When Physiology Meets Pharmacology: GLP-1RA and Metabolic Resilience

Healing_ Passion
2 days ago
4 min read

A major new review in The Lancet Diabetes & Endocrinology offers a fresh perspective on incretin biology. It highlights how hormones like GLP-1 and GIP do far more than regulate insulin—they help the body coordinate digestion, circulation, metabolism, and even aspects of brain function immediately after a meal.

According to the authors, incretins act as a finely tuned “post-meal adaptation system,” increasing blood flow to the gut, supporting nutrient absorption, and maintaining cardiovascular stability. They even suggest that these pathways may have evolutionary roots in the body’s early stress-response signaling, later repurposed for feeding and metabolism.

It’s an attractive theory.

But here’s what the review does not discuss—and what the public urgently needs to understand.

Natural GLP-1 Is Rhythmic and Short-Lived.

GLP-1 Drugs Deliver Extremely High Doses for an Entire Week.**

In normal physiology, GLP-1 is:

released only after meals,
peaks quickly,
and disappears within 1–2 minutes because the enzyme DPP-4 rapidly degrades it.

This creates a momentary pulse—just long enough to help you manage a meal.

But modern GLP-1 drugs are completely different:

1. They use doses hundreds of times higher than natural GLP-1 levels.

Physiological GLP-1 floats around at picomolar concentrations.Therapeutic GLP-1RA levels reach supraphysiological exposure, sustained continuously.

2. They are engineered to resist degradation.

Instead of lasting 1–2 minutes…

Semaglutide’s half-life is ~168 hours.
Tirzepatide’s half-life is ~120 hours.
Even “short-acting” liraglutide lasts 13 hours, not 2 minutes.

3. This means GLP-1 receptors stay activated 24/7.

The body has never experienced this level of continuous GLP-1 activity in human evolution.

So while the Lancet review beautifully describes the evolutionary logic of phasic, meal-linked incretin bursts, today’s anti-obesity drugs do the opposite:

They convert a natural millisecond hormone into a constant, supraphysiological signal saturating the body for months or years.

That difference matters—especially for another hormone we rarely talk about.

GLP-1 Drugs Chronically Suppress Glucagon

Glucagon - The Body’s Main Stress-Response and Energy-Mobilizing Hormone.

In nature, GLP-1 pulses after a meal briefly suppress glucagon to help the body store nutrients.

But when GLP-1 receptors are continuously activated:

glucagon becomes chronically suppressed—day and night,—not just after meals,—even during fasting, stress, illness, exercise, or injury.

This creates a physiologic mismatch.

Glucagon is essential for:

releasing glucose during stress
maintaining energy supply to the brain
supporting ketone production
mobilizing amino acids from muscle to the liver
stabilizing blood sugar during illness
enabling recovery after metabolic challenges

Continuous glucagon suppression may undermine all of these.

This is the “metabolic trade-off” almost nobody is talking about.

The Metabolic Cost of Prolonged GLP-1 Exposure

People on long-acting GLP-1 therapy often report:

reduced physical resilience
faster exhaustion during exercise
more frequent hypoglycemia during illness
muscle loss during weight loss
reduced stress tolerance (“crashing” easily)
cold intolerance
brain fog during fasting
persistent fatigue

Scientifically, these effects make sense:

When glucagon is muted for months or years, the body loses its ability to mobilize energy on demand.

Instead of metabolic flexibility, we get metabolic rigidity.

Instead of resilience, we get fragility.

A Drug That Mimics One Part of Physiology—While Silencing Another

The Lancet review is right: incretins play a remarkable role in coordinating digestion, circulation, and metabolism.

But that role is short-lived, tightly timed, and never designed to be continuous.

So the evolutionary argument cannot be applied to:

weekly 2.4 mg semaglutide injections,
multi-milligram tirzepatide analogues,
100× more GLP-1 exposure than nature intended,
100,000× longer hormone presence (minutes → days),
chronic glucagon suppression.

This isn’t “physiologic enhancement.” It’s pharmacologic override.

And like all overrides, it comes with trade-offs.

We Must Raise Public Awareness—Now, Not Later

Millions will benefit from GLP-1 drugs. They can be lifesaving.

But informed consent requires full transparency—not just about benefits, but also the metabolic consequences of long-term glucagon suppression and the unnatural hormonal exposure created by these drugs.

We need to ask honest questions:

What happens when the stress-response glucagon axis is suppressed for years?
What does long-term metabolic rigidity mean for aging, muscle mass, or immune resilience?
Can we preserve the benefits while protecting the body’s adaptive capacity?

These questions are not threats to GLP-1 therapy—they are part of responsible medicine.

The Takeaway

GLP-1 drugs work. They help people lose weight and control blood sugar.But they also create a hormonal state the human body has never experienced:

Extremely high doses
Prolonged half-life
Continuous receptor activation
Chronic glucagon suppression

The Lancet review celebrates incretin biology—and it should. But real-world GLP-1 drug exposure is far from biology.

As we enter the next decade of GLP-1 use, the most important question is not:

“Do they work?” They do.

The question is:

“Can we use them without compromising the very metabolic resilience we need for long-term health?”

This is a conversation the public deserves to hear.

Avogaro, A., & Fadini, G. P. (2025). Incretins and the cardiovascular system: Bridging digestion with metabolism. The Lancet Diabetes & Endocrinology. Advance online publication. https://doi.org/10.1016/S2213-8587(25)00166-4

Tippairote, T., Hoonkaew, P., Suksawang, A., & Tippairote, P. (2025). Glucagon suppression under GLP-1RA therapy: Hidden trade-offs for muscle and resilience. Diabetology International, 17, 2. https://doi.org/10.1007/s13340-025-00856-4