A look at the science that explains why exercise improves glucose regulation even when insulin cannot.
Abstract
Professor Juleen R. Zierath has spent more than three decades uncovering how exercise reshapes muscle metabolism and why these mechanisms matter for people with obesity or type 2 diabetes. Her work demonstrates that insulin resistance originates in skeletal muscle and that exercise can bypass this defect through alternative pathways that enhance glucose uptake. By connecting molecular biology, circadian timing, gene regulation, and real-world physiology, she has built a foundation for more personalized approaches to metabolic health. Her research offers insight into why movement remains one of the most effective tools for improving glucose regulation and overall metabolic function.
Key Points
- Insulin resistance in type 2 diabetes occurs in the skeletal muscle, where defects in insulin signaling limit glucose uptake, making this tissue central to metabolic dysfunction.
- Exercise bypasses impaired insulin pathways through contraction-driven mechanisms that activate AS160, AMPK, and GLUT4 movement, improving glucose uptake even when insulin is less effective.
- Skeletal muscle is highly adaptable, and Zierath’s work shows how different types of training reshape fuel use, mitochondrial function, and long-term insulin sensitivity.
- Epigenetic and circadian factors influence metabolic health, with exercise capable of modifying DNA methylation patterns and interacting with the body’s internal clocks to improve glucose control.
- These insights point toward personalized exercise and nutrition strategies, grounded in genetics, timing, and individual metabolic responsiveness, rather than one-size-fits-all recommendations.
Setting the Stage
Professor Juleen R. Zierath has spent more than thirty years answering one of the most important questions in metabolic science: what exactly happens inside the body when we exercise, and why does it matter so much for people with obesity or type 2 diabetes?
Her contributions span molecular biology, clinical research, circadian science, and epigenetics. Taken together, they demonstrate why exercise remains one of the most powerful tools we have for improving metabolic health.
She is the 2024 recipient of the EASD–Novo Nordisk Foundation Diabetes Prize for Excellence, one of the most prestigious honors in diabetes research.
Featured Video
Novo Nordisk Foundation video about Professor Juleen R. Zierath and her work
2024 EASD–Novo Nordisk Foundation Diabetes Prize for Excellence, Professor Juleen R. Zierath
https://www.youtube.com/watch?v=Va4CRgVSCzs
A Career Built on Understanding How the Body Responds to Movement
Zierath’s interest began early. As she described in her interview, she grew up active in sports and saw firsthand how lifestyle changes could influence long-term health. Her grandfather survived a bypass surgery when she was young, and the recommendation he received was simple: change his diet and start exercising. He lived into his nineties. That experience stayed with her and shaped her research direction.
Her early academic years took her from the United States to Sweden, where she joined Karolinska Institutet. This move put her at the center of Scandinavian expertise in muscle physiology, metabolism, and exercise science.
The Breakthrough: Exercise Improves Glucose Uptake Even When Insulin Cannot
One of Zierath’s most influential contributions came from work rooted in a question that puzzled researchers for decades:
If insulin signaling is impaired in people with type 2 diabetes, how can exercise still improve glucose uptake?
“[P]eople with diabetes have insulin resistance. It's right in the muscle.”
Her team helped answer this by showing that the insulin resistance found in type 2 diabetes is not abstract or systemic — it's located in the skeletal muscle itself, where insulin’s ability to activate key signaling steps is reduced. This includes impaired activation of proteins such as IRS, PI3K, and AS160 — the steps that normally trigger GLUT4 to move to the cell surface and clear glucose from the bloodstream. In people with type 2 diabetes, that signaling sequence breaks down, so muscle cannot respond normally to insulin.
In other words, the muscle cells of people with diabetes do not respond normally to insulin, which is why glucose uptake becomes difficult.
What Zierath demonstrated is that muscle contraction bypasses this defect. When muscles contract during exercise, they activate a separate pathway — involving proteins like AS160 and AMPK — that moves GLUT4 transporters to the cell membrane even when insulin signaling is impaired.
This discovery provided strong evidence for prescribing exercise as part of diabetes management. It also showed that:
- one week of regular physical activity can significantly improve glucose tolerance
- sustained exercise increases the abundance of GLUT4, improving long-term insulin sensitivity
These findings helped establish exercise as a direct countermeasure to insulin resistance within the muscle.
Muscle Plasticity: Why the Body Changes With Training
Zierath’s work helped define the concept of muscle plasticity — the ability of skeletal muscle to adapt depending on activity, diet, and metabolic state. Because insulin resistance arises in skeletal muscle, understanding how muscle remodels itself with exercise is essential for understanding metabolic health.
Her team examined:
- how sprinters and endurance athletes differ at the molecular level
- how untrained individuals respond differently than well-trained athletes
- how exercise activates energy-sensing pathways like AMPK and calcineurin
This research showed that skeletal muscle is not passive. It is metabolically active, adaptable, and capable of shifting its fuel use depending on need. These adaptations help explain why even modest increases in activity can improve glucose handling in people whose muscle tissue is resistant to insulin.
Epigenetics: Exercise Can Re-Mark DNA
In people with insulin resistance, metabolic genes in skeletal muscle often show increased DNA methylation, which reduces their activity. Zierath’s group demonstrated that:
- people with type 2 diabetes have hypermethylation on promoters of key mitochondrial and metabolic genes (including PGC-1α) in their muscle
- exercise can remove some of these methylation marks
- the loss of these marks increases gene activity, improving mitochondrial function and glucose uptake
- weight-loss surgery can reverse similar patterns
These findings highlight that insulin resistance in muscle is shaped not only by signaling defects but also by gene regulation patterns that influence how the muscle produces energy, uses glucose, and responds to metabolic stress.
Timing Matters: The Circadian Effect
More recently, Zierath’s research has explored circadian biology. Every tissue in the body has its own internal clock, including skeletal muscle, where insulin resistance develops in type 2 diabetes.
Her team found that:
- afternoon exercise lowers blood glucose
- morning exercise can raise it in people with type 2 diabetes
- exercise may help reset reduced or “dampened” circadian rhythms in muscle tissue affected by insulin resistance
By tying exercise timing to metabolic responses, her work reinforces the idea that muscle physiology drives much of the glucose-regulation challenge in type 2 diabetes. When these muscle-based clocks are misaligned, the metabolic response to exercise shifts as well, which helps explain why morning and afternoon exercise can produce opposite effects in people with type 2 diabetes.
A Holistic View of Metabolism
Across her career, Zierath has shown that exercise influences nearly every organ system: muscle, adipose tissue, liver, pancreas, and even the brain. She often describes exercise as the body's most powerful integrative signal — something no single medication can fully replicate.
She also champions an accessible message:
“Everyone should train in principle like an athlete.”
Not in intensity or volume, but in purpose. Athletes vary their training, build strength and endurance, and rest strategically. Zierath argues that principles like consistency, variety, and recovery apply to everyone.
Looking Ahead: Personalized Exercise Prescriptions
Zierath believes the next era of metabolic research will involve individualized exercise and nutrition approaches based on:
- genetics
- epigenetics
- circadian rhythm profiles
- metabolic responsiveness
Her long-term goal is to translate basic science findings into practical guidance for people living with cardiometabolic diseases.
As she put it, we don’t know everything about anything yet, particularly in areas where diet, exercise, nutrients, stress, and temperature all intersect. That complexity is exactly what motivates her work.
Why This Recognition Matters
The 2024 Diabetes Prize for Excellence highlights researchers whose work fundamentally advances diabetes science. Zierath’s contributions stand out because they bridge mechanistic understanding and real-world relevance. They make it possible to connect molecular biology to daily decisions about activity, diet, and health.
Her work also shows that lifestyle interventions are not “soft science.” They have deep biological underpinnings that can be measured, quantified, and translated into improved outcomes.
Closing Thought
Exercise becomes a targeted, physiologically grounded tool that directly improves how skeletal muscle handles glucose, how it responds to insulin, and how the body maintains metabolic balance.
Her work continues to clarify why movement remains central to diabetes care and metabolic health. And it opens the door to a future where exercise is not just recommended broadly, but tailored to the person, their physiology, and their daily rhythms.
Sources
Scientist who promotes ‘exercise as medicine’ awarded prize for trailblazing work on physical activity and diabetes
The 2024 EASD–Novo Nordisk Foundation Diabetes Prize for Excellence has been awarded to Professor Juleen R. Zierath
Professor Juleen Zierath awarded prize for trailblazing work on physical activity and diabetes
