetic (ref #61).
AGE (advance glycation endproducts) they say is more indicated by fructosamine level from high blood glucose. Although diabetics with high fructosamine also have high HbA1c. whereas for a non-diabetic  high fructosamine does not relate to their HbA1c level (ref#16).
This impies that (since most obese individuals never will become diabetic &  longevity/cognitive function of the overweight is good) a lot of the risk factor of small LDL with HbA1c depends on genetics/ epigenetics.
My confusion is if your insistence on HbA1c for non-diabetics is misdirected or just due to it being a common first test people can do.

Amit
11/2/2011 5:15:45 AM |

Wheat is the most common carbohydrate in Israel. It is eaten almost every meal. I think that the largest source of calories is wheat.

Regarding Diabetes there is no awareness that whole wheat is especially bad for such patients. Diabetes association (and many more) do recommend whole wheat. Although they are suggesting to avoid eating large quantity of bread at once.

Wheat is being pushed, though, I don't think that somebody here is pushing wheat deliberately, just coping recommendation from abroad, and using the most cheap and easy carbohydrate.

Amit.

Nora
11/2/2011 12:10:50 PM |

I have been on my Wheat Bellies journey for 8 weeks now. I am trying to follow your suggestions on heart health and I know that you have your plate full right now, but just a request. Have you ever thought of doing healthy heart retreats? I would love to have a chance to go away for a long weekend, have all my blood work done right, have it evaluated, talk to a doctor and then maybe have a few cooking classes. Throw in a few yoga classes or walks for stress reduction and you have a whole picture!!

I have high blood pressure that is 'controlled' to some degree with Tekturna (150mg) and Amlodipine (10mg). This morning it was 150/90, so it is often not very controlled. Since 9/1 and going wheat free, I have lost 23 pounds but still have 50 to lose. My take away from your writings is that plaque is the main cause of heart disease and that keeping a low blood glucose level is the best strategy, but there is not much about high blood pressure in your work. What role does it play and will being a wheat free low carber offer me relief from my high blood pressure? Or will it stay high since I have a family history of high blood pressure and therefore will probably have to continue on my meds. While I, of course, am doing everything in my power to lower my blood pressure, is it not really a number I should focus on when trying to control my heart health?

Renfrew
11/2/2011 9:08:47 PM |

Hi Doc,
have you seen this? You are prominently featured here:
http://www.lef.org/news/LefDailyNews.htm?NewsID=11842&Section=Nutrition
Great summary!

marta
11/4/2011 9:48:08 AM |

Are you going to translate his books into Spanish some day?
I'm very interested in reading them. thanks

Dr. William Davis
11/4/2011 12:48:56 PM |

Hi, Marta--

There has been interest specifically in Wheat Belly for translations. Spanish is at the top of the list.

When that happens, I will announce here and elsewhere. Thanks for asking.

Dr. William Davis
11/4/2011 12:50:33 PM |

Thanks, Renfrew!

Life Extension has been an important supporter of my efforts and vice versa.

Dr. William Davis
11/4/2011 12:53:43 PM |

Hi, Nora--

Excellent suggestion on the heart health retreats. I've thought a lot about it and will likely do it in future. Just not quite sure about the details. One hurdle: Few people want to fly to Milwaukee, so we'd have to find an exotic or interesting, probably warm, place to do it.

Hypertension is indeed a big issue. It is also among the last things to respond to weight loss and diet, often lagging behind many months after weight loss. So it really pays to be patient while you are on this health journey. Given your family history, you still might be left with hypertension, but at least you will have minimized it.

Dr. William Davis
11/4/2011 12:54:43 PM |

Thanks, Amit.

By the way, all anyone has to do is check a fingerstick blood sugar 1-hour after consuming anything wheat to observe the astounding blood sugar consequences of wheat consumption.

Dr. William Davis
11/4/2011 12:58:54 PM |

Hmmm. I'm sorry if I'm being dense, Might, but I'm still not sure I follow.

I'm not actually advocating anything except to show how glycated small LDL is a really bad player. When viewed from multiple different directions, small LDL particles are looking worse and worse. In this instance, having any measure of glycation phenomena, whether fructosamine, glycated albumin, or glycated hemoglobin, suggests that small LDL particles are also being glycated and thereby gaining heightened atherogenic potential.

Sally
11/4/2011 2:02:44 PM |

Dear Dr. Davis,

I am reading your book Wheat Belly and want to thank you so much for writing this book.

I've avoided gluten for years.  Arthritis and other annoying symptoms vanished...but I started gaining weight!   My blood sugar starting rising!   I couldn't understand it!  It was horrifying!  Well thanks to you, I realize that gluten free breads, candies, flours,  frozen pizzas, pastas and those gluten free "tv dinners" sold at Whole Foods did nothing to help my waist line or blood sugar.  I am now following the wonderfully easy plan in your book and am confident the weight will come off.

Thank you for such terrific recipes.  Will you be writing an accompanying Wheat Belly cookbook as well?  I certainly hope so.  Please do!   If not, can you recommend some cookbooks that comply with your eating instructions?

Thanks again for such a life changing book.  Sally

HS4
11/4/2011 9:09:05 PM |

There are a few people in Israel trying to enlighten others about the dangers of wheat and other 'modern' carbs. My sister is one of them, has been trying to think of ways to get some essays to the public. But what Amit says is correct - a lot of wheat is eaten there, many people buy small breads rolls daily - it's very fresh, delicious, so it will be a tough thing to stop. Many of the best restaurants in Israel serve Arabic food which always comes with freshly baked loaves of pita. The 'national snack' is pita stuffed with falafel (fried balls of ground chickpeas, onions, garlic and spices), fresh & pickled vegetablesj, hummus and/or tehina sauce. This is available everywhere and always fresh. Becasue the food is generally very good in Israel and also very fresh it's hard to avoid wheat, which I've noticed every time I visit.

palo
11/5/2011 5:07:43 PM |

Dr. Davis, the evidence speaks for itself that consumption of carbohydrates, increase small LDL, suggesting an LC diet of less than 50 grams to mitigate the damage.
But what about endurance athletes (runners, cyclists, triathletes etc.) that work out one and a half to three hours per day and consume copious amounts of carbohydrate to fuel their long workouts.
Is the exercise neutralizing the carbohydrates' harmful effects? If so, can you suggest a dosage for certain amount of exercise?

Might-o'chondri-AL
11/6/2011 8:26:57 PM |

Hi Dr. Davis,
Non-diabetics just seem to have one feature going for them - their platelets don't respond the same as diabetics. I am inclined to think that albumin in our blood is more relevant than the hemoglobin being glycated . (This is not to criticize your preventative approach , since Type II diabetes can go on to develop & I like what you are teaching us about small LDL.)

" One common qualitative change in plasma albumin is nonenzymatic glycosylation, which occurs during states of prolonged hyperglycemia....Platelet aggregation ...is enhanced in the presence of albumin that has been incubated in a medium containing levels of glucose that are higher than would be seen in normal patients but are consistent with those seen in diabetics....(Journal of Parenteral and Enteral Nutrition 18:516-520, 1994)

Once the glycation of albumin fosters more platelet aggregation in diabetics (& the insulin resistant person!) their platelets show more secretion and adhesion leading to the vascular plaque build up that the insidious small LDL can get into. Yet, for the non-diabetic the +/- 570 insulin receptors on each platelet normally respond differently to their insulin exposure.

Specifically (in non-diabetics) the insulin actually stymies the platelet from becoming "activated" and probably explains how it is that not everyone who eats carbohydrates suffers cardio-vascular insults. Of course there are non-diabetics with genetic variants that adversely affect their plaque dynamics (ex: defect in insulin receptor signalling, that receptor's Beta subunit, G-protein pathways).

( For the techno-nerds: proper insulin receptor response on platelet keeps platelet cAMP level from dropping & so no endoplasmic reticulum calcium floods out into platelet cell cytosol, platelet granule doesn't secrete ATP, platelet alpha-granule doesn't secrete P-selectin & there isn't mitogen-activated signalling to make thromboxane A2 , etc. Basically, in the diabetic/insulin resistant these processes go forward uninhibited by normal insulin signalling & their circulating platelets don't keep rolling along suspended in the bloodstream .)

Adam
11/7/2011 5:27:55 PM |

Omega 3 Fish Oil BAD NEWS for Apoe 4/3!!!

Ok Dr. Davis, I really need your advice on this one. In following TYP, I have been taking 3200 mg day EPA/DHA fish oil 1.4:1 ratio. Recent testing shows I have gotten my HS Omega 3 Index to 9.5, and my Omega 6 to Omega 3 ratio to 2:9 so this pretty good. Now for the bad news....ever since I started taking 3200 mg day fish oil...over a 2 month period my HDL went from 48 to 38, a whopping 20% reduction in the critically important good HDL that I need to remove plaque. I exercise extensively, and I also take 10mg day crestor (crestor is one of the few statins that's supposed to raise HDL not lower it). Now, I have heard from several sources that Fish Oil (more than 1000 mg day) supplements are actually BAD for Apoe4/3 people because it lowers HDL. So now I am confused Dr. Davis.....do I follow your TYP advise and stay on 3200 mg day fish oil in order to keep a close to 10 HS Omega 3 Index....but suffer lower HDL and less plaque removal/reversal....or do I stop the Fish oil in order to raise my HDL but suffer the risks of little to no fish oil??

Please advise...

An extremely confused Apoe 4/3

Might-o'chondri-AL
11/7/2011 11:02:03 PM |

Hi Adam,
HDL drop can be due to accelerated small HDL's breakdown/clearance & if that was mostly lingering small HDL then it didn't have much reverse cholesterol transport function left in it anyway. If total HDL drops but small HDL turnover is now more optimal &/or if it is a greater % of the large HDL then there is better reverse cholesterol transport dynamic despite the total HDL drop.

ApoE has 299 distinct amino acid positions & the difference between the 3 types are due to which amino acid is in positions 112 & 158 ( respectively ApoE4 @112=arginine & @158 =arginine, ApoE3 @112=cysteine & @158=arginine, ApoE2 @112=cysteine & @158=cysteine). Because ApoE4 has arginine at position 112 this then orientates facing away from the standard grouping of 4 helix at that N-terminal to more closely cozy up to the alpha-helix of the C-terminal that in ApoE naturally overlays the N-terminal. Thus ApoE4 can uniquely feature a "salt bridge" to that C-terminal that affects how ApoE unfolds/functions when ApoE goes to work.
ApoE's manner of unfolding at it's N-terminal is crucial to how it deals with lipids, phospholipids (ex: cell membranes)and proteoglycans on a cell surface. Fish oil alters cell membrane phospholipid composition and then the proteoglycans there must suitably interact with that EPA enriched type of cell surface. Since each ApoE's C-terminal presents an interface that challenges how that ApoE works at any target cell the peculiar ApoE4 "salt bridge" uniquely conditions the way interactions play out. (And each of the separate 3 classic types of ApoE can get mutations, mostly at positions 136-150, to complicate degree of LDL receptor interaction, etc.)

James Buch
11/8/2011 3:14:01 PM |

Dear Doctor Davis,

I am wondering if you can clarify the "oxidized LDL Cholesterol" concept. Including, of course the Small LDL as well.

I began wondering if the oxidation is primarily in the package, the LDL wrap, the signaling protein, or the internal body of cholesterol itself. Of course, all of the above is also a possibility.

The nature of the oxidation could be a good clue as to how it is especially detrimental to health, and so far, I haven't found much easily available on the mechanisms of the detrimental effects. While it is useful to know the harmful nature of oxidized small LDL, some insight into the mechanism of harmful effects would be welcome and minimize the nagging question of "Why" for me.

josef
11/8/2011 5:07:20 PM |

This might be of interest:

A large study called the STRRIDE trial looked at the effects of different intensities and volumes of exercise on LDL particle size in sedentary, overweight men and women over eight months [3].  Group A performed 176 minutes of low intensity exercise (walking) per week.  Group B performed 117 minutes per week at a moderate to high intensity (jogging, cycling, or using an elliptical machine).  Group C exercised about the same amount of weekly time as group A, but at the same intensity as group B.

As one would likely guess, group C showed the biggest improvement in changing LDLs from small and dense to large and buoyant.  However, a more telling sign was that group B had a stronger effect than group A, despite exercising an hour less per week.  In other words, intensity is more important for improving LDL particle size than volume of exercise.

A follow-up of the subjects in this study showed some discouraging and encouraging effects on the particle size changes [4].  The discouraging news was that five days of inactivity following the study almost completely attenuated the particle size benefits from the trial.  However, before you start labeling exercise as futile, consider this: while five days of rest basically brought the exercise groups back to baseline LDL particle sizes, they were still much better off than the sedentary control group, who experienced significant digressions in particle size during the course of this study

Might-o'chondri-AL
11/8/2011 7:18:31 PM |

Hi James Buch,
The enzyme hepatic lipase's (HL) lipolytic hydrolysis of the phospho-lipids on the LDL surface changes it so that LDL's load of cholesterol esters can get taken out; this reduces the molecule's volume and thus is then small LDL (smLDL). Men have more HL than women, until they go through  menopause, and this propensity toward smLDL ( that can get oxidized) may explain male's earlier tendency of coronary artery disease. Visceral/central obesity trends to upregulate HL & it seems visceral obesity affects men more than women (of course central obesity in both women & men will raise both  genders'  HL enzyme levels). What decreases HL levels are things like calorie restriction & aerobic exercise (sedentary life increases HL).

Doc harps on avoiding elevated triglycerides after meals that load triglycerides into VLDL  molecules because the enzyme cholesterol ester transfer proetein (CETP) shunts triglycerides from VLDL (& chylomicrons) over to the standard circulating "big bouyant" (large & fluffy) LDL and fosters transfer of cholesterol out of that LDL; the triglyceride takes up less space and thus get smLDL.
Central obesity usually correlates with elevated triglycerides and increased HL levels. However, if triglyceride genetics (or epigentics from Doc's diet ,etc.)  in the obese without that usual accompanying high triglycerides then that upregulated HL doesn't cause a lot of that individual's standard "big bouyant" LDL to become smLDL. HL also hydrolysizes triglycerides (and phospho-lipids) of chylomicrons, BetaVLDL, IDL, LDL & HDL. Both CETP & HL enzymes being elevated alone, or together, can provoke smLDL - genetic polymorphisms exist for both enzymes.

sm LDL has less antioxidants left yet it's surface has higher ratio of poly-unsaturated acids which make it's phospho-lipids more at risk of oxidation. And smLDL has less sialic acid left on it's surface which fosters more poly-anion proteoglycan binding that increases the smLDL molecule's transportability across the endothelial lining into the artery wall .
Doc harps on need for Magnesium because in real time magnesium is what interrupts the oxidation of smLDL from locking into an altered state & then salvaged plain old smLDL doesn't get to go on to be so damaging.

Might-o'chondri-AL
11/9/2011 3:24:05 AM |

Continued for J. Buch,
Oxidized small LDL (oxLDL)  has fragments from it's oxidized PUFA (poly-unsaturated fatty acid) that are reactive aldehydes (ex: malon-di-aldehyde & 4-hydroxynoneal-lysine) which then fragment that smLDL's  lipoprotein ApoB.  That peroxidation of a PUFA acyl chain of  the smLDL phospholipid  leaves a type of carboxyl portion that the beta-2-glyco-protein I (Apo H) binds to using a "reactive" ketone as ligand link. Thus it is the position of the "reactive" ketone (keto-cholesteryl-9-carboxy-nonanoate) on the involved cholesterol molecule's spine that determines the % of glyco-protein bonding that occurs (genetics influences ketone placement on a human cholesterol molecule).

Magnesium (Mg++) in the very early stage of glycated protein (Doc warns against advanced glycation end products) hooking up with LDL reverses the glyco-protein link to the "reactive" ketone. But if deficient Mg allows time to consolidate that contact then only a physiologiclly abnormally high pH will let Mg re-break that bonding.

Immunological T cells respond (with age & gender differences)  to try to get oxLDL off the artery wall;  and, if there is too much to handle there is the risk of developing a so-called oxidized LDL-containing Immune Complex (oxLDL-IC). And this oxLDL-IC provokes cytokines that perpetuate the inflammation response. Over time and older age there is  less output of a malon-di-aldehyde oxLDL  immune response; which is possibly what leads to long established plaque having less lipid component and more involvement of collagen. It is relatively younger plaque that is unstable and more likely to rupture; the collagen draws in more Calcium and unfortunately provokes artery hardening problems.

Now the lipid part from this oxLDL-IC gets into an immunological monocyte cell's endosome  and the ApoB gets into that same monocytes lysosome - sub-compartments inside the cytosol (cell interior). Then the lipid part in the endosome triggers heat shock protein (HSP 70/70B) which wrenches things so that the lysosome can't get to work on the lipid and ApoB prevents the lysosome from doing proper interactions at the inside of that cell's membrane to expel  the burdens. Once oxLDL cholesterol esters bulk  up a macrophage (monocyte) due to increasingly futile lysosome  activity  it becomes the notorious "foam" cell. Eventually that macrophage cell dies and the whole load get's polymerized into plaque.

Might-o'chondri-AL
11/9/2011 8:03:57 PM |

Hi Dr. Davis - with your indulgence:
Back to platelets( see above Nov. 7): vascular remodeling with age &/or ROS exposes a bit of phosphatidyl serine  that platelets can "snag" onto as platelets flow along. Key to accomplish platelet snagging is signaling by  the promoter P2gamma12 and normally insulin signaling down inhibits P2gamma12. But, notably for Type II diabetics (and assumedly proportional to an individual's insulin resistance) their insulin doesn't inhibit that snag signal. Type II diabetics also have P2gamma12 upregulated in their platelets. And if anyone is of P2gamma12  haplo-type H2 those individuals will have even more of the receptors for it and therefore an  increased risk of peripheral artery disease. Irregardless of haplo-type, the Type II diabetic's propensity for peripheral artery problems are compounded by  their basal level of excess P2gamma12 .

Adhesion to the artery then physically involves the platelet surface Glyco-protein Ib & vonWillebrand factor hitched to collagen provoking Integrin 2beta1 (GPVI) so the platelet/collagen sets in place. If the level of promoter P2gamma12 in that challenged site is fortuitously low then the rate of adhesion to the blood vessel is poor. So, predictably, for Type II diabetics the adhesion rate (like platelet secretion & aggregation) is higher than normal. GPVI insult also signals a release of ADP & this ADP (like collagen itself) independently induces aggregation of platelets; the plaque recruits to build itself up to be more fibrous. The plaque matrix serves as nesting for oxLDL & dying macrophage foam cells to polymerize with.

ROS remodeling agents of the vasculature come from mitochondrial activity and  it appears certain (overlooked) relevant gene pheno-types (and their respective polymorphisms) can be pro-plaque (or preventative) - speaking here in the sense of  a primal influence on plaque risk as well as  tendency of the actual amount of plaque. Sirtuin 5 (Sirt5), a mitochondrial Sirt (there are nuclear Sirt too) binds to Uncoupling Protein 5 (UCP5) and governs that (& other) UCP. Sirt (there are 6 types) remodels chromatin (DNA spooled around a histone ) via histone de-acetylase enzyme; while our UCP (there are 5 types) work in the inner mitochondrial membrane governing the proton electro-chemical gradient that is integral to the chain of oxidative phosphorylation (a way to generate ATP, among other functions).

Sirt action on DNA includes (among other dynamics) the cellular level encoding of how individual fatty acid metabolism fine tunes -  lipid fatty acids included.Sirt action on DNA includes (among other dynamics) the cellular level encoding of how individual fatty acid metabolism fine tunes -  lipid fatty acids included. Doc's diet/protocol may ( I suggest) sometimes  tweak out favorable health response(s) via induced epigenetics, because of remodeling that is induced in the chromation DNA unit packaging . Sirt's histone de-acetylase working depends on NAD- to drive Sirt and Doc's diet/protocol theoretically seems to be capable of altering NAD flow patterns from his weaning of cells'  mitochondria off of glucose.

UCP5  rules the inner mitochondrial membrane potential & the rate of oxygen use, which can become relevant to ROS levels. Both UCP5 and Sirt5 are upregulated in hypertension and Type II diabetics; the confluence of having geneticly more UCP5 along with Sirt5 are implicated in increased carotid artery plaque. (Of course nothing is linear in humans so haplo-type T- carrier UCP5 polymorphism rs5977238 benefit with less plaque risk and reduced plaque numbers.) Note: I am skipping over other Sirt & UCP; but will add that lots of pheno-typic UCP1 spins out extra amounts of reactive super oxide to drive down nitric oxide and implicated in accelerated aging of the vasculature.

Jack Kronk
11/10/2011 8:13:40 PM |

Might/Doc - Does this mean that if you DONT have proper insulin receptor response that all of the things listed in the last paragraph become untrue? (meaning bad?)

Would this mean that you are implying a low carb diet would be the best solution due to the insulin issues?

I ask because I cannot raise my HDL for the life of me. It is completely stalled at 40. And my LDL is primarily small dense kind. I have only really had this problem since going "LC Paleo" and adding a ton of sat fat to my diet but then I added back in starches and other carbs and became more moderate carb, while still continuing to eat bacon/eggs/cheese/cream/butter/beef/coconut oil/ghee/nuts etc.

Now I've got people telling me to go back to LC, and exactly the reverse, people telling me that I need to cut out the fats including dairy and go low sat fat.

STG
11/10/2011 11:18:15 PM |

Mito....:
I have viewed your comments at the Hyperlipid and always appreciate your detailed biochemical/physiological explanations per topic. Your grasp of details and mechanisms is amazing! What is your background? Are you a biochemist by trade?

Kent
11/11/2011 4:34:12 PM |

A retreat is an excellent idea! It would be a great time of learning and discussions. I vote for Gulf Shores Alabama

Might-o'chondri-AL
11/11/2011 7:02:07 PM |

HI STG,
My hope here is that I never hijack Dr. Davis' blog ( I never personally posted on Hyperlipid blog). I trust Doc's readers know he is not responsible for any errors I make. Being semi-retired from consulting on agro-industrial projects in developing countries I feed my mind by keeping up with health science & commenting here about correlations to Doc's work.

Might-o'chondri-AL
11/12/2011 9:33:23 AM |

Hi J. Kronk,
Saw your 11 Nov. query &  feel diet advice here is for Doc to offer (not me). Doc discusses ApoE pheno-types he restricts dietary fat for. You "tagged" me where I  was elaborating on platelets' interaction with insulin & how insulin resistance is a game changer (not sure what confusing).

If one is insulin resistant then the signaling to build-up (anabolism) from insulin is selectively diminished and consequently break-down (catabolism) signals get  into play. Proteo-lysis is protein cleaving and HDL's protein component can be more rapidly subject to proteo-lysis; which I presume (?) is why/how some people degrade their HDL so quickly. Genetic quirks (& gender) also hit HDL levels notably;  yet  if quick enough turnover the "stale" HDL  might be being replaced by more functional HDL. According to the "HATS" study HDL alone is not a predictor of coronary artery disease mortality.

Niacin usually decreases rate of catabolism of HDL,  it helps secrete more ApoA1 to make into HDL & decreases amount of  smLDL. Niacin isn't perfect since it alters the extent to which HL (hepatic lipase enzyme) can work on a  HDL molecule to morph  it into the kind of HDL that has the maximum reverse cholesterol transport capability. HL is what hydrolyses the triglycerides in HDL - so, basicly if HDL loaded with trigs it has sparser room for scavenging cholesterol.

One's genetic response to increased levels of circulating palmitate free fatty acid can interfere with insulin signalling in the liver. Whether clinically insulin resistant or due to a genetic quirk (you?),  palmitate can phosphorylate liver insulin receptors in a manner unlike "normal" individuals do in the Akt process (insulin normally should get Akt going to stop liver gluco-neo-genesis - since insulin has glucose to drive into cells ). Essentially "excess" palmitate, in this example, is causing only a partial phosphorylation of Akt & is how researchers can use very high fat diets to induce experimental diabetes .

I don't hear you being insulin resistant, so address genetics of Protein Phosphatase 2A (PP2A), which  has components involved in it's regulation and is subject to different structure. How PP2A parts interact with distinct parts of the Akt molecule can  impair some interactions,  yet leave other parts of Akt responsive ( to do what Akt  is normally designed to do). Palmitate can raise PP2A levels in the liver by 30%; so basically the more PP2A  around and/or the molecule's genetic tweaks the weaker a key part of  the liver's Akt response is going to be.

Since palmitate  being in the liver does not stop insulin there from fostering more trigs there are still post-prandial trigs going into the VLDL . In other words the liver insulin resistance and rogue genetics can leave the part of Akt that governs lipo-genesis still responsive to insulin. Doc warns us about trig enriched VLDL & chylomicrons promptly driving  smLDL that doesn't degrade & small particle numbers measure high; he is more adamant about post-prandial trigs but genetic high overnight trigs can occur.

I don't think coconut oil acts the same way high animal fat sometimes does on Akt . We internally make palmitate when acetyl-CoA acted on by enzyme acetyl CoA carboxylase  to make malonyl-CoA that fatty acid synthase converts to palmitate. I think most of coconut oil's fatty acids are metabolized before getting into that pathway so maybe coconut oil is worth parsing when genetics or insulin resistance drives up smLDL.

STG
11/12/2011 6:16:07 PM |

Mito..
Excuse my error about you posting on the Hyperlipid. I guess I have read your posts elsewhere. In any case, your posts are very educational and explain precisely the biochemistry Thanks for sharing your knowledge!

Mark
8/14/2012 3:24:54 AM |

Hi Dr. Davis,
Iâ€™m 47 yrs old. Iâ€™ve had migraines since I was a teen and I developed Athsma this past January (hate it). During the process of discovery the drs found I have a 50% blockage in one of the 5, non critical, arteries running along the back of my heart. Scared me, to say the least. Iâ€™ve always eaten quite healthfully (for what I knew), am thin @ 6â€² 1â€³/155lbs (was 175lbs in Jan.). Had total cholesterol of 200/LDL of 146/HDL of 50. Drs wanted me to do Lipitor. Researched and said, â€œNo, thanks.â€ Started exercising 5-6 days/wk (lifting + walk/run), taking red yeast rice, fish oils, fish, no meat, no dairy, no eggs, lots of veggies/fruit, etc., but still eat beans, oats (every AM), occasional wraps. After 6 wks my blood work (VAP) was as follows: LDL=86, HDL=43, VLDL=17, TOT. CHOL=146, Trigycerides=66, Non-HDL (LDL+VLDL)=103.

Seemed GREAT to me! The dr wasnâ€™t impressed. Said my â€˜particle sizeâ€™ was small: LDL1(a)=8.1, LDL2(a)=0, LDL3(b)=39.5, LDL4(b)=24.9. Density Pattern=B.

Iâ€™ve continued but donâ€™t know how to elevate my HDL and reduce the particle size/change the pattern to the more favorable â€˜Aâ€™. Getting down about this. Working hard but, seems like I canâ€™t find answers that work, anywhere! What might you would work in my situation? Also, Is niacin ANDRed Yeast Rice a bad idea?
Iâ€™ll hang up and listen. Thank you,
Mark

PS - I left this post on another page, as well.

Neelesh
12/6/2007 3:25:00 PM |

Dr Davis,
I'm unable to get Vitamin D3 (cholecalciferol) in India. What is being sold is calcium + Vitamin D3 or Alfacalciferol or Calcitriol (http://en.wikipedia.org/wiki/Calcitriol).
While I couldn't find much about alfacalciferol, Calcitriol's composition looks very similar to what you describe.
I wonder if they are the same.
-Neelesh

Anonymous
12/6/2007 5:02:00 PM |

Dr. Cannell's arguments make a lot of sense, but his statement that "If he doesn't know how to measure it, weigh it, or spell it, chances are he doesn't know much about it." would carry more weight if he hadn't misspelled nanogram in the immediately preceeding sentence.

g
12/6/2007 9:48:00 PM |

I like the Feng Shui or symmetry of 60-60-60-60....

Actually it's 60-60-60-60-60 if you include Apolipoprotein B...
(although I know you are achieveing TGs<45!)

This is great! Thank you, g

TedHutchinson
12/7/2007 12:21:00 AM |

Those readers who want to check what the research papers actually said may find the NUMBERS that I have emboldened useful. If you just cut and paste the darker number into the search-box at pubmed it should bring up the right paper.
Moan J, et al. Colon cancer: Prognosis for different latitudes, age groups and seasons in Norway. J Photochem Photobiol B. 2007 Sep 19 18029190
Lagunova Z, et al. Prostate cancer survival is dependent on season of diagnosis. Prostate. 2007 Sep 1;67(12):1362-70 17624920
Porojnicu AC, et al.  Changes in risk of death from breast cancer with season and latitude: sun exposure and breast cancer survival in Norway. Breast Cancer Res Treat. 2007 May;102(3):323-8.17028983

Porojnicu A, et al.  Season of diagnosis is a predictor of cancer survival. Sun-induced vitamin D may be involved: a possible role of sun-induced Vitamin D. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):675-8. 17229569

Porojnicu AC, et al.  Season of diagnosis is a prognostic factor in Hodgkin's lymphoma: a possible role of sun-induced vitamin D. Br J Cancer. 2005 Sep 5;93(5):571-4.17229569

Lim HS, et al.  Cancer survival is dependent on season of diagnosis and sunlight exposure. Int J Cancer. 2006 Oct 1;119(7):1530-6.16671100

Zhou W, Vitamin D is associated with improved survival in early-stage non-small cell lung cancer patients. Cancer Epidemiol Biomarkers Prev. 2005 Oct;14(10):16214909
Berwick M, et al.  Sun exposure and mortality from melanoma. J Natl Cancer Inst. 2005 Feb 2;97(3):195-9.15687362
Tangpricha V, et al.  Vitamin D deficiency enhances the growth of MC-26 colon cancer xenografts in Balb/c mice. J Nutr. 2005 Oct;135(10):2350-4.16177194

Schwartz GG, Skinner HG. Vitamin D status and cancer: new insights. Curr Opin Clin Nutr Metab Care. 2007 Jan;10(1):6-11.17143048

Woo TC, et al.  Pilot study: potential role of vitamin D (Cholecalciferol) in patients with PSA relapse after definitive therapy. Nutr Cancer. 2005;51(1):32-6.15749627

Hollis BW, et al.  Circulating vitamin D3 and 25-hydroxyvitamin D in humans: An important tool to define adequate nutritional vitamin D status. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):631-4. 17218096

Tangpricha V, et al.  Prevalence of vitamin D deficiency in patients attending an outpatient cancer care clinic in Boston. Endocr Pract. 2004 May-Jun;10(3):292-3.15310552

Plant AS, Tisman G.  Frequency of combined deficiencies of vitamin D and holotranscobalamin in cancer patients. Nutr Cancer. 2006;56(2):143-817474859

I just feel so upset that I have been misinterpreting Hollis's paper Circulating Vitamin D3 and 25-hydroxyvitamin D in Humans and been telling people that 100nmol/l was a reasonably safe minimum. Looking again at those figures 1 and 2 I take Cannell's point that it may be better, safe rather than just stopping at 40ng 100nmol/l it may be safer, allow a bigger margin for error, to consider 50-60ng/ml 125nmo/l- 150nmol/l as the range for optimal health.
It's bad enough taking the flax and suggesting 4000iu/d is safe and reasonable where no sun exposure is possible.
I suspect I'm going to be even more unpopular suggesting 7000iu may be necessary in some/many cases.

Anonymous
12/7/2007 4:47:00 AM |

Is there any danger from Vitamin D levels that are close to the upper ends of the 'safe' spectrum?

A study in India once linked high D levels (89 ng/mL) to higher incidents of cardiac disease, but that study was a bit iffy.

Info can be found here: http://www.westonaprice.org/basicnutrition/vitamin-d-safety.html

Although the reference to the Indian study is buried a bit deep in that page. A lot of info there though.

Dr. Davis
12/7/2007 11:46:00 AM |

What an excellent summary!

You can see that data probing the health effects, or detrimental effects of higher levels of vitamin D3 (as 25-OH-vitamin D3) are poorly explored. We aim for a blood level of 50-60 ng/ml and have observed no toxic effects whatsoever. In fact, we've observed positive effects well beyond our expectations.

Nonetheless, I think that going above 60 or 70 ng/ml is relatively uncharted territory.

TedHutchinson
12/7/2007 5:34:00 PM |

http://www.vitamindcouncil.com/worst_science.shtml This summary of the Indian research mentioned earlier may help those who are unfamiliar with what is being discussed here.

The problems associated with standardisation of scores between different assessment records is complex and discussed in this paper. Serum 25-hydroxyvitamin d measurement in a large population survey with statistical harmonization of assay variation to an international standard.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17726070 There was pre-publication full text pdf version online, with some nice charts of UK vitamin d status through the year at the back, but I cannot find it now.

There is still a problem between different assay methods and lab accuracy as some of the presentations at this conference make clear.
http://app2.capitalreach.com/esp1204/servlet/tc?cn=asbmr&c=10169&s=20343&e=6950&&
The http://www.deqas.org/ system for ensuring a world standard.

While of course we must not totally turn our back on past research we do have to consider whether the levels reported would stand comparision with current standards of assessment.

While I am not suggesting that anyone should try this at home.
Safety of vitamin D3 in adults with multiple sclerosis used progressively increasing doses of vitamin D3: from 700 to 7000 microg/wk (from 28000 to 280000 IU/wk). I personally believe Vieth to be an honourable man who would, should adverse events have been record would have reported them.
Such very high dose levels are outside of the scope of "NORMAL" vitamin D supplementation but the very fact that when tested, the results have been predictable, does give us confidence thatRisk Assessment for Vitamin D
http://www.ajcn.org/cgi/content/full/85/1/6 does stand up to scrutiny when tested.

In order to reach the levels detailed by Hollis in Circulating Vitamin D3 and 25-hydroxyvitamin D in Humans: those particularly living above latitude 37 are going to have to use more Vitamin D than Krispin Sullivan suggests during the winter months when sunlight is unavailable. It's my view that the risks associated with low vitamin d status are higher than the alleged, unproven risks of supplementing with up to 10,000iu/daily though in practice a total intake of 4000 -7000iu appear to be required during the winter when sun/uvb is not an option.

Vaughny
12/8/2007 1:23:00 AM |

Good material on Vit D. He mentions monthylu blood calcium tests - how critical is this test if one were supplementing in the 4000IU - 6000IU / day range? Would Vit K2 help prevent higher blood calcium?

Dr. Davis
12/8/2007 1:26:00 AM |

Monthly calcium tests are silly. There is absolutely no need for this in 99.9% of people.

No, vitamin k2 will not prevent a rise in calcium. The worry that vitamin D will raise calcium is, for the extreme majority, unfounded.

Mo
12/8/2007 11:33:00 PM |

Isn't it actually possible that from a certain level of D upwards, that D keeps calcium from not only getting too low but also too high?

If your D is low I'd imagine your blood calcium would at first be high or within the upper limits of normal before going on a possible plummet route if your D drops more.

I guess once D has satisfied your bones, it doesn't over do it and distributes to other needy areas.

Thomas
12/9/2007 9:48:00 PM |

Will any fat (nuts) have similar results compaired to olive oil?

How often should blood tests be necessary to test vitamin-d absorption ?

Coulden't find answers to these questions using Google or Dr. Cannell's web site.

Dr. Davis
12/9/2007 11:07:00 PM |

I don't know. I suspect they have some effect, but I've not examined it specifically.

We check our patients every 6 months.

buy jeans
11/3/2010 10:31:11 PM |

While cancer is not our focus on the Heart Scan Blog, Dr. Cannell's always insightful comments provide some helpful thoughts for our management of vitamin D doses and blood levels.

John F Ocel JR
10/13/2011 5:38:58 AM |

DR Carnell im a huge fan of you and i know ur very smart and good at what u do and love to help educate people about there health expecially about vitamin d i am 28 years old 290 pounds 5 foot 10 vitamin d defient and have severe hypertention i take tribenzor 40-10-25 mg's in the am and monopril 20mg's in the pm, and b12 sublingual which works wonders for me mentally well anyways since iveb been taking bob barefoots coral calcium and vitamin d 3 my blood pressure went from 125 70 to 88/37 i felt like crap i stopped the tribenzor 40-10-25mg pill and increaded the monopril to 30 mg;s my pressure has been 126/60 im feeling a feverish warm feeling i wonder if its the vitamin d 3 or coral calcium or too much b12 or could it be the withdrawals of tribenzor is a cobination drug 3 pills in one for hypertention i took alil less then half a pill of the tribenzor and the fever hot flashes went away my doctor already told me that vitamin d doesnt lower bloodpressure so what should i do and what should i say to him i have an appointment the 25th of october for a bloodpressure check up. Please help me fit the batlle of hypertention and give me ur honesy opinion thanks doc god bless u were put on this earth to help people like me thnak you. Just wanted to let u know im taking about 5,800 ius a day thank you.and also when i stop the monopril ive had heart fluttering ive done it before, been on it since i was 16 years old.

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