Insulin receptor antagonist

Researchers at Stanford have developed a potent, insulin-based, insulin receptor antagonist that could be used as a hyperinsulinism therapeutic. Congenital hyperinsulinism (HI) is a genetic disorder of pancreas and beta-cell function characterized by the failure to suppress insulin secretion in the setting of hypoglycemia, resulting in severe hypoglycemia that can cause brain damage or death if inadequately treated. Roughly 50% of HI patients can manage their condition with the existing drugs diazoxide or octreotide, but the other 50% must undergo a pancreatectomy, leading to long-term surgical complications. Thus, there is a large unmet need for patients with congenital HI that are not candidates for current drug therapies. This newly developed insulin receptor antagonist may provide a solution, providing better efficacy and fewer complications than the standard of care for HI. The antagonist has been shown to successfully reduce the activation of the insulin receptor and downstream signaling in vitro in the low nanomolar range. In addition, mice exhibit insulin resistance following treatment with the antagonist in vivo. This invention could be used as a scaffold for a new and improved HI therapeutic.

Stage of Development
Research - in vivo

Figure description:
(a) Ins-AC-S2 alone disrupts blood glucose regulation by suppressing insulin receptor activation. (b) In mice, Ins-AC-S2 treatment leads to insulin resistance, as shown by a suppressed glucose-lowering effect of insulin compared to a vehicle control.
Image credit: Park et al., Journal of Medicinal Chemistry (2023)