High BG Affects Gene Expression

Patient Expert

Some people think that when it comes to diabetic complications, the only thing that matters is your hemoglobin A1c level (A1c). This is the test that is supposed to measure your average blood glucose (BG) level over the past several months.

High BG levels form what are called advanced glycation end products, or AGEs, and these long-lived products seem to gum up the works and cause diabetic complications, as well as normal aging.

Because it's an average, you can get the same A1c result if you have a constant BG level of 100 mg/dL (an unlikely event, but I'm using it to simplify), or if you spend half your time at 50 and half your time at 150 mg/dL. Because most studies of complication rates, for example the famous Diabetes Control Complications and Trial (DCCT), use only the A1c as a measure of control, many people think that's all that matters.

In fact, that's not true at all. Since then, some studies have suggested that the amount of glucose variability is as important as, or more important than, the average BG levels.   Others have suggested that it's not just the AGEs but three other pathways as well that contribute to long-term diabetic complications.

And now, a new study has suggested that even short-term elevations in BG levels can cause so-called epigenetic changes in your genes that persist for a long time after you've brought your BG levels back to normal.

This would explain the persistence of beneficial effects of good BG control many years later, as well as the persistence of a higher rate of complications in people with poor control after their control had improved. For example, a follow-up study of patients in the famous DCCT study showed that the patients who had better control during the study had fewer complications years later, when their A1c levels were almost identical to those who had been in the control group.

In the new study, a group of scientists in Australia and the United States, led by Assam El-Osta, exposed human epithelial cells to high glucose levels (30 mM or about 540 mg/dL) for 16 hours. They then transferred the cells to normal glucose levels (5 mM or about 90 mg/dL) for 6 days.

When they did this, they found that even after 6 days, the expression of some genes was increased in the cells exposed to high BG levels compared with the expression of those genes in cells that had been exposed to glucose at only 90 mg/dL for the entire time.

The effect was dose-related: the higher the glucose level during the 16 hours, the greater the expression of the genes. One of the genes whose expression was increased is one that increases inflammation.

The increase in the expression of the genes did not occur under high-glucose conditions when the experimenters prevented the formation of superoxide accumulation. Superoxide is a highly reactive compound, a free radical, or reactive oxygen species (ROS), thought to cause cell damage as well as some beneficial effects like killing invading bacteria. High BG levels increase the levels of ROS.

To show that these results were not an artifact caused by using cell suspensions, the researchers then studied the same thing in nondiabetic mice. The mice were exposed to 20 mM glucose (360 mg/dL) for 6 hours and then killed (you can see why they didn't try this in humans) after 2, 4, and 6 days of normal BG levels.

They found the same thing. Transient hyperglycemia (high BG levels) induced changes in the mouse genes that persisted for the 6 days of normal BG levels.

So what does all this mean for us? Well, it certainly suggests that it's not good to let your BG levels go over 500 for hours at a time. But then most of us, even those with poor control, don't have levels that high for that long. However, when I was first diagnosed with an A1 of 16 (probably equivalent to an A1c of about 13; this was some time ago when they mostly used a different test), my fasting levels were in the 300s and my BG levels did go over 500 when I ate high-carb ADA-recommended meals.

But how about letting your BG levels go up to 180 for a couple of hours after meals? The fact that the effect was dose related suggests that the higher your BG levels go for some hours (16 hours for the cells in culture but only 6 hours for the mice), the worse the effect will be.

We won't know for sure if lower exposure times will have the same effect until someone does that experiment.

This finding does suggest an explanation for what people call "metabolic memory," the fact that previous exposure to high BG levels can have an effect some time later. If some genes were changed permanently after exposure to high BG levels (the 6 days of the experiment is hardly permanent), you could continue to see deleterious effects even with long periods of good control.

We won't know how long it would take for the expression of the genes the researchers studied to return to normal, assuming they finally do.

But until these studies are done, it makes sense to try to stay on the wagon, to avoid being "really really bad" for a couple of days on the theory that you can be "really really good" next week, the result won't show on your A1c, and the A1c is all that matters.

It's possible that the damage won't be great. But it could persist a lot longer than we expect. We're always having to weigh the possibility of physiological bad effects of dietary indiscretions with the probability of psychological bad effects if we simply never eat any of the foods we're craving.

One solution is to eat the foods we shouldn't at the time of day when we have the least insulin resistance, or when we're getting the most exercise. And then to eat less of some other foods we'd normally eat to balance the total carbs, and only reasonable amounts of the foods we crave. Eating nothing but lettuce for a week and then eating two gallons of ice cream at one sitting probably isn't a great idea.

Diabetes isn't easy. But at least we are given choices, and we do have some control over our health.