Old antipsychotic drugs offer clues to new class of diabetes treatment

Researchers studying new methods for improving blood sugar control in type 2 diabetes have discovered an old class of antipsychotic drugs may offer clues to a novel kind of treatment for hyperglycemia. While the researchers propose the old drugs could be directly repurposed to treat diabetes, they could also be slightly modified to more specifically target blood sugar control.

A few years ago, a team of researchers from the University of Alberta discovered a potential new therapeutic target for type 2 diabetes. Animal studies revealed elevated levels of an enzyme called succinyl CoA:3-ketoacid CoA transferase (SCOT) were tied to hyperglycemia. And, when SCOT levels were reduced in obese mice, signs of glycemia significantly improved.

So instead of trying to develop an entirely new molecule to inhibit SCOT, the researchers turned to computer modeling to find out whether there was a pre-existing drug that could interact with the SCOT enzyme. According to John Ussher, lead author on the new research, this kind of drug repurposing can accelerate the process of clinical development, allowing for a quick jump into early-stage human clinical tests.

“As you already have safety data, it somewhat accelerates the process,” explained Ussher. “And from an economic standpoint, often because a lot of these drugs being pursued for repurposing are older, they’re off patent and cheaper.”

In 2020, Ussher and colleagues first discovered an old anti-psychotic drug called pimozide seemed to successfully inhibit SCOT activity in obese mice. The drug also successfully reversed obesity-induced hyperglycemia in the animals.

Now, in a new study, the researchers have demonstrated several other drugs in the same class of antipsychotics seem to work effectively as SCOT inhibitors. The class of drugs, known as diphenylbutylpiperidines (DPBPs), were developed back in the 1960s and are still used today.

“We’ve tested three drugs now, and they all interact with this enzyme,” said Ussher. “They all improve blood sugar control by preventing the muscle from burning ketones as a fuel source. We believe this SCOT inhibition is the reason these antipsychotics might actually have a second life for repurposing as an anti-diabetic agent.”

Because the DPBP drugs are already approved medicines the researchers hope to quickly move to proof-of-principal human trials. This would establish whether these preclinical findings are reproducible in human patients.

Following that, it is likely the drugs would then need some kind of modification to work as more targeted medicines for type 2 diabetes. Because DPBPs cross the blood-brain barrier they can cause side effects such as fatigue or dizziness. The ideal outcome for this research would be to engineer the drugs to not be able to cross into the brain and solely focus on SCOT inhibition in other parts of the body.

“For us, the excitement is that it looks like the entire family of these compounds interacts with this protein [SCOT] and can improve blood sugar control in type 2 diabetes,” adds Ussher.

The new study was published in the journal Diabetes.

Source: University of Alberta

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