Glucagon blockade restores functional β-cell mass in type 1 diabetic mice and enhances function of human islets
May-Yun Wang, E. Danielle Dean, Ezekiel Quittner-Strom, Yi Zhu, Kamrul Hasan Chowdhury, Zhuzhen Zhang, Shangang Zhao, Na Li, Reshing Ye, Young Lee, Yiyi Zhang, Shiuhwei Chen, Xinxin Yu, Derek C. Leonard, Greg Poffenberger, Alison Von Deylen, Sara Kay McCorkle, Amnon Schlegel, Kyle W. Sloop, Alexander M. Efanov, Ruth E. Gimeno, Philipp E. Scherer, Alvin C. Powers, Roger H. Unger, William L. Holland
Abstract
Significance Both type 1 and type 2 diabetes are associated with reduced β-cell mass or function, resulting from decreased proliferation and increased apoptosis. Understanding the signals governing β-cell survival and regeneration is critical for developing strategies to maintain healthy populations of these cells in individuals. Both forms of diabetes are associated with hyperglucagonemia and an increased plasma glucagon:insulin ratio. Glucagon excess contributes to metabolic dysregulation of the diabetic state and glucagon receptor antagonism is a potential target area for the treatment and prevention of diabetes. Our studies presented here suggest that blockade of glucagon signaling lowers glycemia in mouse models of type 1 diabetes while enhancing formation of functional β-cell mass and production of insulin-positive cells from α-cell precursors.