A Better Diabetes Treatment Hiding in Platypus Venom?

As if egg-laying Australian mammals with webbed feet weren't fascinating enough, it turns out that their venom contains an insulin-stimulating peptide resistant to the forces that usually shorten its effectiveness in humans. Yes, they have venom.

Diabetics may have an unlikely ally: the platypus.

In addition to being entirely unique to Australia and New Guinea, and among the only order of mammals that lay eggs (called monotremes), platypuses have another particular characteristic: they secrete venom. And in this most unlikely of substances, there may be a potential treatment for diabetes.

The venom exists as a weapon for male dominance, deployed from spurs on the hind limbs in competition during mating season. Contained in the venom is a form of the glucagon-like peptide-1 (GLP-1) hormone, which is also secreted in the guts of mammals, humans included. GLP-1 stimulates the release of insulin in order to lower blood glucose, and as such is used commonly in the treatment of type 2 diabetes. Several well-known drugs, like dulaglutide (sold as Trulicity by Lilly) and liraglutide (Novo Nordisk’s Victoza), are GLP-1 agonists.

The problem with GLP-1, however, is how quickly it degrades in the gut due to cleavage by dipeptidyl peptidase-4 (DPP-4), fueling the need for potentially longer-lasting versions of the hormone for extended insulin management. The GLP-1 contained in platypus venom may provide a lead on that.

Researchers from Australia, led by Professor Frank Grutzner of the University of Adelaide, recently took a close look at that venom, publishing their results this week in Scientific Reports. Their study is believed to be the first ever to sequence the cDNA of platypus venom. The team also examined the venom of echidnas, themselves members of order Monotremata, who develop the poison but puzzlingly possess no spur to deliver it.

The researchers took samples from the venom glands, guts, stomachs, hearts, muscles, lymph, cortex, and kidneys of platypuses and echidnas. They found that glucagon (GCG), GLP-1, and DPP-4 were expressed similarly in the tissue samples as in other mammals, but differ noticeably in composition from human GLP-1.

“Importantly,” the authors write, “the inferred sequence of the platypus GLP-1 peptide (pGLP-1) differs in 11 of the 30 amino acids (37%) compared to human GLP-1 (hGLP-1, as reported previously). A smaller difference was seen between platypus and human GLP-2 (30%) or glucagon peptides (20%).” They also found “specific changes” in the DPP-4 cleavage site of the platypus GLP-1 as compared to the human form of the peptide.

The echidna GLP-1 deviated even further from the human example (57%) but surprisingly displayed no changes in DPP-4 cleavage site, displaying evolutionary differences not only between different types of mammals but also within the monotreme order itself.

A major finding was that the GLP-1 peptides found in monotremes decay differently. While “incubation of the peptides with purified human DPP-4 resulted in rapid degradation of hGLP-1 (50% reduction of intact peptide within 1 hour)” the researchers found that “both echidna and platypus GLP-1 were not degraded by human DPP-4…confirming that monotreme GLP-1 is resistant to DPP-4 cleavage.”

They did identify that the monotreme GLP-1 peptides were less potent at activating the GLP-1 receptors, and when they did bind, they initiated a different signaling cascade than the human version does. In an in vitro mouse test, however, they found that pGLP-1 can stimulate insulin release similar to hGLP-1.

The evolutionary reasons for the monotreme GLP-1’s resistance to degradation remain unknown, but Briony Forbes, co-lead author on the study, attributes it to a “tug of war between the different functions” in the venom and gut that “has resulted in dramatic changes in the GLP-1 system.”“Excitingly, stable GLP-1 molecules are highly desirable as potential type 2 diabetes treatments," Forbes says. Professor Grutzner agrees, saying that "These findings have the potential to inform diabetes treatment,” before recommending future research into how these new findings can be developed into medicine.

If their efforts are successful, it won’t be the first diabetes treatment to come out of an animal’s venom. The GLP-1 agonist drug exenatide is derived from that of Heloderma suspectum, the large poisonous lizard from the Southwestern United States best known as the Gila monster.

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