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 consistently 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 the currently available fast-acting insulin therapeutics, which restricts the effectiveness of insulin therapy. Efforts to develop new fast-acting insulins have been limited by the involvement of the same residues in both insulin dimerization and receptor binding, which presents the conundrum that mutations that increase speed of availability also negate signaling. Consequently, no new fast-acting insulins have been approved in the past decade. To overcome this fundamental blockage, we are taking an approach that is inspired by recent insights from the study of fish-hunting cone snails that use a specialized venom insulin variant to rapidly induce hypoglycemic shock in their prey. Our preliminary data show that this venomous insulin is monomeric, binds to human insulin receptor, activates the insulin-signaling pathway, and reduces blood sugar levels in mice. These data provide a strong foundation to learn further insights from the fascinating arsenal of venomous insulins. Successful outcome will provide a platform upon which a powerful new class of therapeutics can be developed for the treatment of diabetes.
We are studying novel insulin molecules discovered from the venom of fish-hunting cone snails to learn how determinants that restrict biological availability can be separated from those that mediate signaling. Successful outcome will allow the development of a new class of stable, concentrated, ultrafast-acting insulin formulations and dramatically advance the treatment of diabetes.