Insulin Receptor Downregulation

A recent study at the Mayo Clinic in Florida has shown that removing the enzyme that degrades insulin in mice improves their glucose tolerance when they're young. But when they get older, the same treatment causes them to become diabetic.

The enzyme in question is called, not very creatively, insulin-degrading enzyme, or IDE. When you secrete insulin after eating carbohydrate (or protein), if there were no way to remove insulin from your system, you'd end up with more insulin than you needed after the blood glucose (BG) levels had returned to normal. So in healthy people, there's a delicate balance between the amount of insulin being put into the system and the amount that is removed.

IDE isn't the only way insulin levels can be lowered, but it's an important one. And because genetic manipulation is difficult in humans and has potentially damaging consequences, the researchers are developing drugs that inhibit IDE either totally or partially and are planning human trials of such drugs.

The researchers showed that mice who lacked IDE through genetic manipulation had higher insulin levels and were "more efficient" at controlling their BG levels.

But as these mice aged, they became insulin resistant, gained weight, and lost control of their BG levels. In other words, they developed classic type 2 diabetes.

The focus of news reports of the Mayo research is on the possibility of developing drugs that would inhibit IDE, a new approach to controlling type 2 diabetes. But I think the research is interesting for another reason: It suggests that anything that increases insulin levels in the short term may result in insulin resistance and type 2 diabetes in the long term.

Chronic high insulin levels in these mice made them become diabetic. You can also produce higher insulin levels by injecting insulin or by taking sulfonylurea drugs that cause your pancreas to secrete more insulin. Could long-term use of sulfonylureas or insulin cause a loss of effectiveness for the same reason?

Another thing that increases insulin levels is eating carbohydrate foods. And for the past 40 years or so, Americans have been bombarded by messages urging them to eat less fat and more carbohydrate. Many have. And diabetes rates are skyrocketing.

Someone with a healthy pancreas that is able to cope with huge carbohydrate overloads can tolerate them, at least in the short run. But as we age, everything tends to wear out. And that's when type 2 diabetes becomes even more prevalent.

The elderly mice were found to have fewer insulin receptors on their cells. With fewer receptors, they needed more insulin to do the same job. In other words, they had insulin resistance.

This downregulation of a receptor when the substance it binds is present in excess is not unusual. Nor is the opposite, upregulation of a receptor when the substance is present at low levels. The cells are constantly trying to maintain the status quo, avoiding being overwhelmed by a sudden influx of something or not getting enough of something that is rare.

A classic example of this is the adaptation to caffeine. Caffeine normally binds to receptors called adenosine receptors. When the adenosine receptors bind adenosine, you tend to get sleepy. Caffeine can also bind to the adenosine receptors and block the binding of adenosine. But the caffeine-receptor complex doesn't make you sleepy. So by keeping adenosine from binding, the coffee makes you feel more alert.

There's just one problem with this. When you ingest caffeine regularly, the body starts making even more adenosine receptors, hoping it can bind the usual amount of adenosine. This means that if you drink caffeinated beverages chronically, you'll need even more caffeine to block the sleep-inducing receptors. Then the body makes more receptors. So then you have to ingest even more caffeine to feel more alert. Eventually, you have to ingest caffeine just to stay awake. You're addicted.

A similar phenomenon could be occurring with insulin. When insulin levels are always high, the body may produce fewer insulin receptors, causing insulin resistance, meaning you need those high insulin levels in order to have normal responses. This theory was proposed in the past, but most evidence suggested that insulin resistance is caused by postreceptor effects, meaning effects that occur after insulin binds to the receptor.

But what if short-term hyperinsulinemia causes insulin resistance via postreceptor effects but very long term hyperinsulinemia causes insulin resistance via downregulation of the receptors? The mice who developed diabetes were 6 months old, but this is fairly elderly for a mouse. Mice generally live only 1 or 2 years, sometimes a little more, depending on the breed.

If so, then eating a high-carbohydrate diet for years and years might cause diabetes, especially if carbs were eaten pretty constantly throughout the day. People eating traditional high-starch diets and maintaining traditional lifestyles, with lots of exercise, don't all develop diabetes. But they don't usually snack all day, and their active lifestyles burn a lot of glucose, so their BG levels don't stay high for very long. And when BG levels aren't high, insulin secretion isn't stimulated.

Many Americans, on the other hand, seem to be constantly snacking. That means constant higher-than-fasting BG levels, even when those levels are not diabetic. Higher BG levels stimulate the secretion of insulin. And constant hyperinsulinemia could cause downregulation of the receptors.

When you're fasting, insulin is normally secreted in pulses, about every 15 minutes. Some researchers have found that pulsatile insulin secretion doesn't increase insulin resistance, but constant infusion of insulin does. Normally the body is in fasting condition overnight and before the next meal. But if one snacks constantly, the insulin levels might be constantly high, with less pulsatility.

A substance losing its effectiveness with time is not limited to insulin. High doses of niacin, much larger than those needed for its vitamin effects, are very effective in reducing lipid levels, especially free fatty acids. Niacin also increases levels of HDL.

A continuous infusion of niacin for more than 5 hours lowered free fatty acids. But when the infusion was increased to 24 hours, there was a "rebound" effect, in which the free fatty acids increased to the level of the controls. In this case, the rebound was not caused by downregulation, but by an increase in lipolysis, the hydrolysis of fats to produce free fatty acids. The researchers showed that this was caused by changes in gene expression.

But the result was the same. Constant high levels of a substance cause the body to try to reduce those levels. In this case, free fatty acids. In the case of insulin resistance, the increased glucose uptake that results from insulin action.

In the case of niacin, researchers found that during the niacin infusion, glucose metabolism was improved. But when they stopped the infusion and the free fatty acid levels rebounded to much higher than normal, insulin resistance resulted.

So many things can cause insulin resistance it's very difficult to tease out the most important causes. But every clue helps. Sometime someone will figure it all out. In the meantime, even if you're not ready to try a low-carbohydrate diet, limiting snacks and limiting the amount of carbohydrate you eat would be a good idea.