Thursday, March 30, 2017

Can a Drug Reverse Insulin Resistance?

A new drug seems to reverse insulin resistance in fat mice, who have normal blood glucose (BG) levels when taking the drug. Of course, we've all seen mice cured of diabetes kazillion times, but I find the approach in this case interesting.

To understand what the drug does, you have to understand a little about what causes insulin resistance, which I'll try to outline. When insulin binds to the insulin receptors on target cells, for example muscle cells, the insulin receptor phosphorylates itself. This means it adds phosphate groups. As a result, a complex chain of reactions is triggered, culminating with glucose transporters called GLUT-4 moving to the cell membrane. This allows glucose to get into the cell.

In general in the body, when something triggers a reaction, something else then slows down or stops the reaction so it won't get out of hand. For example, if you eat carbohydrate, which stimulates insulin secretion, BG falls, and that stimulates glucagon secretion, which keeps the BG from falling too low. If you get an infection, you produce chemicals that cause inflammation. But then if things are working properly, you produce chemicals that stop the inflammation when its job is done.

In the case of the insulin receptor, another enzyme called a phosphatase removes the phosphate groups that the insulin receptor added, and this slows the action down. So it made sense to look for compounds that would inhibit the phosphatase so that a little insulin would have a longer effect.

In the last half of the 20th century, scientists were investigating the effect of vanadium compounds on people with diabetes, as there were reports that it lowered BG levels. The vanadium seemed to inhibit a phosphatase. Unfortunately, because phosphatases are involved with many systems in the body and the vanadium wasn't specific to the insulin receptor, giving people enough of the vanadium compounds to be effective caused too many side effects, and interest waned.

There are many different phosphatases in the body, and what is new about this recent study is that they targeted on specific phosphatase, called LMPTP for low molecular weight protein tyrosine phosphatase. Then they looked for a small molecule that would inhibit LMPTP, and they found one. Giving this drug to the mice, they found no side effects.

One interesting thing is that blocking LMPTP only in the liver, via genetic studies, improved BG control. When one has type 2 diabetes, the liver seems to be insensitive to insulin. When BG levels are low, the liver produces glucose. When BG levels go up, insulin is supposed to stop the liver from producing glucose. But that doesn't happen in type 2. So a drug that could make the liver more sensitive to insulin sounds promising.

In fact, as I noted here, insulin resistance might be protective for the heart. So increasing insulin sensitivity in the liver while retaining it in heart muscle might be just what we need.

Science magazines have been describing this research as if the cure for type 2 diabetes has been found. Far from it.

Reversing insulin resistance might "cure" diabetes in people whose primary defect was insulin resistance, as is often the case in obese people. The studies were done in diet-induced obese mice. But it takes at least two defects to produce type 2 diabetes: insulin resistance and a defect in beta cells that makes them unable to produce the extra insulin needed to overcome that insulin resistance. In people with very little insulin production left, even reducing the insulin resistance might not be enough.

Also, as noted before, these studies are in mice, and often mouse studies don't translate into human treatments. Taking a drug from "proof of concept" to a safe drug for humans is a long process.

Nevertheless, I think this approach is interesting enough to be aware of. Perhaps it will develop into something very useful for type 2.

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