When Insulin Resistance Protects: From Allostasis to Bioenergetic Impedance

A new review in Cell Metabolism challenges one of the most familiar assumptions in metabolic medicine: that insulin resistance, reduced insulin secretion, mild hyperglycemia, and even glucosuria are simply signs that glucose regulation is failing.

Prentki and colleagues propose something more nuanced. In obesity-related prediabetes and early type 2 diabetes, these changes may initially represent allostatic responses to chronic nutrient excess—coordinated adaptations that help protect metabolically vulnerable tissues from receiving more fuel than they can safely process.

This is an important shift in perspective. It moves the discussion from asking only, “What is abnormal?” toward asking, “What is the body trying to protect itself from?”

Insulin resistance as protection against excessive nutrient flow

The conventional model of type 2 diabetes places insulin resistance near the beginning of the disease process. Tissues become less responsive to insulin, glucose remains in the circulation, pancreatic β cells compensate by producing more insulin, and eventually this system fails.

Prentki and colleagues suggest that this sequence may be incomplete.

When muscle, liver, adipose tissue, heart, and other organs are already exposed to chronic nutrient excess, forcing still more glucose into those tissues may increase metabolic stress. Reducing insulin sensitivity can therefore serve an initially useful purpose: limiting further nutrient entry into tissues whose metabolic capacity is already being challenged.

From this viewpoint, insulin resistance is not necessarily equivalent to metabolic failure. At least during early disease, it may function partly as a regulatory barrier controlling nutrient flux.

The same argument is extended to pancreatic insulin secretion. A reduction in glucose-stimulated insulin secretion may help limit chronic hyperinsulinemia, excessive nutrient storage, and β-cell workload.

These responses may therefore form part of a coordinated systemic strategy rather than a collection of unrelated defects.

Mild hyperglycemia may sometimes reflect upstream buffering

The review also raises a more provocative possibility: modest hyperglycemia may sometimes help protect tissues from excessive glucose influx.

This does not mean that chronic or severe hyperglycemia is harmless. Established hyperglycemia clearly contributes to diabetic complications.

The important distinction is between a physiological response and its persistence beyond the conditions in which it remains useful.

Keeping some glucose in the circulation rather than continually pushing it into overloaded tissues may temporarily reduce intracellular nutrient stress. When glucose becomes sufficiently elevated, glucosuria provides another route by which excess fuel can leave the body.

This interpretation offers an interesting context for the success of SGLT2 inhibitors. These drugs lower the renal threshold for glucose reabsorption and promote glucose loss in the urine. Their cardiovascular and renal benefits have often exceeded what would be predicted from glucose lowering alone.

The broader lesson may be that how energy is handled matters as much as the measured glucose concentration itself.

Inflammation may also participate in nutrient redistribution

The authors extend allostatic reasoning to metabolic inflammation.

Inflammatory signaling is usually discussed as a cause of metabolic disease, and chronic inflammation unquestionably becomes damaging. But the immune system also participates normally in nutrient allocation.

During infection, injury, feeding, fasting, and other physiological challenges, cytokines alter glucose and lipid handling so that energy can be redirected toward tissues with greater immediate demand.

Obesity-related inflammation may therefore begin partly as an attempt to reorganize nutrient distribution before becoming chronically activated and maladaptive.

Again, the key issue is not whether the response is simply “good” or “bad,” but whether it remains appropriate, reversible, and proportionate to the challenge.

From allostasis to bioenergetic impedance

These ideas closely parallel the bioenergetic impedance framework we have been developing.

Bioenergetic impedance describes situations in which energetic pressure rises faster than biological systems can safely conduct, process, buffer, redistribute, or recover from that energy.

A simple example is nutrient overload:

nutrient pressure rises → tissue processing capacity becomes constrained → resistance to further substrate entry increases → metabolism is rerouted → compensatory signaling expands across the organism.

Insulin resistance fits naturally within this logic.

When a tissue is already energetically congested, reducing glucose entry can be viewed as a form of adaptive impedance. Resistance protects local capacity by restricting further flow.

The problem begins when the energetic pressure does not resolve.

Persistent nutrient excess can maintain insulin resistance, hyperinsulinemia, inflammatory signaling, substrate accumulation, altered lipid trafficking, and metabolic rerouting. What began as adaptive resistance can progressively become locked into the system.

We describe this transition as moving from adaptive impedance to impedance lock-in.

The distinction is important:

Adaptive impedance is temporary, reversible, and protects recovery capacity.

Persistent impedance becomes increasingly costly, consumes physiological reserve, and can propagate across tissues and regulatory networks.

This helps reconcile two apparently conflicting observations: insulin resistance can initially be protective while also contributing to later metabolic disease.

Both can be true, depending on timing and physiological context.

A broader principle: abnormal does not always mean inappropriate

One of the most valuable aspects of the Prentki review is that it brings allostatic reasoning into a highly conventional area of metabolic medicine.

For decades, clinical interpretation has often treated deviations from normal ranges as abnormalities that should be corrected toward a reference value.

But physiology does not always defend normality. It defends survival.

During stress, the organism may deliberately change glucose distribution, hormone signaling, blood flow, inflammatory activity, appetite, substrate utilization, and energy expenditure.

The resulting laboratory value may therefore represent a compensatory state rather than the primary problem.

This is a central principle of Network Physiology: a change that appears dysfunctional when viewed within one tissue may make sense when viewed across the whole organism.

The clinically relevant question becomes not only:

Is this value abnormal?

but also:

What physiological pressure is producing it, what function is the response serving, and can the system still recover once that pressure is removed?

What this could mean for future metabolic care

This perspective does not imply that high glucose or insulin resistance should simply be ignored. Rather, it suggests that treatment should focus more strongly on the energetic conditions driving the response.

Future metabolic care may therefore increasingly distinguish between interventions that merely normalize a biomarker and interventions that actually reduce the underlying physiological burden.

For example, therapies that reduce excessive nutrient intake, improve mitochondrial and tissue processing capacity, increase physical activity, restore sleep and circadian regulation, reduce inflammatory burden, improve adipose storage function, or safely remove excess substrate may reduce the need for compensatory resistance.

The goal would not simply be to force glucose into tissues more effectively.

It would be to create conditions in which those tissues no longer need to resist glucose entry.

That is a very different therapeutic objective.

Translating the idea into research

The next step is to test these concepts dynamically.

Most metabolic studies still rely heavily on fasting blood samples and static measurements. Yet an adaptive response can only be understood properly by observing what happens before, during, and after a challenge.

Future studies could therefore examine how individuals respond to meals, exercise, sleep disruption, fasting, illness, or other physiological stressors.

The important variables would include not only glucose and insulin, but also how quickly metabolic pressure develops, how strongly compensatory systems activate, how nutrients are redistributed, and how completely the organism returns toward baseline afterward.

This is where bioenergetic impedance may become experimentally useful.

Instead of asking whether one biomarker is abnormal, researchers could examine whether multiple physiological systems show a common pattern of:

increasing pressure, restricted throughput, compensatory rerouting, reduced reserve, and delayed recovery.

Such a framework could help distinguish a healthy adaptive response from a system beginning to lose flexibility.

From treating numbers to understanding physiological states

The Prentki review does not overturn the established risks of diabetes, nor does it suggest that insulin resistance or hyperglycemia are universally beneficial.

Its deeper contribution is conceptual.

It asks us to recognize that physiology often responds to chronic stress by changing the operating state of the organism.

Those changes may initially protect vulnerable tissues. But when the underlying pressure persists, the same mechanisms can become part of the disease process.

That progression—

challenge → adaptation → compensation → persistent burden → loss of recovery

—is central to allostasis, Network Physiology, and our emerging concept of bioenergetic impedance.

The future of metabolic medicine may therefore depend less on asking how aggressively we can normalize individual numbers, and more on understanding why the body produced those numbers in the first place—and whether the physiological conditions that made them necessary have actually been resolved.

Reference

Prentki M, Nolan CJ, James DE, Thorens B, Rhodes CJ, Corkey BE, et al. Insulin resistance and type 2 diabetes as allostatic responses to chronic nutrient excess. Cell Metabolism. 2026;38(8):1540–1556. https://doi.org/10.1016/j.cmet.2026.06.012