Nick NorwitzMD PhD, Oxford-Harvard | Metabolic Health Educator | “Stay Curious”

Why 20% of People Are Exercise Non-Responders

31 Mar 2026 · 1 min

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1:25

In this short talk, metabolism scientist Nick Norwitz explains the concept of the "exercise non‑responder," a condition affecting roughly 20 % of individuals who train consistently yet see little physiological gain. He challenges the common view that this is purely genetic, citing a recent Nature‑published study that implicates elevated blood‑sugar levels as the primary culprit. The study showed that high glucose causes glycation and cross‑linking of the extracellular matrix (the structural scaffold surrounding muscle cells), turning it from a pliable “soil” into a rigid “cement.” This hardened matrix blocks angiogenesis—the formation of new blood vessels needed to nourish muscle during exercise—thereby preventing training adaptations. Norwitz frames the issue as a modifiable problem of blood‑sugar control rather than immutable DNA, and he directs viewers to the Muscle Health Archive at staycuriousmetabolism.com for deeper details.

Chapters

Okay, stop scrolling and listen to me. If you've ever felt like you exercise hard, show up consistently, but you're not seeing the gains you expect, this is a real phenomenon. It's called the exercise non-responder. About 20% of people are exercise non-responders. Now, as a metabolism scientist, that has always fascinated me, and it's usually chalked up to just bad genetics, nothing you can do. But science says otherwise. A very fascinating study published out of Nature Press found the culprit to exercise nonresponsiveness might be blood sugar. What they found is that when you elevate blood sugar in preclinical models, it glycates what's called the extracellular matrix. All right, what's that gobbledygook? The extracellular matrix is the scaffolding around your cells. It gives them structure, including in your muscles. Now, in the muscle, it should be like healthy soil so that when you train, when you run, when you do jumping jacks, you get angiogenesis, the growth of new blood vessels through the soil to nourish the muscles. But high blood sugar leads to glycation or cross-linking of the matrix, turning that healthy soil like into cement, and then new blood vessels can't grow through it. It's fascinating science that describes the exercise non-responder not as a genetic phenomenon, maybe as a problem of poor blood control. So it's not your DNA, it might be the Skittles. And if you want more details and nuances, I want you to go to our muscle health archive at staycuriousmetabolism.com, and you can learn all sorts of cool things about muscles and work out your brain before you work out your body.