Diabetes Forecast

How Inflammation Affects Insulin Resistance

A researcher looks to immune cells for new clues

Mario Kratz, PhD
Research Assistant Professor Fred Hutchinson Cancer Research Center
ADA Research Funding
Clinical Translational Research Award

Inflammation is a familiar phenomenon. Here's what happens beneath the surface: Imagine cutting your fingertip with a dirty knife. Bacteria from the blade enter the wound, where they run into special "sentinel" immune cells that act as watchdogs in the body. The cells are covered with sensitive receptors that recognize an invading cell, like a bacterium, and call for help.

That's when the immune system swings into action. The signs of battle are visible from outside the body: The finger turns red, swollen, and warm; there may even be a little bit of pus. The inflammation is a sign your immune cells are responding aggressively to the infection. "From being harmless sentinel cells, they become specialized warriors," says Mario Kratz, PhD, a researcher at the Fred Hutchinson Cancer Research Center in Seattle. "It's a well-organized, cool process that tends to be strong—and limited in its time frame."

Once the invader is defeated, in other words, the active immune cells are replaced by passive guardians, ready for the next attack. But not always. With the help of a grant from the American Diabetes Association, Kratz is studying the links between inflammation and diabetes. In the past six or seven years, research in mice has demonstrated a strange phenomenon. In obese mice, scientists have found an unusually high concentration of immune cells in fat tissue. "It's almost as if there was an infectious agent in fat tissue that triggers the same response as if you had cut your finger," Kratz says.

Unlike with an infected cut, though, a chronic, low-grade inflammation appears even when there's no underlying infection and no sickness, like a cold or flu, to prompt a typical immune response. "It's associated particularly with obesity and seems to play a role in all of the major diseases—heart disease, diabetes, and certain cancers," says Kratz.

Stranger still, the immune cells aren't just watching; they're activated, ready to take on an invader that isn't there. Just as in humans, the obese mice with chronic inflammation were more likely to become insulin resistant. Insulin resistance is a key component in the development of type 2 diabetes; if the body's cells don't respond to insulin by absorbing sugar, or glucose, from the blood, the consequences can be disastrous.

But the initial mouse experiments left a major question unanswered: Was inflammation causing the insulin resistance, or was it the other way around? To find out, researchers bred mice that lacked the ability to make certain immune cells. Such mice wouldn't survive long outside a sterile lab, but when they were fed a special diet designed to make them obese, they had no signs of inflammation—and no insulin resistance or diabetes. "That strongly suggests it's the inflammation response that causes insulin resistance, not just the fat itself," Kratz says. "It's totally a paradigm shift. Now it seems pretty clear that inflammation plays a major role in the development of insulin resistance."

For researchers, the connection between insulin resistance and inflammation has made the past few years a veritable roller-coaster ride. "There's a game-changing paper coming out every month or so," Kratz says. "But 95 percent of the work has been done in mouse models." While rodents are a time-honored test bed for new observations and theories, it's not always clear that what happens in mice holds true for humans.

That's why Kratz is working to test the connection between inflammation and insulin resistance in people. In a series of pilot studies, he took fat samples from just underneath the skin of volunteers. Using a sophisticated machine called a flow cytometer that can separate and identify individual cells, he did a sort of cell census, counting how many of each cell type were in the samples.

The results were promising. "We got a wealth of data that tells us how many of each cell is in each person's fat tissue," Kratz says. "It gives us insight into whether there is inflammation, and which cells are the major players."

In particular, Kratz paid attention to the immune-system watchdog warriors, called macrophages. He discovered that the presence of a certain macrophage was a red flag. "If there are a lot of a very specific type of macrophage, then people are insulin resistant, and if there are relatively few of these cells, then they're insulin sensitive—no matter how much fat they have in their body," says Kratz.

Now, Kratz is taking his study a step further. People with fat deep inside the body tend to have more serious problems with insulin resistance than people whose fat is concentrated closer to their skin. Working with surgeons to collect fat samples from the abdomens of people undergoing weight-loss surgery, he'll see if there's a change in inflammation levels as patients lose weight after surgery. That will bring Kratz a step closer to unraveling the connection between inflammation and insulin resistance—and, perhaps, a step closer to preventing the onset of type 2 diabetes.

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