Anti-Insulin Receptor Antibodies Improve Hyperglycemia in a Mouse Model of Human Insulin Receptoropathy.

Loss-of-function mutations in both alleles of the human insulin receptor gene (INSR) cause extreme insulin resistance (IR) and usually death in childhood, with few effective therapeutic options. Bivalent antireceptor antibodies can elicit insulin-like signaling by mutant INSR in cultured cells, but whether this translates into meaningful metabolic benefits in vivo, wherein the dynamics of insulin signaling and receptor recycling are more complex, is unknown. To address this, we adopted a strategy to model human insulin receptoropathy in mice, using recombinase delivered by adeno-associated virus to knockout endogenous hepatic acutely in floxed mice (liver insulin receptor knockout [L-IRKO] + GFP), before adenovirus-mediated add back of wild-type (WT) or mutant human Two murine anti-INSR monoclonal antibodies, previously shown to be surrogate agonists for mutant INSR, were then tested by intraperitoneal injections.