title: Glucagon receptor inhibition normalizes blood glucose in severe insulin-resistant mice.
abstract: Inactivating mutations in the insulin receptor results in extreme insulin resistance. The resulting hyperglycemia is very difficult to treat, and patients are at risk for early morbidity and mortality from complications of diabetes. We used the insulin receptor antagonist S961 to induce severe insulin resistance, hyperglycemia, and ketonemia in mice. Using this model, we show that glucagon receptor (GCGR) inhibition with a monoclonal antibody normalized blood glucose and β-hydroxybutyrate levels. Insulin receptor antagonism increased pancreatic β-cell mass threefold. Normalization of blood glucose levels with GCGR-blocking antibody unexpectedly doubled β-cell mass relative to that observed with S961 alone and 5.8-fold over control. GCGR antibody blockage expanded α-cell mass 5.7-fold, and S961 had no additional effects. Collectively, these data show that GCGR antibody inhibition represents a potential therapeutic option for treatment of patients with extreme insulin-resistance syndromes.
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Haruka
authors.initials: H
authors.lastname: Okamoto
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Katie
authors.initials: K
authors.lastname: Cavino
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Erqian
authors.initials: E
authors.lastname: Na
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Krumm
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Sun Y
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Xiping
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591 Jesper.Gromada@regeneron.com george@regeneron.com.
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591 Jesper.Gromada@regeneron.com george@regeneron.com.
authors.forename: Jesper
authors.initials: J
authors.lastname: Gromada
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005934:Glucagon / Q000235:genetics / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D007662:Ketosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation; D010455:Peptides / Q000494:pharmacology; D011972:Receptor, Insulin / Q000235:genetics*; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D010455:Peptides; D018027:Receptors, Glucagon; C532752:S961 peptide; D005934:Glucagon; D011972:Receptor, Insulin; D020155:3-Hydroxybutyric Acid
keywords: antibody; glucagon receptor; insulin receptor antagonist; α-cell mass; β-cell mass