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Glucagon blockade restores functional β-cell mass in type 1 diabetic mice and enhances function of human islets

Wang, MY;Dean, ED;Quittner-Strom, E;Zhu, Y;Chowdhury, KH;Zhang, Z;Zhao, S;Li, N;Ye, R;Lee, Y;Zhang, Y;Chen, S;Yu, X;Leonard, DC;Poffenberger, G;Von Deylen, A;McCorkle, SK;Schlegel, A;Sloop, KW;Efanov, AM;Gimeno, RE;Scherer, PE;Powers, AC;Unger, RH;Holland, WL;

We evaluated the potential for a monoclonal antibody antagonist of the glucagon receptor (Ab-4) to maintain glucose homeostasis in type 1 diabetic rodents. We noted durable and sustained improvements in glycemia which persist long after treatment withdrawal. Ab-4 promoted β-cell survival and enhanced the recovery of insulin+ islet mass with concomitant increases in circulating insulin and C peptide. In PANIC-ATTAC mice, an inducible model of β-cell apoptosis which allows for robust assessment of β-cell regeneration following caspase-8–induced diabetes, Ab-4 drove a 6.7-fold increase in β-cell mass. Lineage tracing suggests that this restoration of functional insulin-producing cells was at least partially driven by α-cell-to-β-cell conversion. Following hyperglycemic onset in nonobese diabetic (NOD) mice, Ab-4 treatment promoted improvements in C-peptide levels and insulin+ islet mass was dramatically increased. Lastly, diabetic mice receiving human islet xenografts showed stable improvements in glycemic control and increased human insulin secretion.