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 anti-receptor
antibodies can elicit insulin-like signaling by mutant INSR in cultured cells,
but whether this translates into meaningful metabolic benefits <i>in vivo</i>,
where 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 <i>Cre</i> recombinase
delivered by adeno-associated virus to knock out endogenous hepatic <i>Insr</i>
acutely in floxed <i>Insr</i> mice (L-IRKO+GFP), before adenovirus-mediated
‘add-back’ of wild-type (WT) or mutant human <i>INSR</i>. Two murine anti-INSR monoclonal antibodies,
previously shown to be surrogate agonists for mutant INSR, were then tested by intraperitoneal
injections. As expected, L-IRKO+GFP
mice showed glucose intolerance and severe hyperinsulinemia, and this was fully
corrected by add-back of WT but neither D734A nor S350L mutant INSR. Antibody injection improved
glucose tolerance in D734A INSR-expressing mice and reduced hyperinsulinemia in
both S350L and D734A INSR-expressing animals, and did not cause hypoglycemia in
WT INSR-expressing mice. Antibody treatment also downregulated both wild-type
and mutant INSR protein, attenuating its beneficial metabolic effects. Anti-INSR
antibodies thus improve IR in an acute model of insulin receptoropathy, but these
findings imply a narrow therapeutic window determined by competing effects of
antibodies to stimulate receptors and induce their downregulation.
Anti-Insulin receptor antibodies improve hyperglycemia in a mouse model of human insulin receptoropathy