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Platypus Venom Spurs Diabetes Treatment

Credit: 169169/Adobe

Credit: 169169/Adobe

By Natasha Bradley

Radical evolutionary changes in a hormone involved in glucose control might lead to a new treatment for type 2 diabetes derived from platypus venom.

Diabetes is one of the biggest health burdens the world is currently facing. About 85% of diabetics have type 2 diabetes, which develops if the pancreas doesn’t secrete enough insulin or the body becomes resistant to insulin’s effects.

Early stages of type 2 diabetes management typically involve lifestyle and diet changes. As the disease progresses, oral medication such as metformin or exenatide are recommended, and eventually insulin injections may be necessary.

We have found a new potential treatment option for type 2 diabetes in a place you might least expect: platypus venom. How could something in venom help people with diabetes? To understand that you might first need some background information.

To function properly, our body needs to maintain a certain level of glucose in our blood. To achieve this, glucose levels are tightly controlled by two major hormones called insulin and glucagon. After we eat a meal, glucose diffuses into the bloodstream, causing an increase in blood sugar concentration (especially if you had that extra bit of chocolate). This triggers the release of insulin, which tells the liver, as well as muscle and fat cells, to absorb glucose from the blood. If there is too much glucose available, insulin will also signal to the liver to convert it to glycogen for energy storage. This will reduce glucose levels to within their optimal range.

However, if we don’t eat for a while or if we exercise and use a lot of energy, our glucose levels will drop. This triggers the release of glucagon, a hormone that tells liver cells to convert glycogen back to glucose for release into the blood. The balance between insulin and glucagon allows dynamic control of glucose concentration; insulin lowers the concentration when it gets too high, and glucagon increases the concentration when glucose levels get too low.

Insulin and glucagon are not the only players in the complex game of glucose control. In 1964, Mcintyre and colleagues found that glucose produces a greater insulin response when ingested orally rather than injected. This suggested that other factors in the gut are involved in the insulin response.

It took many years to identify these factors, but they were eventually identified as glucose-dependent insulinotropic peptide and glucagon-like peptide 1 (GLP-1). Both prime the pancreas for the release of insulin.

Interestingly, this pathway is targeted by the venom of some animals. Two cone snail species have evolved a toxic version of insulin that is expressed in their venom, causing hypoglycaemic shock (dangerously low glucose levels) in the fish upon which they prey.

There are many aspects of GLP-1 that we still don’t understand, but we do know that it’s involved in liver cell growth, appetite control and weight loss. This has made GLP-1 an important target for treatment of type 2 diabetes. Drugs targeting the GLP-1 receptor have been developed, resulting in similar effects produced by GLP-1 itself.

One of the big problems with GLP-1 is that it’s broken down and inactivated within minutes of its release into the bloodstream. This is caused by an enzyme called dipeptidyl peptidase-4 (DPP-4), which cuts the GLP-1 protein at a specific site in its amino acid chain. This finding led to the development of another branch of treatments that inhibit DPP-4, allowing GLP-1 to stick around a little longer and help produce more insulin.

So how are platypuses involved in all this? The humble Australian platypus and echidna are the only existing species of monotremes. They are the only egg-laying mammals, and as the oldest surviving mammalian lineage provide unique insights into mammalian evolution. In addition, monotremes have undergone some unique changes since they diverged from our common mammalian ancestor.

Monotremes have undergone particularly radical changes in their digestive system. The stomach of the platypus and echidna has become completely non-functional, and simply acts like a slightly wider oesophagus. While our stomachs are highly acidic to help kill ingested bacteria and help enzymes in the stomach digest food, the pH in the stomach of monotremes is completely neutral.

When the platypus genome was analysed in 2008, researchers also investigated the genes involved in stomach function and digestion. They found that many conserved genes involved in mammalian stomach size and acid secretion were missing in the platypus. This loss of genes made sense for the platypus, considering its small stomach size and neutral pH, but is very unusual compared with other animals as the genes are present in fish, birds and humans. Along with the missing genes, some had been changed so that they did not appear to function anymore or functioned in a slightly different way.

Surprisingly, our research group has found that GLP-1, which is usually only produced in the gut, was produced in both the gut and venom of platypus. Furthermore, its GLP-1 had undergone some remarkable changes to its sequence.

One particular change was very exciting because it was at the location where DPP-4 cuts and inactivates GLP-1. Even though this is only a single amino acid change, it has big potential as it suggests that platypus GLP-1 may be resistant to DPP-4 breakdown.

We have confirmed this with both platypus and echidna GLP-1 tested against human serum. Additionally, we showed that monotreme GLP-1 was capable of stimulating the release of insulin in the pancreatic cells of mice.

As strange as it sounds, this isn’t the first time venom biochemistry has had clinical implications. In fact, the most common type 2 diabetes treatment on the market was developed from a hormone found in the venom of the gila monster (a type of lizard). This hormone, called exendin-4, is also resistant to DPP-4 degradation, just like monotreme GLP-1.

Exendin-4 is a gene that is similar to GLP-1 and may have evolved from GLP-1. At some point, the gene encoding GLP-1 was duplicated and expressed in gila monster venom instead of the gut. This gene then underwent evolutionary changes to optimise its function in venom, and became exendin-4. One of the major differences is that exendin-4 is a different gene only expressed in venom, while monotremes express the same GLP-1 in both venom and the gut with different functions.

Generally, venom is used as protection to fend off other species or catch prey. However, platypus venom is only produced by males, and is used to attack other males to induce hypoglycaemic shock and affect their ability to mate.

This has created an interesting tug-of-war between the dual functions of GLP-1 in the gut and venom of platypus. We think that this dual function in the gut and venom led to the changes observed in GLP-1.

Interestingly, monotremes have developed a different way of breaking down GLP-1, which is likely to have evolved to help platypuses become more resistant to its effects in the venom. This has made monotreme GLP-1 an exciting new avenue for treatment of type 2 diabetes.

The next step towards a new treatment is testing monotreme GLP-1 in a mouse model. We recently received funding to explore the therapeutic potential of monotreme GLP-1 further. We will be testing the effects of monotreme GLP-1 on glucose tolerance, weight loss, food intake and other metabolic parameters.

Although there is much work to be done, we hope that insights from monotreme GLP-1 will provide a basis for more effective treatments of type 2 diabetes.

Natasha Bradley is a PhD student in the Department of Molecular and Biomedical Sciences at the University of Adelaide.