The Origin Story: Apples, Phlorizin, and Glucose Wasting

My friend and colleague

was actually the one who first mentioned that SGLT2 inhibitors trace their roots back to apples. I love stories like this where science and trivia overlap so I dug in to learn more and wanted to share what I found. Big thanks to Brian for sparking the curiosity and inspiration behind this one.

In the 1830s, chemists isolated a natural compound from apple tree bark (and to a lesser degree from the apple itself) called phlorizin (also spelled phloridzin). It’s a glucoside of phloretin, part of the polyphenolic family that gives apples some of their antioxidant and metabolic effects.

Researchers later discovered that when animals or humans were given phlorizin, they started excreting large amounts of glucose in their urine even though their blood glucose wasn’t dramatically elevated. This was puzzling, because under normal physiology, the kidneys reabsorb nearly all filtered glucose in the proximal tubule to prevent energy loss.

That phenomenon glucosuria without hyperglycemia was the first clue that the kidneys had a specific glucose transport mechanism that could be pharmacologically blocked.

By the mid-1900s, scientists identified that glucose reabsorption occurs through sodium-glucose co-transporters (SGLTs), primarily SGLT2 in the proximal tubule (responsible for ~90% of glucose reuptake) and SGLT1 further downstream.

Phlorizin turned out to be a competitive inhibitor of both SGLT1 and SGLT2, preventing glucose reabsorption and causing its excretion. However, phlorizin itself wasn’t a good drug it was poorly absorbed orally and was rapidly hydrolyzed in the intestine to phloretin, which blocked other transporters nonspecifically and caused GI issues.

So, researchers asked: Could we make a stable, orally bioavailable derivative that selectively blocks SGLT2?

That question directly led to the modern SGLT2 inhibitor class.

Medicinal chemists used the phlorizin scaffold as the blueprint, modifying the C-glucoside linkage (to resist enzymatic cleavage) and tweaking ring structures to increase selectivity for SGLT2 over SGLT1.

This optimization produced:

-Dapagliflozin (Farxiga)

-Empagliflozin (Jardiance)

-Canagliflozin (Invokana) and others.

All of these are synthetic derivatives of the natural apple compound phlorizin. SGLT2 inhibitors work by reducing renal glucose reabsorption, leading to glycosuria (urinary glucose loss) and modest caloric deficit. But they also trigger a metabolic shift toward fat oxidation, mild ketone production, and improved mitochondrial efficiency which is why they’ve shown powerful benefits beyond diabetes, including:

-Heart failure protection (through improved energetics and osmotic diuresis)

-Renal protection (through reduced intraglomerular pressure

-Improved redox tone (via mild fasting-mimetic signaling, AMPK activation, and NAD⁺ preservation)

In essence, they induce a controlled, pharmacological caloric restriction signal, echoing what fasting or exercise would do all rooted in the original apple compound.

The apple bark compound phlorizin → revealed renal glucose transporters (SGLT1/2) → inspired the synthetic drug class that now defines a cornerstone of modern metabolic and cardiovascular medicine.

Nature gave the first draft.

Chemistry refined the manuscript.

Mitochondrial physiology explained the story.

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