University of Utah, United States, researchers have found that the structure of an insulin molecule produced by predatory cone snails may be an improvement over current fast-acting therapeutic insulin.
Exposure to commonly used insecticide associated with diabetesUniversity of Utah, United States, researchers have found that the structure of an insulin molecule produced by predatory cone snails may be an improvement over current fast-acting therapeutic insulin.
The finding suggests that the cone snail insulin, produced by the snails to stun their prey, could begin working in as few as five minutes, compared with 15 minutes for the fastest-acting insulin currently available.
Biologist Helena Safavi, co-author on a paper describing the cone snail insulin published in Nature Structural & Molecular Biology, said that studying complex venom cocktails can open doors to new drug discoveries. “You look at what venoms animals make to affect the physiology of their prey, and you use that as a starting point,” she says. “You can get new ideas from venoms. To have something that has already been evolved — that’s a huge advantage.”
Along with colleagues from Australia, U biochemists Danny Chou and Maria Disotuar, and biologists Joanna Gajewiak and Baldomero Olivera contributed to the study. Also, organophosphates (OP), the most frequently used insecticides worldwide, could induce high blood sugar (hyperglycemia) and glucose intolerance when decomposed by gut bacteria, according to a study published in the open access journal Genome Biology.
Surveying 3080 people in a rural population in India, scientists at Madurai Kamaraj University showed that the prevalence of diabetes in people regularly exposed to OP insecticides was three fold higher (18.3 per cent) than in unexposed people (6.2 per cent), while the prevalence of traditional risk factors like obesity, hypercholesterolemia and physical inactivity in this population was low.
To examine whether chronic exposure to OP may be a risk factor for hyperglycemia, the researchers fed groups of up to ten mice an OP insecticide in drinking water for a period of 180 days, which is the equivalent of 12-15 years of human life. OP-fed mice exhibited a slow and steady increase in blood glucose levels and significantly elevated blood sugar levels after 180 days, as well as impaired glucose intolerance compared to controls.
OP pesticides target the neurotransmitter acetylcholine esterase, which acts on the synapses of nervous and muscular systems and causes convulsion, respiratory failure and death of insects and mammals. The researchers were surprised to find no changes in levels of acetylcholine esterase in the blood of OP-fed mice. The discovery prompted them to investigate the role played by the gut microbiota in OP-induced hyperglycemia by transplanting fecal samples from both OP-fed animals and controls in randomly selected mice. The researchers found that mice, which received fecal transplants from OP-fed mice exhibited significant glucose intolerance. The authors also noticed changes in the gut microbiota, including higher numbers of OP degrading bacterial enzymes. Degradation of OP produces short chain fatty acids – specifically acetate – which in turn leads to the generation of glucose, elevated blood sugar levels and glucose intolerance, according to the researchers.
Further tests on fasting blood and fecal samples from the human study population suggested similar links between OP degradation and hyperglycemia in humans. Based on these findings, the authors conclude that the effects of chronic exposure to OP pesticides on the gut microbiome may be a risk factor for diabetes. They suggest that the use of OP pesticides should be reconsidered.
Meanwhile, human insulin is a hormone that is produced in the pancreas and secreted to aid in the body’s uptake of glucose. The insulin molecule consists of an “A” region and a “B” region. Diabetes mellitus disorders arise from impairment of the body’s normal production of insulin. The most effective treatment for diabetes is injection of synthetic insulin. But a part of the B region causes insulin molecules to stick together and form aggregations of six insulin molecules. It’s how insulin is stored in the pancreas. But injected insulin must de-aggregate into individual molecules before doing a person any good – and that process can take up to an hour. The fastest-acting insulin on the market, Humalog, still takes 15-30 minutes to become active. “The ideal scenario would be to take the region off of the B chain,” Safavi said. “But then you completely abolish insulin activity.”
Chou, Safavi, and colleagues found that insulin produced by the cone snail Conus geographus lacked the segment of the B region that causes aggregation. Tests on insulin receptors in the lab showed that although the snail insulin was less effective than human insulin, it was still effective, and could possibly start acting in five minutes.
The Conus geographus snail is a predatory cone snail, eating fish. C. geographus and its relatives have developed complex brews of venoms to rapidly paralyze prey fish. Some snails use venom to overload the fish’s nervous system, sending it into “excitotoxic shock.” Others, including C. geographus, secrete insulin, alongside other compounds, into the water, causing the blood sugar in nearby fish to plummet and sending the fish into hypoglycemic sedation. Once the fish is stunned, the snail engulfs and consumes it.
In 2015, Safavi and U biology professor Baldomero Olivera described C. geographus’ so-called “weaponized insulin,” suited for quick action. In a related paper published August 16 in Molecular Biology and Evolution, Safavi and colleagues describe how weaponized insulins evolved rapidly to more effectively target prey.
“It makes sense because the snail has to very rapidly induce insulin shock in its fish prey, so it has evolved something very fast acting,” Safavi said.
Studying the structure of the cone snail insulin could help researchers modify human insulin to lose its self-aggregation but retain its potency, Safavi said. “Now we can look at the human insulin and see if we can make it more snail-like.”
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