Australian researchers have discovered remarkable evolutionary changes to insulin regulation in two of the nation’s most iconic native animal species – the platypus and the echidna – which could pave the way for new treatments for type 2 diabetes in humans.
The males of the extraordinary semi-aquatic mammal – one of the only kind to lay eggs – have venomous spurs on the heels of their hind feet.
The poison is used to ward off adversaries.
But scientists at the University of Adelaide and Flinders University have discovered it contains a hormone that could help treat diabetes.
The hormone, known as glucagon-like peptide-1 (GLP-1), is normally secreted in the gut of both humans and animals, stimulating the release of insulin to lower blood glucose.
But GLP-1 typically degrades within minutes.
In people with type 2 diabetes, the short stimulus triggered by GLP-1 isn’t sufficient to maintain a proper blood sugar balance. As a result, medication that includes a longer lasting form of the hormone is needed to help provide an extended release of insulin.
“Our research team has discovered that monotremes – our iconic platypus and echidna – have evolved changes in the hormone GLP-1 that make it resistant to the rapid degradation normally seen in humans,” says co-lead author Professor Frank Grutzner, from the University of Adelaide’s School of Biological Sciences and the Robinson Research Institute.
“We’ve found that GLP-1 is degraded in monotremes by a completely different mechanism. Further analysis of the genetics of monotremes reveals that there seems to be a kind of molecular warfare going on between the function of GLP-1, which is produced in the gut but surprisingly also in their venom,” he says.
The platypus produces a powerful venom during breeding season, which is used in competition among males for females.
“We’ve discovered conflicting functions of GLP-1 in the platypus: in the gut as a regulator of blood glucose, and in venom to fend off other platypus males during breeding season. This tug of war between the different functions has resulted in dramatic changes in the GLP-1 system,” says co-lead author Associate Professor Briony Forbes, from Flinders University’s School of Medicine.
“The function in venom has most likely triggered the evolution of a stable form of GLP-1 in monotremes. Excitingly, stable GLP-1 molecules are highly desirable as potential type 2 diabetes treatments,” she says.
Professor Grutzner says: “This is an amazing example of how millions of years of evolution can shape molecules and optimise their function.
“These findings have the potential to inform diabetes treatment, one of our greatest health challenges, although exactly how we can convert this finding into a treatment will need to be the subject of future research.”
GLP-1 has also been discovered in the venom of echidnas. But while the platypus has spurs on its hind limbs for delivering a large amount of venom to its opponent, there is no such spur on echidnas.
“The lack of a spur on echidnas remains an evolutionary mystery, but the fact that both platypus and echidnas have evolved the same long-lasting form of the hormone GLP-1 is in itself a very exciting finding,” Professor Grutzner says.
The importance of Glucagon like peptide 1 (GLP-1) for metabolic control and insulin release sparked the evolution of genes mimicking GLP-1 action in venomous species (e.g. Exendin-4 in Heloderma suspectum (gila monster)). We discovered that platypus and echidna express a single GLP-1 peptide in both intestine and venom. Specific changes in GLP-1 of monotreme mammals result in resistance to DPP-4 cleavage which is also observed in the GLP-1 like Exendin-4 expressed in Heloderma venom. Remarkably we discovered that monotremes evolved an alternative mechanism to degrade GLP-1. We also show that monotreme GLP-1 stimulates insulin release in cultured rodent islets, but surprisingly shows low receptor affinity and bias toward Erk signaling. We propose that these changes in monotreme GLP-1 are the result of conflicting function of this peptide in metabolic control and venom. This evolutionary path is fundamentally different from the generally accepted idea that conflicting functions in a single gene favour duplication and diversification, as is the case for Exendin-4 in gila monster. This provides novel insight into the remarkably different metabolic control mechanism and venom function in monotremes and an unique example of how different selective pressures act upon a single gene in the absence of gene duplication.