The efficient and long course treatment of type 2 diabetes is something that is still much researched and debated by science. A new study, released this week through the journal Nature, has shown that Monotremes, a mammal order that contains both the platypus and the echidna, could show the way towards novel and more efficient treatment.
Type 2 diabetes and human glucose regulation
According to The British Dietetic Association (BDA), Diabetes is a condition where the amount of glucose (sugar) in your blood is too high because the body cannot use it properly. In Type 2 diabetes this is caused either by the pancreas’ inability to produce enough of the hormone insulin (that helps glucose enter body cells and be efficiently utilized by the body) and/or the insulin that is produced does not work correctly (insulin resistance).
There are two keys types of treatment for Type-2 diabetes:
- Medication that helps the body produce more insulin
- Medication that aims to make tissues more sensitive to insulin
It is the neuropeptide (small molecule used by neurons to ‘communicate’) GLP-1 (Glucagon-like Peptide 1) that promotes insulin release into the bloodstream. It also inhibits glucagon release. Both of these actions aim to reduce blood glucose levels when they are too high. GLP-1 plays an essential role in both metabolism regulation and is one of the only insulin stimulating hormones, along with GIP (Gastric Inhibitory Polypeptide) known to be produced by humans. Both are released from intestinal cells after food intake.
Components of the incretin (metabolic hormones that stimulate a decrease in blood glucose levels) and insulin systems, whilst playing play an essential role in human metabolic regulation, is exploited in a rather different way by venomous species.
These species make the most of the importance of glucose regulation in maintaining efficient body function: Their venom contains incretin molecules that causes a rapid and debilitating effects of low blood glucose which quickly incapacitates their prey by causing severe hypoglycemic shock. Within this context, the GLP-1 is more resistant to DPP-4 enzyme breakdown meaning that GLP-1 has more time to promote insulin release and thus makes the venom more efficient in ‘draining’ the prey’s glucose resources.
This ‘enzyme resistant’ form of GLP-1 however is only found in the venom of these specialized animals, not in their active metabolic system: They have 2 GLP-1 systems: One, with longer lifespan, to conserve the efficiency of their venom and a second, shorter in lifespan and similar to human GLP-1, used in their digestive metabolism. Examples of the evolution of venom components affecting glucose homeostasis include:
– The Gila Monster lizard (Heloderma suspectum) expresses a Glp-1 like gene, Exendin-4, in its venom. The functions of this gene currently underpins a major type 2 diabetes drug.
– Cone Snail’s Venom also contains a fish-like insulin mimetic that is used to incapacitate prey
– Various snake species, including the Malaysian King Cobra, produce GLP-1 degrading enzyme (DPP-4) in their venom.
Although scientists have already learnt a considerable amount from these species, this new study has demonstrated that monotremes use an alternative system to construct and use GLP-1 which could prove highly instrumental in developing more efficient Type-2 Diabetes drugs.
Indeed, in the human body, any GLP-1 released into the bloodstream is quickly degraded in the gut by specialised enzymes (DPP-4). This short lifespan of GLP-1 much complicates the treatment of Type-2 diabetes as the life-span of the molecule is too short to promote sufficient insulin production for insulin resistant tissues. The problem is getting the longer lived GLP-1 like substances, observed in some venoms, to work as efficiently within the human body as the ‘normal’ GLP-1… And the platypus might hold the answer.
The study focused on monotremes as they are currently viewed as issued from the most ‘basal’ lineage of extant mammals. Additionally they also present unique metabolic mechanism changes, that are differentiated from other mammals on a molecular and genetic level, in their digestive system. This includes for example modification to protein breakdown mechanics. Additionally, monotremes produce venom during the breeding season – for example the platypus has develops a venomous claw. All of these factors led researchers to believe they could be an interesting candidate for discovering new glucose management resources.
A study of the genomic sequencing specific to the regulation of protein function revealed that, contrary to other animals that use GLP-1 in venom, monotremes have one unique GLP-1 molecule, that is used both in their venom and in their metabolism. This is the first time this has been observed and exploitation of such mechanisms could pave the way for faster acting and more efficient drugs for treating Type-2 Diabetes with less compatibility issues. The researchers also observed that monotreme, especially platypus, GLP-1 demonstrated unique affinity traits and activation characteristics. The potential uses of which are extremely exciting but as yet unsure.
The British Dietetic Association (BDA), 2016. ‘Diabetes Type 2’ Available here: https://www.bda.uk.com/foodfacts/diabetestype2.pdf
Tsend-Ayush, E. C. Myers, M. Andrikopoulos, S. Wong, N. Sexton, P. M. Wootten, D. Forbes, B. E. and Grutzner, F. (2016) ‘Monotreme glucagon-like peptide-1 in venom and gut: one gene – two very different functions’ Scientific Reports 6 : 37744
Read the full article here: http://www.nature.com/articles/srep37744
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