Thursday, February 5, 2015

Venomous Insulin: Cone Snails and Their Specialized Chemical-Weapon

By Diana Zafra

As a biologist with a sweet tooth who consumes more sugar than any dentist would approve of, I’m amazed with how the beta-cells in my pancreas responds to the high glucose levels, in my blood, with the release of insulin. Insulin is a necessary regulatory hormone that transports and stores glucose into our cells for the production of energy.  

Although insulin is necessary for regulating glucose in the blood from getting too high (hyperglycemia) or too low (hypoglycemia), there is a dark side to this hormone. I was pretty intrigued when I read about a recent experiment that discovered its use as a chemical-weapon. Just think about that: insulin is used in nature to kill. Cone snails produce a cocktail of neurotoxins that include large amounts of insulin, to facilitate predation.

Brief Introduction to Cone Snails
Two species of cone snail that have net-like mouths to swallow prey

In the genus Conus, members usually have two mechanisms of secreting their venom. Some members inject their venom by harpooning fish while the second mechanism involves releases of venom into the surrounding area when they detect fish nearby. 

Conus produce conotoxin, or venom, that targets the nervous system and is produced in a long venom duct, similar to a “hypodermic needle,” used to inject its prey. The red part in the picture below is where the insulin and conotoxins are located.
Safavi-Hemami et al. PNAS 2014.

Hu et al. BMC Genomics 2012.  
The most dangerous species of cone snail is Conus geographus, and they have a net-like false mouth to swallow their prey whole. In order to catch their faster swimming prey, such as schools of fish, they release the nirvana cabal, the toxin combination of venoms released, to disorient and slow them down. This allows the snail to make its way towards the fish and engulf them whole. After a couple of hours, they regurgitate the scales and bones, while digesting their soft tissue (Yum!).

Experiments on Zebrafish
The use of venom by cone snails to paralyze their prey is no novelty and recordings date back to 1956. However, a recent experiment conducted by Dr. Helena Safavi-Hemami, from The University of Utah, discovered that within the nirvana cabal, there was a high presence of insulin in the dorsal end of the needle inside of the snail. In the experiment, the venom of C. geographus was both injected directly into zebrafish and released into the water columns in which zebrafish larvae were then observed for changes in mobility.

Zebrafish! Aren't they cute? 
When analyzing the individual components in the venom, they discovered two main types of insulin. One type, labeled conus insulin 1 (Con-Ins-G1) made up 99% of the distal end of the injection tip. This immobilized zebrafish when injected due to glucose levels falling far below what is necessary for the cells to properly function, otherwise known as a hypoglycemic shock.
Fig 5A Showing insulin activity in zebrafish
The graph above depicts the results of an experiment where zebrafish blood glucose was measured prior to any treatment (baseline group). Then they were injected with streptozotocin (STZ), which is an agent used to induce hyperglycemia. That’s when the higher glucose levels in the blood are observed (p<.01). Shortly afterwards, the STZ injected zebrafish were injected with human insulin, while others were injected with the snail cone insulin and both significantly (P< .003) reduced the blood glucose levels.  

When the Con-Ins-G1 was added to the water, they observed zebrafish larvae swimming much slower than the control group, where no insulin was added. (Select the link below to see the effects!)

It appears that the insulin in their venom is tailored to match their prey’s insulin. The insulin in their venom matches fish insulin more than molluscan insulin. Expression of insulin in most mollucs is primarily expressed in their cells that make up their nervous system such as neurons and cerebral ganglia. The insulin in the venom is believed to activate the other chemical compounds of the nirvana cabal and induce hypoglycemic shock on its prey. This insulin is also much smaller than that discovered on any other organism, which scientists speculate allows for its quick action. This is the first time insulin has been documented to be used as venom in nature.

Although Conus geographus measure only between 4-6 inches in size, its venom is so powerful that there have been instances of human deaths from accidental encounters. In humans, plunging drops in glucose result in disorientation, unconsciousness, and eventually death by respiratory paralysis, if left untreated. This snail was even coined “cigarette snail” because old tales claimed that if stung by one of these snails, you'd be dead before you finished smoking a cigarette. 

The Future of This Novel Insulin
So how could these types of studies ever come to relate to people? Why should we be interested in this venomous insulin?  These types of studies could lead to new pharmaceuticals.
A drug resulted from gila monster venom!

It wouldn't be the first time since the discovery of exendin-4 protein from venom in gila monsters resulted in the development of the commercial drug exenatide, used to treat diabetes mellitus. Exendin-4 isn't insulin and varies from the mechanism of cone snail insulin because it causes its prey to overproduce its own insulin. Yet these types of studies may help scientists understand how insulin size could influence its action and could help with use for drug therapies. As with most exciting novelties in science, further studies for this novel insulin will likely be focused on finding out the the genes responsible for the production of this deadly insulin. 


Journal articles
Hu, H., P. K. Bandyopadhyay, B.M. Olivera, and M. Yandell. 2012. Elucidation of the molecular envenomation strategy of the one snail Conus geographus through transcriptome sequencing of its venom duct. BMC Genomics 13:284. doi:10.1186/1471-2164-13-284

Safavi-Hemami, et al. 2014. Specialized insulin is used for chemical warfare by fish hunting cone snails. Proceedings of the National Academy of Sciences published ahead of print January 20, 2015, doi:10.1073/pnas.1423857112.

Online sources

Cone Snail
Jason Biggs and Baldomero Oliver

Gila Monster

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