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Glucagon receptor antagonism increases mouse pancreatic δ-cell mass through cell proliferation and duct-derived neogenesis
- Gu, Liangbiao, Cui, Xiaona, Lang, Shan, Wang, Haining, Hong, Tianpei, Wei, Rui
- Biochemical and biophysical research communications 2019 v.512 no.4 pp. 864-870
- animal disease models, antagonism, antagonists, blood glucose, c-peptide, cell proliferation, diabetes, glucagon, glucagon receptors, glucose, homeostasis, humans, hyperplasia, insulin secretion, islets of Langerhans, mice, monoclonal antibodies, neonates, somatostatin
- Pancreatic δ-cells, 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 δ-cells are couple with β-cells to suppress α-cell activity. Under certain circumstances, δ-cells could also be trans-differentiated into insulin-producing β-cells. Thus, pancreatic islet may benefit from δ-cell hyperplasia. However, an effective way to increase δ-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 δ-cell number and increased plasma somatostatin level in both normoglycemic and type 1 diabetic (T1D) mice. The increased δ-cells were due to both δ-cell proliferation and derivation of duct lining cells. Notably, the enlarged δ-cell mass could reduce β-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 δ-cells might be a source of the newborn β-cells. Collectively, these observations suggest that treatment with the glucagon receptor monoclonal antibody can increase pancreatic δ-cell mass by promoting self-replication and inducing duct-derived neogenesis both in normoglycemia and diabetic mice.