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A Common Type 2 Drug May Improve Insulin Resistance

Zhenqi Liu, MD
Photo courtesy of University of Virginia

Zhenqi Liu, MD

Occupation
Endocrinologist, University of Virginia School of Medicine

Focus
Insulin Action

American Diabetes Association Research Funding
Translational Research

Doctors pay a lot of attention to the body’s biggest blood vessels. That’s understandable: When the arteries and veins that move blood in and out of the heart fail or clog, the result can be a heart attack or stroke.

But just as freeways wouldn’t be much good without off-ramps and surface streets, the body uses a system of smaller blood vessels, called the microvascular system, to transport blood to and from individual cells. The network of tiny tubes—most are thinner than a human hair—reaches through every part of the body. “For muscle cells to get all the oxygen and nutrients they need, they rely on microvasculature,” says Zhenqi Liu, MD, an endocrinologist at the University of Virginia School of Medicine in Charlottesville.

Hormones, too, rely on the microvascular system to reach their final destination. Those include insulin, which can’t do its job unless it’s transported through the small blood vessels to cells.

Insulin is best known for its role in signaling the cells to take in glucose from the blood. But it also plays a role in blood flow, signaling blood vessels to expand, or dilate, allowing more blood to pass through the blood vessels and reach cells. For reasons researchers still don’t understand, that response is dulled or absent in the small blood vessels of many people with type 2 diabetes, a phenomenon called microvascular insulin resistance. “Their blood vessels don’t dilate,” says Liu. The result is less blood flowing to the body’s cells.

People with type 2 diabetes also tend to have less-extensive networks of small blood vessels to feed blood to cells than people without diabetes. The combination of less blood flow and fewer blood vessels “can explain a lot, clinically,” Liu says. People with type 2 get tired more easily, and their heart muscles are often weaker, potentially the result of cells chronically starved for oxygen and other nutrients.

With the help of a grant from the American Diabetes Association, Liu is trying to better understand how insulin—both the stuff the body makes naturally and the drug people with diabetes inject—affects the microvascular system and how that response can be improved. His focus is on a class of injectable drugs called glucagon-like peptide-1 receptor agonists, known as GLP-1s. Examples include liraglutide (Victoza), exenatide (Byetta), semaglutide (Ozempic), and dulaglutide (Trulicity).

Though the drugs were originally designed to help people with type 2 diabetes produce insulin, researchers found that they had a positive effect on the health of large blood vessels. They can reduce the risk of cardiovascular problems, such as heart attack and stroke. “We don’t know exactly why yet,” Liu says.

Liu is looking at whether GLP-1 receptor agonists also have beneficial effects in small blood vessels. Research in animals has already shown that the drugs improve how well the body’s smallest blood vessels dilate in response to insulin. Now he’s looking at how the drugs work in humans to see if the effects are similar. “The long-term idea is to improve microvascular responses to insulin and the amount of capillaries in tissue,” he says.

To do so, he injects volunteers with bubbles of an inert gas through a catheter inserted into a vein. The bubbles are smaller than a red blood cell, but they are large enough that they can’t pass through blood vessel walls. “They can flow where the red blood cells go, but they’re big enough to stay in the blood vessels,” Liu says.

With a special ultrasound scanner, Liu can use the bubbles as a tracer, mapping the amount and location of microbubbles in the body painlessly. He’s comparing two groups of people with type 2 diabetes and insulin resistance—some of whom are injecting insulin. One group is given GLP-1 receptor agonists, while the other is assigned to a supervised exercise program. Liu’s team scans their blood flow in both heart and skeletal muscle before and after. The goal is to see if the drugs make a difference in the way the microvascular system works

So far, there are indications that the benefits of GLP-1 receptor agonists go beyond the body’s big blood vessels. Liu’s initial results show that small blood vessels expand readily in response to either insulin or GLP-1 signals in healthy humans, but in insulin-resistant people, the vessels only expand in response to GLP-1 signals. In a pilot study, insulin-resistant animals taking GLP-1 receptor agonists for several weeks had more capillaries than control animals. “It’s both a functional improvement and structural improvement,” Liu says.

There’s lots more research to be done on GLP-1 drugs. But Liu’s research shows that they may have beneficial effects on all levels of the circulatory system, from macro to micro. “They may increase the function and number of small blood vessels and deliver more oxygen, nutrients, and hormones to improve tissue and organ vitality and function,” Liu says.

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