Glucagon receptor inhibition normalizes blood glucose in severe insulin-resistant mice

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 10; pp. 2753 - 2758
• Main Authors: Okamoto, Haruka, Cavino, Katie, Na, Erqian, Krumm, Elizabeth, Kim, Sun Y., Cheng, Xiping, Murphy, Andrew J., Yancopoulos, George D., Gromada, Jesper
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07-03-2017
• Series: From the Cover
• Subjects: Biological Sciences; Glucose; Hyperglycemia; Insulin resistance; Mutation; Risk assessment; Rodents; β-cell mass; antibody; glucagon receptor; α-cell mass; insulin receptor antagonist
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1621069114

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.