When Muscles Can’t Take Sugar In: How the Body Adapts — and What It Costs

A fascinating new study published in Cell Reports (Liboz et al., 2025) has shed light on how the body compensates when muscles struggle to take in glucose during insulin resistance. The results highlight not only the remarkable adaptability of our organs, but also the hidden trade-offs that can push us from resilience into breakdown — exactly what the Exposure-Related Malnutrition (ERM) framework is designed to capture.

The Study in Brief

Researchers at Sorbonne University and colleagues used several mouse models of insulin resistance — including glucocorticoid treatment, genetic lipodystrophy, and insulin receptor blockade — to investigate how the pancreas responds when muscles can’t efficiently import glucose.

Here’s what they found:

• Muscle distress signals: When muscle cells become insulin-resistant, they secrete “distress molecules,” called myokines. Three stood out: myostatin (MSTN), amphiregulin (AREG), and epiregulin (EREG).

• Pancreatic adaptation: These myokines acted on the pancreas, stimulating beta-cell differentiation and expansion. The pancreas responded by increasing both the size and number of insulin-producing islets, boosting insulin output to maintain blood sugar balance.

• 3D whole-pancreas imaging: Using advanced imaging, the team showed a sharp rise in islet density — especially small islets — as the main structural adaptation.

• Age does not block adaptation: Both young and older mice retained the ability to expand beta-cell mass when challenged with insulin resistance.

In short, when muscles can’t pull in glucose, they send help signals, and the pancreas answers by working harder and growing bigger.

Adaptation vs. Maladaptation: The ERM Perspective

This is a textbook case of what the ERM (Exposure-Related Malnutrition) and Stress Adaptation Framework describes:

1. Stage 1 — Early ERM (Functional adaptation):With mild insulin resistance, the pancreas increases insulin secretion without changing its size. Short-term success — blood sugar stays stable.

2. Stage 2 — Intermediate ERM (Structural adaptation):With stronger resistance, muscle signals ramp up, and the pancreas expands its beta-cell mass by adding more islets. This is structural adaptation — effective but costly.

3. Stage 3 — Advanced ERM (Compromise):If insulin resistance persists, the pancreas remains locked in overdrive. The adaptive response becomes a chronic burden. Regenerative capacity strains, stress pathways activate, and resilience begins to fray.

4. Stage 4 — Maladaptive ERM (Failure):Eventually, the system tips. Beta cells can no longer keep up, insulin output falters, and diabetes develops.

Why This Matters

This study underscores how resilience is never free. The body solves one problem — muscles struggling to take up glucose — by shifting the burden to another organ, the pancreas. This “rob Peter to pay Paul” strategy keeps us alive in the short run but risks exhaustion in the long run.

The ERM framework helps us recognize this progression early, by identifying the bioenergetic trade-offs and cross-talk between tissues before collapse happens. In real-world terms, it means looking for the subtle early warning signs of metabolic strain and intervening before adaptation turns into exhaustion.

✨ Take-home message:

When muscles can’t bring in glucose, they cry for help. The pancreas answers by growing and working harder. But like any rescue mission, it comes with costs. Understanding these stress-driven trade-offs is the key to shifting from a reactive to a preventive, resilience-informed approach to health.

Liboz, A., Beaupère, C., Roblot, N., Rousseau, E., Tinevez, J.-Y., Guilmeau, S., Burnol, A.-F., Gueddouri, D., Prieur, X., Annicotte, J.-S., MacDonald, T. L., Fève, B., Guillemain, G., & Blondeau, B. (2025). Beta-cell adaptation unveiled: The role of myokines in insulin-resistant mice. Cell Reports, 44(9), 116283. https://doi.org/10.1016/j.celrep.2025.116283

#Insulin resistance, #Beta-cell adaptation, #Myokines (MSTN, AREG, EREG), #Islet density and mass, #Stress adaptation and maladaptation