Treating Diabetes with Lizard Spit

Yes, you read that title correctly.

Well, more specifically, it’s the saliva of Heloderma suspectum, better known as the Gila Monster – a two-foot long, desert-dwelling lizard native to North America (pictured).

This is the story of how a once-completely-unknown molecule in lizard spit has become one of the most promising treatments for the 415 million people in the world living with diabetes today.

Back in 1992, a group of scientists decided to conduct some research into the venom of the Gila Monster, as their bite was known to cause intense and long-lasting pain. In doing so, they stumbled upon one molecule in particular, which was eventually named exendin-4. This molecule was discovered to be structurally and functionally similar to the bodily hormone, glucagon-like peptide-1, or GLP-1¹.

GLP-1 is released from the gut in response to food intake, and acts on beta cells of the pancreas to enhance the secretion of insulin². As diabetes is primarily caused by insufficient insulin action, GLP-1 had been previously considered as a potential therapy for the disease, but its short half-life (of around 2 minutes) made it virtually useless³. However, the molecule from the lizard spit – exendin-4, was found to have a much greater half-life in the body, due to some structural differences to GLP-1⁴.

The fact that this molecule could act as GLP-1, but remain active for longer was ground-breaking for the field of diabetes research. One of the main issues with other diabetes treatments, such as sulphonylureas, is that they enhance insulin secretion regardless of blood sugar levels. This means that if a patient takes the drug during a period of low blood sugar, they are at a huge risk of having a hypoglycaemic attack⁵. GLP-1 however, only enhances insulin secretion in the presence of glucose – just as effective as other treatments, but much safer!

The effects of GLP-1 (and exendin-4) don’t end there, either! It also induces weight loss⁶, which is an extremely beneficial property – particularly as 85% of patients with type II diabetes develop this as a direct result of obesity⁷.

For these reasons, the discovery of exendin-4 was hugely exciting to the world of diabetes, and a more easily-reproducible, synthetic version was quickly produced and approved – exenatide¹.

Although a successful drug, exenatide never reached its full potential. The main reason for this lies in its administration method – twice-daily injections. As exenatide is a protein drug, it cannot be taken orally, as proteolytic enzymes in the stomach would simply digest it before it had a chance to be absorbed into the bloodstream. Patients disliked this administration method, particularly as it was twice-daily, which meant compliance was low⁸. Although many other so-called ‘GLP-1 agonists’ were subsequently developed, they all had this same problem, preventing the whole drug class from reaching its true potential⁹.

However, this all changed when in April 2020, Novo Nordisk’s oral formulation of the GLP-1 agonist ‘semaglutide’ was approved by the European Medicines Agency¹⁰. In this formulation, the semaglutide molecule is bound to a molecule called SNAC – a buffer which acts to neutralise the stomach pH immediately surrounding it, and therefore, protecting it from degradation¹¹. This drug completely puts GLP-1 agonists on the map, and is set to change the face of diabetes treatments forever.

To me, the fact that all of this has come from lizard spit, provides hope that treatments for many other diseases may be out there somewhere too – just waiting to be discovered.

Chas Smith

References

1. Eng, J., Kleinman, W., Singh, L., Singh, G., and Raufman, J. (1992). Isolation and characterisation of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem. 267: 7402-5.
2. Herman, W. (2015). Response to Comment on Inzucchi et al. Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach. Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38:140–149. Diabetes Care38: e143-e143.
3. Hemmingsen, B., Sonne, D., Metzendorf, M., and Richter, B. (2017). Dipeptidyl-peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 analogues for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk for the development of type 2 diabetes mellitus. Cochrane Database Of Systematic Reviews.
4. Kolterman, O., Buse, J., Fineman, M., Gaines, E., Heintz, S., and Bicsak, T. et al. (2003). Synthetic Exendin-4 (Exenatide) Significantly Reduces Postprandial and Fasting Plasma Glucose in Subjects with Type 2 Diabetes. The Journal Of Clinical Endocrinology & Metabolism88: 3082-3089.
5. Nenquin, M., and Henquin, J. (2016). Sulphonylurea receptor-1, sulphonylureas and amplification of insulin secretion by Epac activation in β Diabetes, Obesity And Metabolism18: 698-701.
6. Chelikani, P., Haver, A., and Reidelberger, R. (2005). Intravenous infusion of glucagon-like peptide-1 potently inhibits food intake, sham feeding, and gastric emptying in rats. American Journal Of Physiology-Regulatory, Integrative And Comparative Physiology 288: R1695-R1706.
7. Sullivan, P., Ghushchyan, V., and Ben-Joseph, R. (2008). The impact of obesity on diabetes, hyperlipidemia and hypertension in the United States. Quality Of Life Research17: 1063-1071.
8. Nguyen, H., Dufour, R., and Caldwell-Tarr, A. (2017). Glucagon-Like Peptide-1 Receptor Agonist (GLP-1RA) Therapy Adherence for Patients with Type 2 Diabetes in a Medicare Population. Advances In Therapy34: 658-673.
9. Federici, M., McQuillan, J., Biricolti, G., Losi, S., Lebrec, J., and Richards, C. et al. (2018). Utilization Patterns of Glucagon-Like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus in Italy: A Retrospective Cohort Study. Diabetes Therapy9: 789-801.
10. A/S, N., 2020. Rybelsus® (Oral Semaglutide) Approved For The Treatment Of Adults With Type 2 Diabetes In The EU. [online] GlobeNewswire News Room. Available at: https://www.globenewswire.com/news-release/2020/04/04/2011789/0/en/Rybelsus-oral-semaglutide-approved-for-the-treatment-of-adults-with-type-2-diabetes-in-the-EU.html
11. Buckley, S., Bækdal, T., Vegge, A., Maarbjerg, S., Pyke, C., and Ahnfelt-Rønne, J. et al. (2018). Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. Science Translational Medicine10: eaar7047.