May 19, 2022

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Diabetes is a deadly lifestyle disease that continues to plague humanity.

Diabetese is a lifestyle disease that continues to plague humanity.

Diabetes is a disorder in which the body’s cells fail to take up glucose from the blood. Tissues waste away as glucose-starved cells are forced to consume their own proteins. Diabetes is the leading cause of kidney failure, blindness, and amputation in adults. Almost all the increase in diabetes in the last decade is in the 85% of diabetics who suffer from type II, or “adult-onset,” diabetes. These individuals lack the ability to use the hormone insulin.

Your body manufactures insulin after a meal as a way to alert cells that higher levels of glucose are coming soon. The insulin signal attaches to special receptors on the cell surfaces, which respond by causing the cell to turn on its glucose-transporting machinery.

Individuals who suffer from type II diabetes have normal or even elevated levels of insulin in their blood, and normal insulin receptors, but for some reason the binding of insulin to their cell receptors does not turn on the glucose transporting machinery like it is supposed to do. For 30 years researchers have been trying to figure out why not.

How does insulin act to turn on a normal cell’s glucose transporting machinery? Proteins called IRS proteins (the names refer not to tax collectors, but to insulin receptor substrate) snuggle up against the insulin receptor inside the cell. When insulin attaches to the receptor protein, the receptor responds by adding a phosphate group onto the IRS molecules. Like being touched by a red-hot poker, this galvanizes the IRS molecules into action. Dashing about, they activate a variety of processes, including an enzyme that turns on the glucose-transporting machinery.

When the IRS genes are deliberately taken out of action in so-called “knockout” mice, type II diabetes results. Are defects in the genes for IRS proteins responsible for type II diabetes? Probably not. When researchers look for IRS gene mutations in inherited type II diabetes, they don’t find them.

The IRS genes are normal. This suggests that in type II diabetes something is interfering with the action of the IRS proteins. What might it be? An estimated 80% of those who develop type II diabetes are obese, a tantalizing clue.

What is the link between diabetes and obesity? Recent research suggests an answer to this key question. A team of scientists at the University of Pennsylvania School of Medicine had been investigating why a class of drugs called thiazolidinediones (TZDs) helped combat diabetes. They found that TZDs cause the body’s cells to use insulin more effectively, and this suggested to them that the TZD drug might be targeting a hormone.

 

The researchers then set out to see if they could find such a hormone in mice. In search of a clue, they started by looking to see which mouse genes were activated or deactivated by TZD. Several were. Examining them, they were able to zero in on the hormone they sought. Dubbed resistin, the hormone is produced by fat cells and prompts tissues to resist insulin. The same resistin gene is present in humans too. The researchers speculate that resistin may have evolved to help the body deal with periods of famine.

 

Mice given resistin by the researchers lost much of their ability to take up blood sugar. When given a drug that lowers resistin levels, these mice recovered the lost glucose-transporting ability.

Researchers don’t yet know how resistin acts to lower insulin sensitivity, although blocking the action of IRS proteins seems a likely possibility.

 

Importantly, dramatically high levels of the hormone were found in mice obese from overeating. Finding this sort of result is like ringing a dinner bell to diabetes researchers. If obesity is causing high resistin levels in humans, leading to type II diabetes, then resistin-lowering drugs might offer a diabetes cure!

 

On the scent of something important, resistin researchers are now shifting their efforts from mice to humans. Much needs to be checked, as there are no guarantees that what works in a mouse will do so in the same way in a human. Still, the excitement is tangible.

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