Diabetes Forecast

Probing Muscle Cells for Clues to Insulin Resistance and Diabetes

By Andrew Curry ,

Zhengping Yi, PhD

Bioanalytical Chemist and Biologist,
Arizona State University

Insulin Resistance
ADA Research Funding
Clinical Translational Research Award

Body builder or couch potato, we all need muscles to keep us going. From bulging biceps to organs like the heart, stomach, and tongue, we're mostly muscle, contracting and relaxing constantly.

All muscles aren't the same, though. Skeletal muscles, the ones that attach to our bones, relax and contract to move the body around. Yet they do a lot more than move. Skeletal muscles are "also very important because they help remove sugar from our blood after meals," says Arizona State University researcher Zhengping Yi, PhD. This secondary role makes intuitive sense: The muscles that keep us moving need fuel the most, so it's efficient to keep the body's supplies of glucose close at hand, within the muscle itself.

Getting the fuel to skeletal muscle requires a chain of signals deep inside the body's cells. After a meal, the amount of glucose in the blood goes up. That prompts the pancreas to start pumping out insulin, which in turn tells muscle cells to slurp up and save blood glucose, storing it to use the next time you lift a barbell, walk around the block, or take a bike ride.

Sometimes, though, there's a failure to communicate at the molecular level. Yi is interested in a particular break in the signal chain: when the skeletal muscles don't absorb glucose from the blood despite the flood of insulin in the bloodstream giving them the green light. At its most basic, that failure is what doctors call insulin resistance. "In lean, healthy people, there's sensitivity to insulin. In an obese person, that sensitivity drops, and in diabetic [patients] there's almost none," Yi says. Over time, that can have dire consequences.

Insulin resistance is a major contributor to type 2 diabetes. As the pancreas struggles to get the attention of the muscles, it "just keeps producing more and more insulin," says Yi. But to no avail: As time goes on, blood glucose concentrations rise, and the overworked insulin-producing cells in the pancreas burn out and fail.

Could there be something different about insulin-resistant muscle cells that is blocking the signaling? To find an answer, Yi is tapping the power of proteomics, a budding field of research that made its first appearance in the 1990s. Proteomics looks at the function of proteins from within the body's cells.

Proteins make the body tick. The long strings of twisted, folded molecules are some of the most basic things our cells produce, and their interactions—multiplied in each cell, thousands upon thousands of times—keep cells working together. "Proteins are molecules in the human body that dictate how signals are transmitted," Yi says. "When they become activated, they can transfer a signal downstream or recruit another protein to complete a task."

Yi suspects that the proteins that "hear" the signal to absorb glucose from the blood are broken in people with insulin resistance and diabetes. "There are very complicated networks in the cell to complete this insulin function," he says. "If proteins are dysfunctional, cells may not be able to transfer the signal downstream."

To pin down the problem, Yi is recruiting volunteers and taking pieces of muscle tissue from their quadriceps, the big muscles on the upper thighs. It's a tiny amount—a few thousandths of an ounce—but enough to conduct the proteomic research Yi specializes in. "A lot of participants are interested because family members or friends have diabetes. They want to know, 'How can I prevent diabetes for my children later on?' " Funded by a three-year grant from the American Diabetes Association, Yi has begun with muscle biopsies of people with skeletal muscle that responds well to insulin. Once he knows how the protein signaling should work, he'll look at samples from obese volunteers and those with type 2 diabetes to figure out what, if anything, is different about their skeletal muscle. "We want to understand how these networks function in the lean, healthy state, and how they look in people with diabetes," Yi says.

The ultimate goal is to isolate any areas where insulin-resistant muscle proteins don't match the healthy ones, and then target them with drugs or other therapies—and keep people from developing type 2 diabetes to begin with. Says Yi: "We have to understand why they're different, and maybe in the near future we can design a drug or an exercise intervention to reverse insulin resistance and keep cells functioning normally."

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