Irl. B. Hirsch, MD
TCOYD Newsletter, Vol. 23, 2007

Understanding pro- and anti-oxidants, and their role in diabetes complications

In the past few years, much has been learned about why people with diabetes get complications from diabetes. These complications tend to involve tissues from the vascular system and are broadly defined as microvascular (involving the small blood vessels) and macrovascular (involving the larger blood vessels). Examples of the microvascular type include eye disease (diabetic retinopathy) and kidney disease (diabetic nephropathy) while those of the macrovascular type include problems with the heart and blood vessels leading to the brain (heart attack and stroke).

One other class of complication should be mentioned, those involving the nervous system, called “neuropathy”. There are many different types of neuropathies, but the one that patients most often complain about is pain and numbness involving the feet.

One of the greatest medical debates of the last century was the controversy whether, or not, high blood glucose, or poorly controlled diabetes, increased ones risk for one of these diabetes-related complications. It was not until 1993 that this question was definitively answered with a large American study, the Diabetes Control and Complications Trial.

An A1C level of 7% dramatically reduced one’s risk for microvascular disease and neuropathy. It wasn’t until the follow-up of this study reported in 2005 that those in the study with the A1C of 7% also had a tremendously reduced risk of macrovascular events. A similar study was published for type 2 diabetes in 1998, although in that study the benefits improved therapy did not result in fewer macrovascular complications.

So, if good glucose control makes a difference, how does this happen? This has been an interest of mine for a few years now. To understand the mechanisms we think are important, one also needs to appreciate the concept of “oxidative stress”.

First, we all remember that oxygen is critical for life. When we breathe oxygen, glucose combines with oxygen to form water and carbon dioxide (and ENERGY!). However, at times the oxygen can form free radicals (reactive oxygen species) if the glucose is too high, (or too variable, I would argue). The other term for these dangerous chemicals is “pro-oxidants”. Some amounts of pro-oxidants are normally found in the blood, but they are usually neutralized by other compounds (which you’ve probably heard of) called “antioxidants”. So even if there are too many reactive oxygen species, also called pro-oxidants, in the normal situation there are no problems since the anti-oxidants essentially “eat up” the bad guys.

Unfortunately, there are situations in human disease where too many reactive oxygen species take over. A few of these diseases include arthritis, Lou Gehrig’s Disease (also called amyotrophic lateral sclerosis, or ALS), and even aging. In these examples, there are not enough anti-oxidants to neutralize the pro-oxidants. When there are not enough anti-oxidants to “eat up” the pro-oxidants, the result is referred to as “oxidative stress”.

What does this have to do with diabetes and its complications? There have been 4 different chemical pathways discovered that seem to be responsible for the vascular complications of diabetes. Although these pathways are not directly— related to each other, it is interesting that these reactive oxygen species seem to fuel each one of these reactions so that the reaction end-products resulting in the complication is turned on by these pro-oxidants. While this may explain oxidative stress with microvascular complications, it also appears oxidative stress is important for the bad cholesterol, LDL-cholesterol, making it more likely to form a plaque or clot, responsible for heart attack and stroke. Oxidative stress, therefore, can lead to microvascular, neuropathic, and macrovascular complications.

So how does one improve, or “turn off” this oxidative stress? The most obvious way seems to be to take anti-oxidants. My guess is many of you reading this take vitamin E, vitamin C, betacarotene, and other anti-oxidants having heard somewhere that these supplements will improve your health. Indeed, research studies in test tubes have shown these vitamins can work as powerful anti-oxidants and turn-off oxidative stress. The problem is, the human trials have not shown benefit from using these supplements. In fact, there is evidence that those who take vitamin E may have an increased risk of heart attack and stroke! The explanation for this paradox is not known for sure, but is thought to involve the fact that vitamin E may reduce the absorption of statins we often use to treat high cholesterol [atorvastatin (Lipitor), simvastatin (Zocor), pravastatin (Pravachol), lovastatin (Mevacor), rosuvastatin (Crestor)].

So, if anti-oxidants aren’t the answer, is there anything we can do to improve oxidative stress? The answer is, maybe. There is currently a huge controversy about how glucose variability and how reducing the after-meal spikes may improve oxidative stress. While the research is promising, it is not yet conclusive. Still, there is enough evidence that many diabetes organizations around the world have recommendations for after-meal (postprandial) hyperglycemia. For example, both the American Association of Clinical Endocrinologists (AACE) and the International Diabetes Federation (IDF) recommend a 2-hour after-meal glucose no higher than 140 mg/dL. This is very difficult for some people, especially if they are starting higher than this or their HbA1C is above 7%. Still, this is all based on the research suggesting these high spikes are dangerous and by reducing their frequency and elevation we can have a better defense against oxidative stress and, therefore, complications of diabetes.

Finally, what this also means is that we should use the tools we have to prevent the spikes after eating. Perhaps the best strategy is simply reducing the amount of carbohydrate. No matter what medication you take, the greater the amount of carbohydrate the greater the glucose spike. If you don’t know how the carbohydrate affects your blood glucose, I encourage you to check two-hours after a large meal to see for yourself.

Of course, we have a variety of medications that specifically target the mealtime spikes. These medications include the oral drugs Prandin, Starlix, Precose, Glyset, and Januvia. Byetta, currently a twice daily injection, also targets the mealtime spikes. For people who take insulin, the insulins that work the best for reducing the glucose peaks include Humalog, NovoLog, and Apidra. Symlin, a newer medication which can be taken with insulin, will also smooth out the postprandial spikes.

Researchers are further examining the relationship between oxidative stress, complications, and glucose variability. The use of real-time continuous glucose monitoring is giving us an exciting tool which should allow us to make more discoveries about this important topic.

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