Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549.
Medical Service, Veterans Administration North Texas Health Care System, Dallas, TX 75216.
Proc Natl Acad Sci U S A. 2021 Mar 2;118(9). doi: 10.1073/pnas.2022142118.
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.
我们评估了胰高血糖素受体单克隆抗体拮抗剂 (Ab-4) 在 1 型糖尿病啮齿动物中维持血糖稳态的潜力。我们注意到，血糖持续改善，并且在治疗停止后很长时间仍然存在。Ab-4 促进了β细胞的存活，并增强了胰岛素胰岛质量的恢复，同时增加了循环胰岛素和 C 肽。在 PANIC-ATTAC 小鼠中，一种可诱导的β细胞凋亡模型，允许在 caspase-8 诱导的糖尿病后对β细胞再生进行有力评估，Ab-4 使β细胞质量增加了 6.7 倍。谱系追踪表明，这种功能性胰岛素产生细胞的恢复至少部分是由α细胞到β细胞的转化驱动的。在非肥胖型糖尿病 (NOD) 小鼠发生高血糖后，Ab-4 治疗促进了 C 肽水平的改善，并且胰岛素胰岛质量显著增加。最后，接受人胰岛异种移植的糖尿病小鼠显示出血糖控制的稳定改善和人胰岛素分泌的增加。
