"It never gets easier, you just go faster." - Greg Lemond

Thursday, February 21, 2013

Relationship between glycemic index and serum cholesterol

"For a large proportion of the population, the effect of higher-carbohydrate diets, particularly those enriched in refined carbohydrates, coupled with the rising incidence of overweight and obesity, creates a metabolic state that can favor a worsening of the atherogenic dyslipidemia that is characterized by elevated triglycerides, reduced HDL cholesterol, and increased concentrations of small, dense LDL particles." - Siri-Tarino et al. 2010 (1)

“It was the opinion of some Cholesterol Conference participants that recommendations based on attempts to isolate the effects of dietary cholesterol from complex dietary patterns and extrapolations from calculated models are flawed and may lead to unintended negative consequences. It is, perhaps, more effective to recommend broader dietary patterns where there is more direct evidence for an effect on health outcomes.” – Brownawell and Falk 2010 (2)

Cholesterol may be regarded as an "evil" dietary component, but the fact remains that cholesterol is an essential molecule for human development and bodily function.  The critical role of cholesterol in maintaining health is most evident in those suffering from genetic mutations that result in the impairment of cholesterol synthesis; they suffer from craniofacial abnormalities, syndactyly, polydactyly, genital malformations, jaundice, and congenital heart disease (3).  Furthermore, cholesterol serves as the precursor for bile acids as well as many hormones that we regard as invaluable for physical development such as testosterone, estrogen, progesterone, as well as the adrenal hormones (4). Certainly there is a reason that (dietary) cholesterol has become somewhat of a pariah - circulating blood (serum) cholesterol levels are a good predictor of/reason for cardiovascular disease.

More recently blood cholesterol has been described by the sort of protein that it is associated with as it travels through our circulation in cholesterol/protein complexes of various sizes.  Thus when we talk about LDL or HDL we are describing the entire circulating complex, rather than just the total cholesterol found in circulation.  Without going into the mechanisms by which LDL or the LDL:HDL ratio or particle size contributes to cardiovascular disease or metabolic syndrome, I think its safe to conclude that high LDL levels in the blood in the absence of high HDL levels is associated with unfavorable outcomes regarding our health.

Diet and Cholesterol
Consuming animal products, results in the consumption of dietary cholesterol, plain and simple.  Whether it be eggs, milk, cheese, or steak, these contain some amount of cholesterol.  Don't make the common mistake to assume that all high fat foods contain cholesterol; for example avocado, despite its buttery texture and plethora of fats, avocado is a fruit, and cholesterol-free.  Based on this observation, one might conjecture that avoidance of animal products (i.e. veganism) would facilitate tight regulation of serum cholesterol levels by reducing all dietary cholesterol.  Certainly from a dietary standpoint, this is one very powerful way of eating that is beneficial for those predisposed to be at a greater risk of cardiovascular disease (5). 

Cholesterol also plays a hugely important role in the synthesis of bile salts (bile) (4).  These compounds are synthesized in the liver, stored in the gall bladder, and secreted into the intestine to help better absorb fats by emulsifying them and reducing their hydrophobicity.  Because bile is derived from cholesterol, one dietary approach is to increase the amount of bile that is lost in the feces (6, 7).  Normally the body reabsorbs bile during digestion, but certain plant components, mainly fiber, can bind bile and cause it to be lost in the stool (6).  Thus, the body must synthesize new bile from cholesterol, which is thought to help lower serum cholesterol levels.

Regulation of Cholesterol Synthesis
Because of the critical importance of cholesterol in cell structure and function, our bodies do not rely on dietary cholesterol as the sole source of cholesterol.  Perhaps even more important than dietary cholesterol, endogenous cholesterol (cholesterol synthesized by our bodies) is a/the major contributor to the total cholesterol pool within our bodies (4).  The importance of manipulating this pathway is emphasized by the methods for treating elevated serum cholesterol in a clinical setting.  One of the most commonly prescribed drugs in for treating this condition is a family of drugs known as Statins (8).  Statins are HMG-CoA reductase inhibitors, an enzyme found mostly in the liver responsible for the synthesis of cholesterol that is not obtained through the diet (4).  Inhibition of HMG-CoA by Statins has been shown to lower serum cholesterol levels by nearly 50%, supporting the notion that endogenously synthesized cholesterol makes up a large portion of total serum cholesterol levels (8).  Follow me so far?  HMG-CoA produces endogenous cholesterol.
Cholesterol Trafficking Pathways (Eatingacademy.com)

Focusing on this pathway is of particular interest to me and leads me to ask several questions.  How does our body regulate cholesterol levels in the absence of minimal dietary cholesterol?  Does diet still influence this pathway?

I guess the short-answer is yes, further investigation into this concept reveals that dietary cholesterol travelling in cholesterol remnants such as LDL or HDL reaching the liver results in feedback inhibition on HMG-CoA reductase, such that, during a period of elevated dietary cholesterol, the body receives a signal to reduce endogenous cholesterol synthesis (4).  Feedback inhibition is one mechanism that phytosterols, a plant component known to reduce circulating cholesterol levels, are thought to work.  Indeed, phytosterols have a very similar structure to cholesterol, supporting the notion that feedback inhibition results from phytosterols in the diet.

 The concept of feedback inhibition results in the eventual question, well then what happens when cholesterol is removed from the diet entirely?

Interestingly, in the absence of dietary cholesterol, endogenous cholesterol levels can vary widely.  In my understanding, serum cholesterol levels are tightly related to endogenous synthesis rates i.e. HMG-CoA reductase activity (4), a high degree of which is attributed to hormonal and genetic regulation of HMG-CoA reductase (9).  Since genetic regulation of HMG-CoA activity is more or less beyond our control at this time, I'll talk about hormonal regulation of HMG-CoA activity.  Especially and specifically metabolic hormones such as insulin, glucagon, thyroid hormone, and glucocorticoids.

The concept that insulin stimulates the liver to synthesize cholesterol was first published as early as 1969 (as far as I could find).  Interestingly, in animals, complete absence of insulin signaling, HMG-CoA reductase levels are nearly non-existent, suggesting a critical role for insulin in maintaining basal cholesterol synthesis (10).

If insulin is a major driver of cholesterol synthesis, is there evidence that dietary modifications independent of changing dietary cholesterol can result in more promising outcomes regarding cholesterol and cardiovascular health?

Evidence and Conjecture
I've spent a long time looking for specific studies that are well controlled in regards to the relationship between serum cholesterol and glycemic load of meals. While there may not be many studies designed to directly examine this relationship from a mechanistic standpoint, there are a plethora of dietary studies available that look at the correlations between study and draw conclusions based upon.

In 2006 a group of scientists published a study in the Journal of Nutrition that compared the effectiveness in reducing risk factors associated with cardiovascular disease (mostly serum cholesterols).  The authors chose to compare the American Heart Association Diet (AHAD) and a Low Glycemic Index Diet (LGID) containing plant phytosterols (11).   While both diets resulted in improved blood panels, the LGID diet was more effective than the AHAD diet at improving blood panels when studying the affect of the diets on serum cholesterol levels.  Similar findings were recently reported recently in two other separate occasions in women (12, 13), and has also been reporte din men (14) strongly supporting the notion that reducing glycemic load is associated with reduced cardiovascular disease risk. 
A direct opposite, a study looking at Japanese women found increasing the glycemic load of the diet resulted in reduced HDL (15).  Because high HDL levels are considered protective, we again find a situation in the literature where diets with a high glycemic load appear to have negative impacts on the LDL:HDL ratio, one of the most important biomarkers of risk.  These are just some examples of numerous publications looking at relationships between glycemic load (and thus insulin load) and cholesterol levels.  I should point out that there are other studies that found no benefit to reducing glycemic index, although I'd argue the data seems to generally support my position.  On a side note:  Do you think your doctor knows about these studies and/or is aware of this sort of evidence????

Take Home Message(s).
I'm not going to go so far as to criticize carbohydrates, rather argue that food choices should be made with glycemic index in mind.  This is especially important as food labels will use just about every catch phrase to try to get you to buy the product.  Just because you see a low-fat, cholesterol free food, the glycemic index may be very high.  I don’t think this is a shocking concept to anyone concerned with what they’re eating, however, I hope to have made a relatively convincing argument here that dietary cholesterol is likely not a major culprit in the ailing health of Americans.  Because of the aforementioned studies regarding the role of insulin and glycemic load in regulating cholesterol synthesis, I feel confident saying that highly insulinogenic diets, even in the absence of dietary cholesterol, have the potential to be counter productive for persons watching cholesterol levels.

My idea of a pyramid

I think the evidence presented here supports the importance of including adequate fiber in the diet.  (Soluble) Fiber has the potential to reduce cholesterol levels through at least two mechanisms discussed here.  #1 fiber lowers the glycemic index of a meal, thus reducing the amount of insulin that will be secreted.  #2 fiber also is capable of binding to bile, causing it to be excreted, and forcing the body to use endogenous cholesterol to synthesize new bile.

I could go on and on about what the food industry has done to us by creating these "low-fat" foods, where sugar is relied on for taste rather than fat.  I'll try not to indict anyone, but I do think that fat the potential to influence cholesterol levels in the diet, similar to fiber. Fat and protein stimulate the secretion of bile through the production of CCK.  Thus, adequate fat is required in the diet to maintain or support bile secretion during the consumption of a meal.  Furthermore, fat and protein also lower the glycemic load of a meal, emphasizing the importance of having a diet adequately balanced in macro-nutrients.

Hmm what kind of diet is high in fiber, contains adequate fat and protein, and is generally low glycemic index and/or non-insulinogenic.  If you follow my blog, you probably know what I’m thinking about already (cough, cough, paleo, cough, cough).

Works Cited

1.         Siri-Tarino PW, Sun Q, Hu FB, Krauss RM. Saturated fat, carbohydrate, and cardiovascular disease. Am J Clin Nutr.  Mar;91:502-9.
2.        Brownawell AM, Falk MC. Cholesterol: where science and public health policy intersect. Nutr Rev.  Jun;68:355-64.
3.         Irons M, Elias ER, Tint GS, Salen G, Frieden R, Buie TM, Ampola M. Abnormal cholesterol metabolism in the Smith-Lemli-Opitz syndrome: report of clinical and biochemical findings in four patients and treatment in one patient. Am J Med Genet. 1994 May 1;50:347-52.
4.         Ness GC, Chambers CM. Feedback and hormonal regulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase: the concept of cholesterol buffering capacity. Proc Soc Exp Biol Med. 2000 May;224:8-19.
5.         Craig WJ. Health effects of vegan diets. Am J Clin Nutr. 2009 May;89:1627S-33S.
6.         Lattimer JM, Haub MD. Effects of dietary fiber and its components on metabolic health. Nutrients.  Dec;2:1266-89.
7.         Story JA, Furumoto EJ, Buhman KK. Dietary fiber and bile acid metabolism--an update. Adv Exp Med Biol. 1997;427:259-66.
8.        Nawrocki JW, Weiss SR, Davidson MH, Sprecher DL, Schwartz SL, Lupien PJ, Jones PH, Haber HE, Black DM. Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor. Arterioscler Thromb Vasc Biol. 1995 May;15:678-82.
9.         Goedeke L, Fernandez-Hernando C. Regulation of cholesterol homeostasis. Cell Mol Life Sci.  Mar;69:915-30.
10.       Ness GC, Wiggins L, Zhao Z. Insulin increases hepatic 3-hydroxy-methylglutaryl coenzyme A reductase mRNA and immunoreactive protein levels in diabetic rats. Arch Biochem Biophys. 1994 Feb 15;309:193-4.
11.       Lukaczer D, Liska DJ, Lerman RH, Darland G, Schiltz B, Tripp M, Bland JS. Effect of a low glycemic index diet with soy protein and phytosterols on CVD risk factors in postmenopausal women. Nutrition. 2006 Feb;22:104-13.
12.       Shikany JM, Tinker LF, Neuhouser ML, Ma Y, Patterson RE, Phillips LS, Liu S, Redden DT. Association of glycemic load with cardiovascular disease risk factors: the Women's Health Initiative Observational Study. Nutrition.  Jun;26:641-7.
13.       Jones JL, Comperatore M, Barona J, Calle MC, Andersen C, McIntosh M, Najm W, Lerman RH, Fernandez ML. A Mediterranean-style, low-glycemic-load diet decreases atherogenic lipoproteins and reduces lipoprotein (a) and oxidized low-density lipoprotein in women with metabolic syndrome. Metabolism.  Mar;61:366-72.
14.       Mosdol A, Witte DR, Frost G, Marmot MG, Brunner EJ. Dietary glycemic index and glycemic load are associated with high-density-lipoprotein cholesterol at baseline but not with increased risk of diabetes in the Whitehall II study. Am J Clin Nutr. 2007 Oct;86:988-94.
15.       Amano Y, Kawakubo K, Lee JS, Tang AC, Sugiyama M, Mori K. Correlation between dietary glycemic index and cardiovascular disease risk factors among Japanese women. Eur J Clin Nutr. 2004 Nov;58:1472-8.


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