For people with diabetes, maintaining optimal blood glucose levels is effective in delaying or even preventing long-term complications. Tremendous efforts have been made in developing fast-acting and long-lasting analogues to provide better glycemic control compared to native insulin. Unfortunately, most people are unable to meet their target glycemic range, and aggressive efforts to reach this goal can cause frequent and potentially life-threatening episodes of hypoglycemia. A key challenge lies in the slow onset and long duration of fast-acting insulin action, which affects the feasibility of intensive insulin therapy. However, there are no new fast-acting insulins that have been approved in the past decade. To address this challenge, we take a bioinspired approach to develop an ultrafast-acting insulin (UFI) to overcome the obstacles. Fish-hunting cone snails use a specialized venom insulin to rapidly induce hypoglycemic shock in fish. We and collaborators have shown that this venomous insulin is monomeric, binds to human insulin receptor, activates the insulin signaling pathway, and reduces blood sugar levels in mice. These strong preliminary results provide a rational basis to develop an UFI based on the snail venom insulin structure. In this proposal, we seek to study the biochemical and cellular properties of a series of venomous insulin molecules. This new ultrafast-acting insulin technology utilizes evolutionary biology, protein engineering, and peptide chemistry approaches to develop a new therapeutic that could revolutionize clinical care and improve the health of people with diabetes.<br/> <br/>

Human monomeric insulin derived from cone snail venoms

253rd National Meeting (2017)

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