Weaponized insulin: how the venom of a sea-dwelling predator could treat diabetes

Written by: Padmini S. Pillai

Original Article: Safavi-Hemami et al. PNAS 2015
The Gist of it:
The history of medicine is filled with tales of converting poisons into potions. Researchers have now discovered that the venomous cocktail released by deadly sea-dwelling snails could potentially lead to a fast-acting diabetes drug.
Cone snails are native to coral reefs found in the warm waters of the Indo-Pacific. These predators hide in tiny crevices to stalk schools of small fish and paralyze them with neurotoxin-laden harpoons. A subset of cone snails called net-hunters trap their meals by first secreting a venom called nirvana cabal to disorient potential victims. Next, they extend a false mouth to engulf their now delirious prey. An injection of paralytic toxins then serves as the final blow. Scientists knew nirvana cabal was responsible for the rapid deceleration and dazed stupor of these fish, but what ingredient in this noxious cocktail was causing fish to fall prey to the snails’ deadly embrace?
A study led by Dr. Baldomero Olivera found that insulin is the major component of nirvana cabal. Produced by pancreatic cells in humans, insulin lowers blood sugar levels in the body. In cone snails, the nervous system makes insulin to control sugar metabolism. In contrast, the weaponized insulin net-hunters use on prey is made in the venom gland. When fish take in the venom through their gills, it enters their bloodstream, causing hypoglycemia, or low blood sugar, rapidly slowing their movement. This allows the snail to seize its prey.
Olivera’s team analyzed DNA from the venom glands of two cone snail species and found a sequence that looked like that of the insulin gene of fish, not the insulin gene of the predator itself. They injected the molecule encoded by that DNA, called Con-Ins G1, into zebrafish and observed a significant drop in blood sugar. Similarly, when added to a fish tank, Con-Ins G1 caused fish to slow down and swim less. Likewise, worm-eating cone snails produce worm-specific insulin in their venom glands instead of the fish-specific insulin. This suggests that the type of weaponized insulin released by the net-hunting cone snail depends on its diet.
The conclusions of this study are not entirely morbid. Studies into the structure of cone snail venom insulin and a comparison with human insulin could possibly lead to better diabetes medications with fewer side effects. It turns out that this venomous, picky eater’s need to slow down its prey could eventually pave the way for a new generation of life-saving drugs.
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Cone snail venom contains a fast-acting insulin to slow down prey.

The Nitty Gritty:
The researchers performed next-generation sequencing on the transcriptome of the Conus geopraphus venom gland and identified a transcript, Con-Ins G1, with high sequence similarity to fish insulin. Con-Ins G1 was most highly expressed and almost exclusively found in the distal region of the venom gland, closest to the injection apparatus. C. tulipa, another cone snail that uses the net-hunting strategy to capture prey, expressed similar insulin transcripts. Analysis of mollusc- and worm-hunting cone snails revealed that the type of insulin expressed in the venom gland correlated with its diet. Sequencing of the Con-Ins G1 protein by mass spectrometry revealed novel post-translational modifications. Chemical synthesis of the molecule was performed using selenocysteines. To study the effects of synthetic Con-Ins G1 (sCon-Ins G1), streptozotocin was injected intraperitoneally into zebrafish to induce hyperglycemia. Administration of sCon-Ins G1significantly lowered blood glucose, which was similar to the effect of human insulin. When sCon-Ins G1 was applied to the water column of a fish tank containing zebrafish larvae, researchers observed reduced locomotor activity, as measured by time spent swimming and movement frequency.
Original Research Article: Safavi-Hemami, H., et al. “Specialized insulin is used for chemical warfare by fish-hunting cone snails.” Proceedings of the National Academy of Sciences of the United States of America 201423857 (2015). doi:10.1073/pnas.1423857112

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