Mammalian physiology has driven the evolution of endogenous insulin for effective control of hepatic glucose output and the appropriate insulinization of the periphery, e.g., muscle, fat, and kidney. The use of native insulin as a therapeutic, primarily by subcutaneous injection, alters its distribution in the body, which can lead to over insulinization of the periphery and under insulinization of the liver. Moreover, delivery through the subcutaneous tissue alters the time action profile of insulin. Consequently, the development of a therapeutic insulin or insulin receptor agonist as an effective subcutaneous therapy requires the consideration of the disposition of the therapeutic and the chemical properties that dictate the molecule properties, if safer and more effective therapies are to be created. Moreover, in addition to physiology, the pharmacology imparted by the insulin receptor and insulin must be considered to ensure it recapitulates the biology of native insulin. This talk will lay the foundation of the biology, both physiological and pharmacological, that limits current treatments and impacts the engineering of future insulin receptor agonist therapies.

Evolution of therapeutic insulin and insulin receptor agonists: Physiological and pharmacological considerations

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ACS Spring 2023

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