For people with diabetes, maintaining optimal blood glucose levels is crucial in delaying and preventing short and long-term complications. One of the key challenges lies in the slow onset and long duration of fast-acting insulin action, which affects the feasibility of intensive insulin therapy. This delay is due to insulin’s propensity to form dimers and hexamers which limits its diffusion into the bloodstream after injection. To develop an ultra-fast acting insulin (UFI), insulin hexamers and dimers must dissociate into monomers to permit absorption into the bloodstream. The last 8 amino acids on the B-chain are crucial for dimer formation and insulin receptor binding, however removing these 8 residues to yield a monomeric insulin results in an inactive analogue. Thus a truly monomeric, UFI does not exist and efforts to develop it have led to limited success<i>. </i>In this project we are inspired by a recently discovered and naturally occurring UFI (Con-Ins G1) produced by the fish-hunting cone snail, <i>Conus geographus.</i> Con-Ins G1 is monomeric, binds to the human insulin receptor, activates the insulin signaling pathway, and is able to rapidly induce hypoglycemic shock in fish despite lacking the dimer forming region. Using solid-phase peptide synthesis and total chemical synthesis in conjunction with mutational studies, we have generated a series of analogues to obtain a better understanding of how various residues on Con-Ins G1 play a critical role in binding to the human insulin (HI) receptor. Thus far we have identified key amino acids which seem to play a synergistic role in how Con-Ins G1 binds to the HI receptor. Our goal is to understand how both Con-Ins G1 and HI bind to the HI receptor with the ultimate goal of generating human monomeric UFI which could dramatically improve the lives of diabetic patients by providing improved glycemic control.

Venomous insulin molecules: A bioinspired approach for the treatment of diabetes

256th National Meeting (2018)

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