Pancreatic delta-cell, which produce somatostatin, play an indispensable role in glucose homeostasis by inhibiting glucagon and insulin secretion in a paracrine manner. Recent studies have shown that delta-cell are couple with beta-cells to suppress delta-cell activity. Under certain circumstances, delta-cell-cells could also be trans-differentiated into insulin-producing beta-cells. Thus, pancreatic islet may benefit from delta-cell hyperplasia. However, an effective way to increase delta-cell mass has been rarely reported. Here, we found that REMD 2.59, a human monoclonal antibody and competitive antagonist of the glucagon receptor, massively boosted delta-cell number and increased plasma somatostatin level in both normoglycemic and type 1 diabetic (T1D) mice. The increased delta-cells were due to both d-cell proliferation and derivation of duct lining cells. Notably, the enlarged delta-cell mass could reduce beta-cell burdens by inducing FoxO1 nuclear translocation in normoglycemic mice. Moreover, some somatostatin-positive cells were co localized with C-peptide in T1D mice, suggesting that beta-cells might be a source of the newborn beta-cells. Collectively, these observations suggest that treatment with the glucagon receptor monoclonal antibody can increase pancreatic delta-cell mass by promoting self-replication and inducing duct-derived neogenesis both in normoglycemia and diabetic mice. (C) 2019 Elsevier Inc. All rights reserved.