If your cell was a race car then diabetes is driving it you to drive it at its maximum speed, 24/7, while feeding it dirty fuel.
This constant stress creates massive engine damage & we call it oxidative stress.
Luckily, your car has an internal mechanic. This mechanic's job is to clear out the gunk and replace worn-out parts to keep the engine pristine. In your cells, this mechanic is called Autophagy.
But in diabetes, the damage is so relentless that the mechanic gets overwhelmed, breaks down, and the entire system fails.
This breakdown isn't just a broken engine. It’s kidney failure. It's blindness. It's heart attacks. And it's all because this one, single process is broken.
What is Autophagy?
This process, Autophagy (from the Greek for "self-eating") is your cell's essential garbage disposal and recycling unit. The terrifying part is that in diabetes, it becomes a double-edged sword.
If it fails, your cells drown in toxic waste. If it becomes too active, your cells can literally "eat" themselves to death, committing cellular suicide.
We need to find a zone... Not too little, not too much. Because hitting that spot might be the only way to save organs from diabetes.
How Autophagy Works
So how does this mechanic actually work? The key process is Macroautophagy. A double-membraned vesicle, the autophagosome, forms around the damaged material. It then fuses with the lysosome, where powerful hydrolases degrade the contents.
But here’s the most critical concept, the one that explains the "overwhelmed mechanic": Autophagic Flux. Flux is the entire dynamic process, from formation to degradation. In diabetes, we often see a "traffic jam". The mechanic tries to bag up the trash (autophagosomes form), but the garbage truck (lysosome) never shows up. This toxic buildup of vesicles is the real disaster.
Mixed Signals: The Brakes & Accelerators
Autophagy fail in diabetes because the central command center (the nutrient-sensing signaling hubs) is overwhelmed.
Back to our Car...
The brake in the car is called mTOR.
mTOR: the mechanistic target of rapamycin. It senses growth signals, like high insulin, and suppresses autophagy. In diabetes, chronic high insulin keeps this brake permanently floored, preventing cleanup.
Ok. Now we know the brake. What about the accelerators in the car?
AMPK & SIRT1: Opposite to mTOR is AMP-activated protein kinase (AMPK). When energy is low, AMPK switches on autophagy. And in diabetes, it is often suppressed.
This creates a cycle. Chronic high sugar generates huge amounts of Reactive Oxygen Species (ROS) (that is the "engine damage"). This damage requires removal, but it also impairs the autophagy itself. This is the loop that make it worse.
Complications
Now, this whole thing manifests differently in every organ.
In the kidney, there are delicate filtration cells called Podocytes. And these podocytes are dependent on autophagy. When autophagic flux fails, damaged mitochondria accumulate, causing podocyte death and kidney failure.
And in the heart perhaps it is the most controversial. The therapeutic window is too thin: too little autophagy causes damage accumulation, too much causes cellular self-destruction.
And then the eye... In the eye it is so paradoxical, activating autophagy is good for one type of cells, but not good for the other. Activating autophagy is good for the retinal neurons. YET, in the retinal blood vessels, high glucose enhances autophagy, and this promotes the pathological blood vessel growth that causes blindness.
So a single systemic drug could save one part of the eye while destroying the other. Which means we need to be very precise.
Therapeutics: What We Know
Researchers are developing drugs focused on restoring or fine-tuning autophagic flux.
The hero of T2D Metformin works partly by activating AMPK (the accelerator), thereby inducing protective autophagy.
It was also found that newer anti-diabetic drugs like SGLT2 inhibitors and GLP-1 receptor agonists are demonstrating organ protection, and emerging evidence suggests they work, in part, by activating the AMPK/SIRT1 axis.
Good to Know.
Now since the accumulation of damaged mitochondria (the junk/engine gunk) in a problem, the selective form of autophagy called Mitophagy (mitochondrial cleanup) becomes a prime target for future, highly specific drugs. This is the "smarter mechanic" that only fixes the broken parts.
The Challenge
The ultimate challenge is moving beyond broad, systemic activators. We don't need an "ON-OFF switch"; we need "dimmer switches"... Drugs that can be finely tuned and delivered specifically to the right cells.
One last disappointing problem is that we lack ways to monitor this process in real-time in patients. We do not have non-invasive biomarkers.
The way to monitor the process now is to take biopsies. That means we cannot do clinical trials on actual patients, we can only try this on animals/tissues.
Sadly, it is a long way to go from here.
Targeting autophagy is not about building a bigger fire or dumping more trash. It’s about precision. If we can learn to control this fundamental process of cellular "self-eating," we can break the cycle of diabetes and potentially prevent the complications that destroy lives.