Endothelial Dysfunction - How Insulin Resistance Progresses to Heart Disease
Ryan Bradley, ND, MPH June, 2009
Although there are several factors that influence the development of diabetes - genetics and autoimmunity for Type 1 diabetes, and lifestyle and genetics for Type 2 - the major goal for both types is the same: prevention of heart disease and complications. In the case of Type 2 diabetes, numerous lifestyle factors are known to be causative of insulin resistance - specifically, not living an active lifestyle and over-eating certain foods. Yet environmental factors also appear to contribute, including more recent observations that toxins in our environments, including diesel exhaust and pesticides, may contribute to the development of diabetes (Lee et al. Diabetologia, 2008). Yet, not everyone progresses from pre-diabetes to diabetes, and not everyone with diabetes develops heart disease. How can this be?
These conditions share certain characteristics, yet there still appears to be a continuum of severity, and, importantly, there appears to be an opportunity to shift the progression of diabetes, even once it develops. Is it possible that there is one common mechanism between diabetes & heart disease? And that this mechanism can be impacted therapeutically to help protect the delicate system of vessels that carry oxygen and nutrients throughout our bodies? In this article, I will review current understanding of the importance of the inner lining of our blood vessels- called the endothelium - and the dysfunction that occurs at this inner lining that appear to be a common disruption throughout the continuum of insulin resistance through the development of diabetes, and on to heart disease.
The endothelium is the innermost lining of all of your arteries, large and small. The normal function of the endothelial lining is to produce a chemical called nitric oxide (NO), which causes the vessel to expand, or dilate, in response to either an increased need for oxygen, or in order to deliver more nutrients to the tissues of the body. Let me give a few specific examples, which I think will help this system become more familiar.
Often when people develop heart disease, especially later in the condition when chest pain occurs with even short bursts of activity, they are prescribed a drug called nitroglycerine. This drug is used because it is rapidly converted to NO in the body, causing the arteries to dilate, and thus more oxygen gets to the heart, and hopefully the pain stops. However, the vessels normally produce their own NO, in response to several stimuli, including exercise and also food intake.
Now think about the energy and oxygen your body needs during exercise- say when you go for a brisk walk or jog. In response to the demand for energy and oxygen, the heart increases its rate, and this increases the pressure applied to the inside of the vessels; the increase in pressure normally causes the endothelium to make more NO, and thus deliver more oxygen and fuel to the tissues in order to sustain exercise. Now, wouldn’t it also make sense that if the body wanted to deliver fuel to the muscles, even in the absence of exercise, that there would be a mechanism to do this as well- say after a meal? Surprise! The hormone insulin is the trigger that allows for this delivery to occur. Insulin stimulates the production of NO by the endothelium so that blood flow is increased to the tissues, like your muscles, allowing the absorption of the nourishment from your meal!
What Can Go Wrong?
Although the research is still emerging on the numerous causes of dysfunction of the endothelium, there is some convincing research that has demonstrated endothelial dysfunction, or the inability to produce NO normally, can be caused by several very common exposures - including exposures in our diet and exposures in our environment.
Regarding the dietary causes of endothelial dysfunction, we owe much of our understanding to researcher Antonio Ceriello, MD (Ceriello et al. Circulation, 2002; Ceriello et al. Diabetes. 2004). Dr. Ceriello and his team have performed numerous experiments investigating endothelial dysfunction following meals, or post-prandial. The basics of his experiments are as follows: he fed a group of people various standardized meals, and then measured the dilation of their blood vessels plus several markers of oxidation and inflammation for several hours following the feeding. The “meals” were either an oral glucose tolerance test, containing 75g of glucose, a high-fat shake consisting almost entirely of whipped cream, or a combination of the high-glucose and the high fat “meal”. The summary of his findings is that both high-glucose and high-fat meals disrupt the endothelium, however the glucose meal appears to do it very rapidly, i.e. within an hour; the high fat meal seems to do it later, but the effects last longer i.e., between 2-3 hours after the meal; and the combination does both, i.e. occurs rapidly and lasts a long time, from 1-3 hours following the meal.
Importantly, Dr. Ceriello has performed these experiments in people with both types 1 & 2 diabetes - and in people without diabetes at all - and the effects were very similar, except that people with diabetes started out with much higher measures of oxidation and inflammation that those without diabetes. Also measured was oxidized LDL cholesterol (See Complementary Corner, November 2006), and C-reactive protein, which appear to increase in parallel with elevated blood glucose and blood fat. Also tested were meals with high- and low-levels of advanced glycosylation end products, the tasty caramel like chemicals that get formed during browning, toasting, roasting and frying foods (See Complementary Corner, December 2006), which also disrupt endothelial function, resulting in reduced NO production, increased blood clotting, and higher levels of oxidation products forming in the vessels. These findings suggest that all of us- even those of us without diabetes - are susceptible to this phenomenon, and that the dietary choices we make can either cause this to happen very quickly and very often, or very rarely.
Why Does a Little Endothelial Dysfunction Matter?
It is true that the endothelium is like the skin inside our blood vessels, and like skin, it repairs and replaces itself rather quickly. And, also like skin, there is a very large area covered with this layer. So, who cares? We slough off our skin, and it gets replaced, no big deal, right? Not so fast. This belief may be true if the reaction stopped there, but it doesn’t. In fact the disruption in our endothelium continues, and involves other systems in the body, including the immune system. It turns out that our blood vessels have receptors for toxic chemicals too, including oxidized LDLs, C-reactive protein, and advanced glycosylation end products, and when these compounds bind their receptors, they trigger a whole cascade of events, including the activation of the immune system’s inflammatory response. Our blood vessels release messengers called cytokines, and these messengers cause our immune cells, called macrophages, to navigate through our blood vessels and swallow up, or engulf, these toxic compounds. What happens to them?
Well, probably not surprisingly, they get taken to the dump- and the closest dump happens to be the deeper, inner layers of our arteries, leading to plaque buildup, or atherosclerosis. Now you might be thinking, why in the world would our body respond by triggering our immune system and creating plaque buildup from drinking a milk shake? I think it is important to consider the intelligence of this approach. The human body is designed to compensate for injury in very select ways, and in the case of vascular injury, it compensates by trying to seal up the problem, i.e., create clots, and get the culprit as far away as possible from the delicate inner lining of the vessels. Before thinking of this as counter-productive, consider the alternative? If these toxins were not removed and stored, they would continue to impair the delivery of blood and nutrients, and in sensitive tissues this could rapidly cause low oxygen levels, leading to rapid tissue destruction and death. Our body is smart, it is up to us to treat it correctly.
Unfortunately, not only does the inflammatory response that accompanies endothelial dysfunction contribute to atherosclerosis, but the inflammation also impairs the function of numerous other receptors, including the receptors for insulin in the liver, kidneys and muscles, and the receptors for both insulin and glucose in the pancreas. Over time, these disruptions lead to the slow, but progressive, development of insulin resistance and compromise to the pancreas, limiting its ability to detect blood sugar and respond by releasing insulin. Of course, this is a vicious cycle, because the development of insulin resistance and insulin deficiency both lead to higher blood sugar and higher blood fat, perpetuating the dysfunction.
Can Endothelial Dysfunction be Fixed?
The first treatment recommendation will sound very familiar to you: dietary change. Given the above discussion about the contribution of fat, sugar, and advanced glycosylation end products to a dysfunctional endothelium, the elimination, or significant reduction, of foods high in these pro-inflammatory factors is the first step to returning normal function. Dietary recommendations for an anti-inflammatory, endothelial protection diet can be found in Complementary Corner - Dietary Top 10 List: Rules of Thumb to Eat for Health with Diabetes).
Improve Blood Glucose and Lipid Control
Although obvious, it is important than blood glucose be reduced down to normal, or near-normal levels, ideally through diet and lifestyle change, in order to reduce the continued oxidative stress that occurs due to high blood glucose. Admittedly, we’ve seen recently from large clinical trials, that aggressive blood glucose lowering using drugs does not clearly benefit most people with diabetes, in terms of their cardiovascular outcomes. However, healthy lifestyle clearly does make a difference in cardiovascular outcomes, and therefore achieving as much reduction as possible, using exercise and dietary change, is a sure bet for protection. Also, glucose is not the only culprit. Blood cholesterol, i.e. LDL, and blood fat, i.e., triglycerides, are also pro-inflammatory substances and they too, need optimal treatment to protect your endothelium.
Nutritional and Botanical Supplements
Nutritional and botanical supplements should not be used in place of dietary change, and in some cases, I would even speculate supplements would do more harm if not used in combination with dietary change. It is dietary choices, i.e. what you do and do not put in your body, that creates a pro-inflammatory, metabolic environment that leads to impaired vascular function; although supplements can and do help, they do not replace the value of changing the metabolic environment. Some nutritional and botanical supplements that appear to help the endothelium and/or help prevent the oxidative process from starting are:
The amino acid L-arginine is the immediate donor for the nitric oxide produced in the endothelium, making it a great candidate for supplementation. However, caution is warranted. Adding too much nitric oxide into a pro-oxidative environment clearly leads to the production of MORE, not less, reactive species (specifically reactive nitrogen species), which can modify the endothelium, and compromise function (Ceriello, et al. Diabetes. 2004). Therefore, in my opinion, L-arginine should only be used under three circumstances: 1. The diet have already been changed to an anti-inflammatory, endothelial protective diet 2. Blood glucose is well controlled and 3. It should be taken together with the antioxidant n-acetylcysteine (NAC). Several clinical studies investigating l-arginine support my opinion.
The first was a study by Palloshi et al. that evaluated 6 grams per day in patients with high blood pressure (Palloshi et al. Am J Card. 2006). Although blood pressure was reduced by the L-arginine supplementation, biomarkers of oxidative stress associated with endothelial dysfunction (e.g. ADMA) were unchanged at the end of the study. This suggests to me that high doses of L-arginine can over-ride the system and lead to more nitric oxide production, but it does not impact the underlying oxidative mechanisms of the dysfunction.
This pro-oxidant issue may have had dire consequences in another clinical trial that investigated L-arginine immediately following heart attack (Schulman, JAMA, 2006). In this study, L-arginine (9 grams per day) was administered within 48 hours of patients having a heart attack; the rationale was the donation of nitric oxide may improve blood flow and outcomes following the heart attack. Unfortunately, more people in the L-arginine group died! This finding, while a striking finding for a nutritional intervention, is not surprising if you consider the underlying biochemistry. A heart attack is an extremely pro-oxidative event; as blood flow is returned to the heart muscle reperfusion injury results from the heart muscle cells returning their metabolic function. Adding a donor of nitric oxide into a pro-oxidative environment appears to lead to the production of more reactive nitrogen species, and thus may impair function more than improve function. Although I can’t be certain, my speculation is that the 48 hour window following the heart attack was just too vulnerable of a period to add L-arginine.
Finally, some good news. Martina et al. appear to understand the underlying biochemistry quite well, as they evaluated L-arginine combined with the potent antioxidant n-acetylcysteine (NAC) (Martina et al. Diabetes Care. 2008). Combined, L-arginine and NAC (1200 mg + 600mg twice daily for six months) appeared to not only reduced blood pressure in participants with diabetes and high blood pressure, but also improved antioxidant status, reduced oxidized LDLs, lowered C-reactive protein, and reduced biomarkers of endothelial modification! To me, this study is one the more profound clinical trials I have seen in some time, as the investigators demonstrated good understanding of a complex antioxidant/oxidant balance, and demonstrated it is possible to not only achieve blood pressure reduction from L-arginine, but also impact the underlying dysfunction.
Pycnogenol® is a propriety nutritional supplement derived from the bark of the Maritime Pine tree. This readily available supplement is an antioxidant polyphenol mixture that has been evaluated in clinical trials for hypertension, blood glucose lowering, and in models of endothelial dysfunction. Specifically investigating endothelial dysfunction, Liu et al. administered 100mg per day to 59 participants with high blood pressure, and measured their production of nitric oxide and their need for blood pressure medications (Liu et al. Life Sciences. 2004). After three months of treatment, nitric oxide production was significantly increased in the Pycnogenol® group, and more than half of the participants were about to reduce, or stop, their blood pressure medications during treatment. See Complementary Corner July 2007 for more detailed information on other actions of Pycnogenol®.
Clinical researchers Stirban et al. clearly demonstrated benfotiamine (1050 mg/day), a synthetic form of the B vitamin thiamine, reduces oxidative stress and improves endothelial function when people were fed a highly glycosylated meal (Stirban et al. Diabetes Care. 2006). Benfotiamine also appears to be an effective treatment for neuropathy, possibly also due to its ability to reduce the effects of glycosylation, although larger clinical trials are needed in this area.
Although not yet definitively tested in clinical trials, the food spice turmeric appears to be a potent antioxidant, and is especially effective at reducing the oxidation of lipids. Researchers Rukkumani et al. have published numerous papers detailing their findings that turmeric appears to not only reduce the oxidation (peroxidation) of lipids directly, but it also appears to protect the liver from excess consumption of already peroxidized fats (i.e., from high-temperature cooking like baking, broiling, grilling) (Rukkumani, et al. J Med Food. 2005 & Rukkumani et al. Phytother Res. 2003.) There may be good health reasons for why this culinary spice has been in the diet of Indo-Asian cultures for centuries!
Medications - Statins/Red Yeast Rice
Although not the most popular class of medications for patients, statin medications, e.g. simvastatin, used for lowering LDL cholesterol, appear to improve endothelial function, possibly by protecting LDLs from oxidation (Ceriello et al. Circulation. 2002). Both short- and long-term use of statins appear to reduce endothelial modification by reactive nitrogen species, and improve blood flow. Similar benefits have been demonstrated with natural source of “statins”, or Red Yeast Rice, as they share the identical mechanism of action (Zhao, et al. Circulation, 2004). Regardless of your treatment choices, maintaining LDL cholesterol at a good level (between 75-100 mg/dl) is a critical step in improving endothelial function, and possibly to regressing any atherosclerotic disease that is present.
Your endothelium is not to be taken for granted, and in fact, it serves as a vital protective layer that protects your larger vascular structures from more damage. Dietary factors clearly impact endothelial function, with high-fat, high-sugar content, and highly glycosylated foods being the most harmful. Nutritional supplements like L-arginine and NAC, benfotiamine and Pycnogenol® have all demonstrated the ability to reduce endothelial dysfunction, and in some cases, reduce blood pressure, however caution is warranted for using some supplements, such as L-arginine by itself, and dietary change should precede any supplementation. Finally, lowering LDL cholesterol, reducing its susceptibility to oxidation, whether through medications, supplements or dietary means, also appears critical to protecting your inner most layers!
The good news is, with good dietary choices, good blood glucose and lipids control, and appropriate supplementation, endothelial function does appear to improve, and substantial improvements in nitric oxide production, reductions in blood pressure, and medication use are achievable.
In health - Ryan Bradley, ND, MPH