New Insulins, Biosimilars, and Insulin Therapy.

Exogenous insulin has greatly changed the outlook for patients with diabetes ever since its discovery and isolation. Yet, serious complications can result as patients experience both hyperglycemic and hypoglycemic states, even when they strictly follow an insulin regimen. Several chemically or genetically modified insulins have been developed that tune the pharmacokinetics of insulin activity for personalized therapy. In this article, we demonstrate a strategy for the chemical modification of insulin intended to promote both long-lasting and glucose-responsive activity through the incorporation of an aliphatic domain to facilitate hydrophobic interactions, as well as a phenylboronic acid for glucose sensing. These synthetic insulin derivatives enable rapid reversal of blood glucose in a diabetic mouse model following glucose challenge, with some derivatives responding to repeated glucose challenges over a 13 h period. The bestperforming insulin derivative provides glucose control that is superior to native insulin, with responsiveness to glucose challenge improved over a clinically used long-acting insulin derivative. In addition, continuous glucose monitoring reveals responsiveness matching that of a healthy pancreas. NEW INSULINS, BIOSIMILARS, AND INSULIN THERAPY S-53