Exercise Hormesis: Why Stress Makes You Stronger — and Why Some Medications May Quiet the Signal

Most people know that exercise is “good for you,” but few understand why it is so powerful.

The secret lies in hormesis — the biological principle that small, controlled doses of stress trigger the body to adapt, rebuild, and grow stronger.

Exercise is the ultimate hormetic stressor. It raises your heart rate, burns energy, challenges your mitochondria, pushes your muscles, and even temporarily increases inflammation and free radicals.

But after the workout, your body responds with:

• better insulin sensitivity

• more efficient mitochondria

• stronger muscles

• improved vascular function

• enhanced metabolic flexibility

• deeper resilience to future stress

This “stress → adaptation → strength” cycle is the reason exercise protects against chronic disease.

Yet a new line of research shows that some common medications may quiet this hormetic signal, limiting the benefits of exercise in subtle but important ways.

What a New RCT Revealed: Metformin Can Blunt the Benefits of Exercise

A recent randomized controlled trial published in The Journal of Clinical Endocrinology & Metabolism tested whether metformin — one of the world’s most widely used diabetes medications — affects the body’s vascular response to exercise.

The findings were striking:

✔ Exercise improved vascular insulin sensitivity in both large arteries and tiny muscle capillaries

✔ But when participants took metformin, those benefits disappeared

✔ Aerobic fitness (VO₂max) improved with exercise alone — but not with metformin

✔ Inflammation-resolving signals were blunted

✔ Fasted glucose improved less when metformin was combined with exercise

In short:

Metformin lowered blood glucose, but it also suppressed the stress-response signals required for exercise to create deeper metabolic improvements.

This doesn’t mean metformin is “bad.”It means that how it lowers glucose comes with trade-offs.

And this same pattern is now being seen with GLP-1 receptor agonists (GLP-1 RAs) like semaglutide and tirzepatide.

The Hidden Commonality: Both Metformin and GLP-1RA Shift Energy Allocation Away From Stress Adaptation

Although these drugs work differently, they share a surprising mechanistic overlap:

They suppress glucagon signaling — the hormone your body uses to mobilize fuel during stress.

When glucagon is quieted:

• the liver produces less glucose

• ketone production drops

• amino acids are not cleared properly

• metabolic flexibility decreases

• stress-response pathways weaken

This helps lower fasting glucose — which is useful and sometimes necessary. But it also shifts the body into a low-energy, low-flexibility state, which makes hormetic adaptation harder.

This means:

• the “exercise signal” is quieter

• the mitochondrial response is smaller

• vascular improvements are blunted

• muscle remodeling is less robust

• recovery is slower

• the metabolic system becomes more fragile under stress

This is exactly what the RCT revealed about metformin — and what multiple studies now show about GLP-1RA–related muscle loss and reduced exercise tolerance.

Why This Matters for Long-Term Health

Exercise is powerful because it challenges the system. Your body senses the stress, mobilizes energy, repairs tissues, and becomes more resilient.

But when the hormonal stress signals are muted:

• energy mobilization is limited

• mitochondria don’t get the “push” they need to adapt

• the vascular system doesn’t remodel

• the muscle doesn’t receive proper repair cues

• inflammation isn’t fully resolved

• resilience declines over time

In other words:

Lower glucose does not automatically mean better metabolic health. It depends on how the glucose was lowered.

Medications that quiet the stress-response system can flatten the very signals that exercise relies on to rebuild a healthier metabolism.

So What Should People Do?

This isn’t a call to stop medications. For many people, metformin or GLP-1RA can be life-changing.

Instead, this is an invitation to understand the biology:

• Exercise is a hormetic stress — you want the signal to be strong.

• Some medications make that signal quieter.

• Lower glucose does not always mean “metabolically stronger.”

• The goal is not just glucose control, but restoring metabolic resilience.

For anyone using these medications:

✔ Keep exercising

✔ Prioritize protein and resistance training

✔ Monitor strength and muscle mass

✔ Support mitochondrial health (sleep, nutrition, micronutrients)

✔ Work with a clinician to personalize the approach

The key message is simple:

Good metabolic health is not only about lowering glucose — it’s about restoring your body’s ability to respond to stress and adapt.

Exercise remains one of the strongest ways to build that resilience. Understanding how medications may interact with that process helps us make better, more informed, and more personalized choices for long-term health.

Malin, S. K., Heiston, E. M., Battillo, D. J., Ragland, T. J., Gow, A. J., Shapses, S. A., Shah, A. M., Patrie, J. T., & Barrett, E. J. (2025). Metformin blunts vascular insulin sensitivity after exercise training in adults at risk for metabolic syndrome. The Journal of Clinical Endocrinology & Metabolism, 00(0), 1–12. https://doi.org/10.1210/clinem/dgaf551