When a person with diabetes says they have a hard time exercising and performing daily activities that require movement, endocrinologist Jane Reusch, MD, takes it seriously. It’s a common and significant issue, as studies show people with diabetes generally have lower exercise and functional capacity, which are key indicators of health and mortality risk.
“Studies suggest that a decrease in functional status could mean nearly double the likelihood of dying prematurely. Your functional capacity is a potent predictor of longevity,” says Reusch, a professor in the Division of Endocrinology, Metabolism, and Diabetes at the University of Colorado Anschutz Department of Medicine.
As an internationally recognized physician-scientist and leader in diabetes care, Reusch has spent decades researching the potential physiological causes of exercise intolerance in people with type 1 and type 2 diabetes — particularly among women, who face higher cardiovascular risks — in collaboration with Judy Regensteiner, PhD, and Kristen Nadeau, MD, MS.
Reusch leads pivotal work across the CU Anschutz campus as co-director of the CU Diabetes Research Center, associate director of the Ludeman Family Center for Women's Health Research, director of the Research Studio Program at the Colorado Clinical and Translational Sciences Institute, and a leading diabetes physician and merit investigator at the Rocky Mountain Regional Veterans Affairs Medical Center.
More than 40 million people in the United States were estimated to have diabetes as of 2023, according to the Centers for Disease Control and Prevention. As a translational researcher, Reusch aims to help these patients by turning lab discoveries into real-world clinical changes. Through extensive collaborations with other researchers, Reusch and her colleagues have advanced knowledge about why diabetes may lead to decreased functional capacity and potential interventions, and they continue to investigate pressing issues such as the influence of glucagon-like peptide-1 (GLP-1) drugs.
“The heart and skeletal muscle are connected by a vascular network, and exercise intolerance in diabetes is a microvascular complication, at least in part,” Reusch says. “We’re trying to understand whether we can reverse this exercise intolerance.”
Jane Reusch, MD, third from right, and Judy Regensteiner, PhD, center, frequently collaborate on research at CU Anschutz. Image courtesy of Reusch.
Much of Reusch’s journey to becoming an award-winning physician-scientist began at CU Anschutz, which she joined in 1986 as an internal medicine resident before later becoming an endocrinology fellow and then a faculty member. Her first decade on campus primarily focused on conducting basic science in the lab, specifically looking at protein chemistry. Then, she teamed up with Regensteiner, a distinguished professor of medicine and director of the Ludeman Family Center for Women's Health Research.
One of their initial studies examined exercise capacity in sedentary women with and without diabetes. It found that women with diabetes had decreased exercise capacity, an alarming finding considering that other studies were beginning to demonstrate that a person’s functional capacity is a key predictor of mortality risk. Functional capacity is measured by a person’s ability to perform everyday movements like getting up from a chair, how fast and far they can walk, and how much oxygen their body uses when exercising (commonly measured as VO2 levels).
“Your functional capacity is a great barometer of health because it demonstrates whether your heart, lungs, skeletal muscle, and blood and nervous systems are working in concert to get you to move,” Reusch says. “We’ve been trying to disentangle the factors that contribute to that, and we’ve been focusing on insulin action. The ability to respond to insulin correlates exquisitely with the ability to exercise.”
Research has shown that a person who is insulin resistant is more likely to have lower functional capacity — and it doesn’t take much time for patients to feel the effects. In fact, decreased functional exercise capacity is evident in newly diagnosed adults and youth with type 1 and type 2 diabetes, she explains.
“This has implications for longevity,” Reusch says, underscoring the need to better understand what leads to this intolerance and how it might be stopped. Increasing functional capacity even by a small amount can decrease mortality risk.
Reusch investigated whether insulin-sensitizing drugs could improve functional capacity. In one study, she found that an insulin-sensitizing drug known as rosiglitazone led to participants improving their functional status and cardiorespiratory fitness. The downside, however, was the drug was also associated with weight gain, so Reusch believed it would not be a widely adopted solution.
“However, it showed us that we’re asking the right kinds of questions, and gaining a better understanding of what is occurring could inform ways to bypass this,” Reusch says.
Jane Reusch, MD, right, working alongside Layla Abushamat, MD, MPH, a former fellow in the CU Anschutz Division of Endocrinology, Metabolism, and Diabetes. Image courtesy of Reusch.
Traditionally, scientists suspected that there may be an intrinsic defect in the skeletal muscle of people with diabetes, Reusch explains. However, by measuring mitochondrial respiration in the body, she discovered this was not the case, prompting her to suspect there may be an issue with blood flow.
Through collaborative research, Reusch and her colleagues determined that perfusion — meaning the delivery of oxygenated blood and nutrients — to the heart and body’s skeletal muscle is insufficient in patients with diabetes. When a person does not receive enough perfusion when exercising, it is correlated with cardiac stiffening, specifically in the central arterial system. This can put extra workload on the skeletal muscle and heart.
Insulin can cause blood vessels to dilate by regulating an enzyme called nitric oxide, Reusch explains. Insulin specifically targets the blood vessels in the heart and skeletal muscle that need to be responsive to store fuel after a person eats a meal, and it can dictate where the glucose and insulin are delivered in the body. Reusch hypothesizes that insulin does this by sending signals that stimulate nitric oxide synthase (NOS).
For patients with insulin resistance, this process does not work well, leading to insufficient perfusion. Reusch wanted to test whether targeting and manipulating NOS directly could influence exercise capacity.
“We realized that we have a drug to test that: GLP-1s,” she says. “They stimulate NOS, which can lead to an upstream of blood flow.”
In her research to test whether GLP-1s could overcome the impact of insulin resistance, Reusch saw success among animal models in the ability to boost exercise capacity. However, those positive results did not fully translate to humans; the GLP-1s did not improve functional exercise capacity, but they appeared to improve heart and vascular function.
Now, Reusch and her team are exploring several theories as to why blood flow is not getting to where it needs to be during exercise, which she refers to as “vascular inflexibility.” For example, the researchers are examining different methods of targeting insulin sensitivity, endothelial dysfunction (a disorder that interferes with heart and skeletal muscle perfusion and is associated with low cardiorespiratory fitness in diabetic patients), and the muscle architecture of patients.
“Many of these patients have inflexibility of blood flow, which can then lead to mitochondrial dysfunction, structural abnormalities, and impaired oxygen extraction,” Reusch says. “In the longer term, we want to interrogate skeletal muscle, cardiac, and bone health in the context of GLP-1s.”
In the epidemiology research that Reusch has examined, muscle mass is a consistent predictor of how long a person lives. Thus, a loss of muscle (commonly seen in patients with frailty) typically meant an increase in the likelihood of premature death. GLP-1s, however, are complicating that understanding.
In line with effective weight loss, GLP-1s decrease muscle mass. Despite this loss, research has shown there is an overall prevention of cardiac and all-cause mortality, Reusch explains.
“It’s a clinical paradox, because these people are living longer,” Reusch says. “Dr. Regensteiner, Dr. Sarah Wherry, and I are very interested in understanding this functional status over time, because I’m worried about this for a couple of reasons.”
Her first concern is for patients who lose muscle mass while on the medication and then regain weight once they stop taking the drug (weight cycling).
“We don’t know what will happen 10 years from now in a population of people who have lost lean mass, including bone and muscle,” she says.
Reusch and her colleagues are setting out to address these issues through examination of the GLP-1 effects in younger and older people on lean mass (muscle and bone quality), strength, and fitness.
“Right now, without prospective data, organizations are proactively warning about the risk of frailty, especially in women and the elderly. We need to study this carefully for two major reasons,” she says.
The first reason is that GLP-1s provide evidence-based benefits for diabetes, obesity, cardiovascular disease (atherosclerosis and heart failure), kidney disease, and other conditions, Reusch explains.
“We do not want to unnecessarily withhold GLP-1s from those at risk for developing frailty, as these people can benefit the most from these drugs,” she says.
The second reason is that if there are harmful impacts of these drugs on patients’ strength, endurance, function, or bone, then researchers need to understand the side effects to design strategies (such as diet, exercise, or medications) to prevent frailty and fracture — all while not abandoning evidence-based uses of these transformative medications.
“As an example, if a physician is caring for a 70-year-old patient who could benefit from a GLP-1 for treating their heart, kidney, and diabetes, the physician still may not prescribe the medication due to a concern about the loss of muscle mass,” she says. “I don’t want us creating an unnecessary barrier to care, but I’m simultaneously concerned about the loss of muscle.”
Hoping to find answers, Reusch is researching the potential impacts of GLP-1s in several upcoming projects. One of those projects, in collaboration with Wherry and Regensteiner, will examine the muscle quality of pre- and post-menopausal women (and age-similar men) who are taking GLP-1s.
“A large percentage of reproductive-age females are eligible to be prescribed GLP-1s, so we may have a lot of women who may be losing skeletal muscle and bone mass,” Reusch says, highlighting the importance of the research. “This may be surprising, but I believe that in our study, we will see GLP-1s lead to lower muscle mass, but improved muscle quality, at least in the short term.”
Reusch hypothesizes that in the first 10-12 months of study participants taking GLP-1s, due to the metabolic benefits, there will be a decrease in lipids (fats) within the muscle, as well as better perfusion and mitochondrial function.
“I’m very confident we will see improved muscle quality in the short term, but I’m not confident it will transfer to the longer term,” she says, noting that she wants to study the long-term effects of these medications and help decipher if there are actual risks associated with the loss of muscle mass in these patients.
At CU Anschutz, Reusch says researchers have a “unique set of technical tools” and the ability to collaborate with experts from a variety of fields to answer these ongoing, complex, and important questions to help patients.
“GLP-1s are a transformative class of medications, but with that change comes potential benefits and risks that we need to understand,” Reusch says. “I really want to understand how these medications might help our patients maintain their exercise functional status while maintaining their heart health.”