October 4, 2016

Cone snail venom reveals insulin insights

At a Glance

  • Researchers found that a fast-acting insulin from the cone snail can bind and activate the human insulin receptor.
  • The 3-D structure and other findings from the study provide insights for designing rapid-acting insulins to better manage diabetes.
Cone snail The marine cone snail Conus geographus hunting a fish.Baldomero Olivera, Ph.D., University of Utah

The marine cone snail releases a venom cocktail to stun its prey. The venom includes insulin, which acts within minutes to immobilize nearby fish by inducing hypoglycemic shock—a sedation-like state caused by extremely low blood sugar. Scientists have been intrigued by how rapidly this insulin works compared to human insulin.

In people, when blood glucose levels rise, such as after a meal, insulin is released from the pancreas into the blood stream. It binds to insulin receptors on tissues to trigger them to take in glucose from the blood. Diabetes occurs when this process doesn’t work correctly. In type 2 diabetes, the most common form, tissues in the body lose their sensitivity to insulin, and pancreatic cells can’t make enough insulin to keep glucose levels in check. In type 1 diabetes, the body’s own immune system attacks and destroys pancreatic cells. Many people rely on injections of synthetic insulin to manage their diabetes, and the timing can be crucial.

Human and cone snail insulin Comparison of the structures of cone snail insulin (red/white) and human insulin (blue/white and green). The green B-chain terminal segment is absent in the cone snail insulin. Michael Lawrence, Ph.D., Walter and Eliza Hall Institute of Medical Research

Human insulin is stored in the pancreas as a cluster of 6 insulin molecules bound together. To work, the human insulin molecules have to first separate into 6 individual units, a time-consuming process. In contrast, the cone snail has the smallest known insulin found in nature and works rapidly. 

An international research team led by Drs. Helena Safavi of the University of Utah and Michael Lawrence of the Walter and Eliza Hall Institute of Medical Research in Australia set out to characterize cone snail insulin to gain insights into therapeutic insulin design. The research was supported in part by NIH’s National Institute of General Medical Sciences (NIGMS). Results were published online on September 12, 2016, in Nature Structural & Molecular Biology.

Each insulin molecule consists of an A and a B chain. Cone snail insulin lacks a segment of the B chain. In human insulin, this region functions to help the hormone assemble in a cluster for storage and to interact with the insulin receptor. The researchers synthesized and purified snail insulin. They found that despite its smaller structure, the snail insulin could bind the human insulin receptor and turn on the receptor to activate signaling. 

To determine how the shorter snail insulin could bind, the team assessed its 3-D structure by using X-ray crystallography. They created a model of snail insulin bound to the human insulin receptor and compared the binding to that of human insulin.

“We found that cone snail venom insulins work faster than human insulins by avoiding the structural changes that human insulins undergo in order to function—they are essentially primed and ready to bind to their receptors,” Lawrence says. 

“You can get new ideas from venoms,” Safavi says. “To have something that has already been evolved — that’s a huge advantage.” 

—by Carol Torgan, Ph.D.

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References: A minimized human insulin-receptor-binding motif revealed in a Conus geographus venom insulin. Menting JG, Gajewiak J, MacRaild CA, Chou DH, Disotuar MM, Smith NA, Miller C, Erchegyi J, Rivier JE, Olivera BM, Forbes BE, Smith BJ, Norton RS, Safavi-Hemami H, Lawrence MC. Nat Struct Mol Biol. 2016 Sep 12. doi: 10.1038/nsmb.3292. [Epub ahead of print]. PMID: 27617429.

Funding: NIH’s National Institute of General Medical Sciences (NIGMS), National Health and Medical Research Council of Australia, Utah Science and Technology Initiative, European Commission, Victorian State Government Operational Infrastructure Support, and the University of Utah Diabetes and Metabolism Center.