@article{9b6371b6b0f74a56b6736b79f1865db2,
title = "Glucagon blockade restores functional β-cell mass in type 1 diabetic mice and enhances function of human islets",
abstract = "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.",
keywords = "Diabetes, Glucagon, Insulin, Islet, Regeneration",
author = "Wang, {May Yun} and Dean, {E. Danielle} and Ezekiel Quittner-Strom and Yi Zhu and Chowdhury, {Kamrul H.} and Zhuzhen Zhang and Shangang Zhao and Na Li and Reshing Ye and Young Lee and Yiyi Zhang and Shiuhwei Chen and Xinxin Yu and Leonard, {Derek C.} and Greg Poffenberger and Deylen, {Alison Von} and McCorkle, {S. Kay} and Amnon Schlegel and Sloop, {Kyle W.} and Efanov, {Alexander M.} and Gimeno, {Ruth E.} and Scherer, {Philipp E.} and Powers, {Alvin C.} and Unger, {Roger H.} and Holland, {William L.}",
note = "Funding Information: We thank our friend and colleague R.H.U. for 62 y of scientific inspiration. We thank Pat Kilian and the staff at the Juvenile Diabetes Research Foundation (JDRF) for their expert guidance and support. Human pancreatic islets were provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-funded Integrated Islet Distribution Program at City of Hope (NIH Grant 2UC4DK098085). This research was supported by JDRF SRA-2016-149-Q-R (to W.L.H., P.E.S., R.H.U., A.C.P., and E.D.D.), R01DK112866 (to W.L.H.), and K01DK117969 (to E.D.D.). This research was performed using resources and/or funding provided by the NIDDK-supported Human Islet Research Network (RRID:SCR_014393; https:// hirnetwork.org; UC4 DK104211 and DK112232) and by DK106755 (to A.C.P.), DK20593 (to A.C.P.), DK117147 (to A.C.P.), and the Department of Veterans Affairs (BX000666). Funding Information: ACKNOWLEDGMENTS. We thank our friend and colleague R.H.U. for 62 y of scientific inspiration. We thank Pat Kilian and the staff at the Juvenile Diabetes Research Foundation (JDRF) for their expert guidance and support. Human pancreatic islets were provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-funded Integrated Islet Distribution Program at City of Hope (NIH Grant 2UC4DK098085). This research was supported by JDRF SRA-2016-149-Q-R (to W.L.H., P.E.S., R.H.U., A.C.P., and E.D.D.), R01DK112866 (to W.L.H.), and K01DK117969 (to E.D.D.). This research was performed using resources and/or funding provided by the NIDDK-supported Human Islet Research Network (RRID:SCR_014393; https:// hirnetwork.org; UC4 DK104211 and DK112232) and by DK106755 (to A.C.P.), DK20593 (to A.C.P.), DK117147 (to A.C.P.), and the Department of Veterans Affairs (BX000666). Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = mar,
day = "2",
doi = "10.1073/pnas.2022142118",
language = "English (US)",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "9",
}