We think of insulin resistance as a bad thing. But could it sometimes be a good thing?
Christopher Nolan and colleagues think so. And some others agree.
These researchers argue that under conditions of "overnutrition," meaning eating more than your body requires, insulin resistance (IR) is a protective mechanism that keeps the heart cells from taking up too much glucose. We need glucose, but we also know that glucose can be toxic when it's present in excess.
However, we tend to think of blood glucose (BG) levels as being the only important factor. In fact, the glucose levels inside cells are also important. In general, when BG levels are high, the levels inside the cell are also higher than normal because of mass action. Hence the body has evolved a mechanism to protect some tissues, mostly skeletal and cardiac muscle, from taking up too much glucose when the BG levels in the blood are high. This is insulin resistance, and it means the extra energy is diverted to fat instead.
However, not all cells require insulin to take up glucose, and hence IR won't protect these tissues. Such tissues include the endothelial cells that line our blood vessels and may be one reason high BG levels contribute to vascular disease. Thus reducing BG levels when they're too high is essential for good health.
But how we reduce BG levels may also be important. Some treatments like the drug metformin reduce the amount of glucose the liver produces through gluconeogenesis and ships out into the blood. This should be beneficial.
Some drugs like the glitazones seem to increase the number of new and active fat cells, which can take fatty acids and glucose out of the blood. This reduces the BG levels but also can lead to weight gain.
However, other drugs like insulin, or the sulfonylureas that make us secrete more of our own insulin, overcome the IR and hence force more glucose into the muscle cells. This will reduce our BG levels and make us and our physicians happy. But in the long run, is it damaging the heart cells? That's what Nolan and colleagues argue. And it could be one reason that reducing BG levels doesn't have a huge effect on heart disease.
In other words, treatments designed to overcome what is believed to be the primary cause of type 2 diabetes (in addition to genetics) may not be the best for everyone. And research into new drugs that would reduce IR might not be as useful as research into other types of treatment.
Nolan and colleagues argue that such treatments are especially harmful for people with massive IR who require massive amounts of insulin to overcome it. And if this subset of patients are harmed by intensive treatment with IR-reducing drugs, then the results of clinical studies that included such patients would be unclear. Some patients would be helped and others would be harmed.
This could explain the results of the ACCORD trial, which some interpreted to mean that aggressive BG lowering was harmful. Later analysis showed that those who were harmed were those who got aggressive treatment but it wasn't effective. In other words, the harm caused by the drugs was not offset by the benefit of lower BG levels.
Unfortunately, the best approach, according to Nolan and colleagues, is to focus on the other cause of type 2 diabetes: overnutrition. This is not good news for those of us born with excessive appetites. It's very difficult to eat less when your body is screaming for more food. But it's one reason many people with huge appetites find that low-carbohydrate diets are useful. Such diets tend to reduce appetite because the high fat content slows down gastric emptying so you feel satisfied for hours after eating. This doesn't happen to everyone, but it does occur with most. It did with me.
Unfortunately, too many people diagnosed with type 2 diabetes want to be able to take a pill and continue to eat the standard American diet that everyone else eats. This may work in the short term, but Nolan and colleagues argue that such an approach causes harm in the long term.
What if a new drug that reduced IR to normal came on the market. Would I take it? I used to think this would be my dream drug, letting me eat like all my friends and neighbors. But now I'm having second thoughts. As so many research papers conclude, "More research is needed." Let's hope some of that research addresses the question of IR as harmful or protective.
Researchers don't routinely measure glucose levels inside cells, but technology is advancing so quickly that this might become feasible and affordable in the future. Also useful would be techniques for measuring IR in different tissues. For example, IR in fat would keep you thinner, but it would also reduce fat's ability to take up some of the excess glucose for storage as fat.
More research is needed.
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11 months ago