Saturday, October 10, 2015

Does Insulin Resistance Protect the Heart?

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.


  1. This is brilliant and so helpful, thanks.

  2. Thanks, Judi. I'm here to try to help.

  3. Peter at Hyperlipid has a series of posts on "Physiological" Insulin Resistance, see the sidebar. IMO this is more evidence for the same - IR evolved as an adaptive mechanism for food partitioning and food storage and only when it becomes chronic does it cause problems. It wouldn't matter much if it disrupts lipid metabolism (small dense LDL etc.) as long as the broken particles were rapidly going into store.

    In my case I'm pretty sure the insulin was out of phase with the blood glucose, and when the excess insulin dropped the BG too far I HAD TO EAT RIGHT NOW!!! before I literally fell over.

    This is pretty much the biggest thing that low carbing fixed - without postprandial BG spikes I got no post-postprandial insulin spikes, and now I think nothing of going 6 - 8 hours and often 10 hours or more without the slightest need to eat, whatever I'm doing.

    Despite all that I never gained weight, it took real dedication from a dietician carefully removing every scrap of fat from my already high carb diet, except for some "heart healthy" Omega 6 margarine and "vegetable" oil to make me fat.

    Tell that to most dieticians and a depressing number of doctors and nurses and they will look at you as if you'd grown extra limbs, and explain patiently that diabetes is caused by being fat, and being fat is caused by eating fat, and that CVD is caused by "cholesterol" which is caused by eating fat. So I must have been lying about my diet, and now that I have improved my health I must finally be complying . . .

    At last there appears to be a critical mass of researchers now looking at what ACTUALLY happens.

  4. Insulin out of phase with carbs is typical of type 2: "Too much too late." I almost never ate breakfast, but when I had to be in newsroom at 7 to do the wire desk, I'd reward myself with a doughnut. Almost exactly 4 hours later, I was convinced I'd drop dead if I didn't eat something. I could set my watch by it. This is because the phase 1 response is missing so BG gets higher and then you secrete phase 2 on the basis of this high BG, which the body assumes was despite a phase 1 response and hence secretes too much.

    1. Yup, and I bet you were told (or discovered for yourself) to eat more carbs more regularly, when the actual "cure" is to eat fewer carbs so the insulin never spikes?

      My current "big picture" is that many genes evolved to be helpful in totally different circumstances. The modern (food) environment causes these genes to be locked on, and your mission, should you choose to accept it, is to change the environment to change the gene expression.

      We are better than the general population at storing food to guard against famine, probably the increase in carbs especially fructose and the decrease in healthy saturated fats and their replacement with Omega 6 is a strong signal that hunting is getting hard and winter is coming so IR must be switched on. But winter never comes and we go on storing food until we burn out our betas, which takes less time for some than for others.

      Reversing the diet signals that normality has returned and the stored fat is no longer required to fuel us through starvation or migration to where the food still is. To unstore the fat IR gets switched off so demand for insulin drops.

      I'm less certain that developing drugs to change the end result without changing the pathway further down would have the same effect on the metabolism. Metformin being an exception since it appears to change many metabolic factors right down to the mitochondria, and aids rather than impedes food partitioning.