Most excitingly we found the

Most excitingly, we found the increased δ-cells hold the ability to trans-differentiate into β-cells in T1D mice. It has been shown that after near-total β-cell loss, juvenile mice display δ-to-β-cell conversion to recover diabetes, involving de-differentiation, proliferation and re-expression of islet developmental regulators [5]. However, its current application was limited in adult for insufficient δ-cell number along with decreased capabilities of de-differentiation and proliferation. In our study, co-localization of somatostatin and C-peptide was found in the pancreatic islets of T1D mice, and plasma insulin level and β-cell mass were also upregulated by the GCGR mAb treatment, suggesting that δ-cells were probably converted to β-cells. The δ-cell lineage-tracing mice will be helpful to identify the cell fate of the somatostatin-positive δ-cells in the future.
Acknowledgements This work was supported by the National Key Research and Development Program of China (2016YFA0100501), and the National Natural Science Foundation of China and the Natural Science Foundation of Beijing (81830022, 81770768, 7192225, 91749101, 81570692 and 81670701). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank Dr. Hai Yan (REMD Biotherapeutics, Camarillo, CA) for his kindly gift of REMD 2.59.
Introduction Regulation of carbohydrate metabolism is important for all vertebrates (Polakof et al., 2011a). When blood sugar levels are increased in mammals, insulin is secreted by beta gsk3 inhibitor of pancreatic islets to signal the uptake and storage of glucose by tissues such as the liver and fat (Röder et al., 2016). In contrast, glucagon is released from alpha cells of the islets when blood glucose levels are low and results in the production of glucose by the liver (Röder et al., 2016). In humans, glucagon is encoded by the proglucagon (GCG) gene, which also encodes two other glucagon-like peptides (GLP-1 and GLP-2) that also have important roles in the regulation of metabolism (Estall and Drucker, 2006). In mammals, GLP-2 has been shown to have roles maintaining intestinal function (Rowland and Brubaker, 2011). The role of GLP-2 in fish has not been established, but as it is only produced from a transcript found in the intestine, its role is likely similar and involved in the maintenance of the digestive tract (Irwin and Wong, 1995). GLP-1 acts as an incretin hormone in mammals, as it is produced by intestinal L-cells and primes pancreatic islet beta cells to secrete insulin when blood glucose levels increase (Deacon and Ahrén, 2011, Campbell and Drucker, 2013). GLP-1 also has additional biological functions in other tissues such as the brain and heart (Drucker, 2016, Muscogiuri et al., 2017), and in some species, such as the platypus, the salivary gland (Tsend-Ayush et al., 2016). In fish, GLP-1 is not an incretin hormone, and instead has biological functions that are similar to those of glucagon (Mommsen and Moon, 1990, Plisetskaya and Mommsen, 1996, Moon, 2004). It also regulates feeding behavior (Silverstein et al., 2001), analogous to its function in mammals (Turton et al., 1996). The similarity in the roles of glucagon and GLP-1 on glucose homeostasis in fish, which contrasts to their divergent roles in mammals (Estall and Drucker, 2006, Campbell and Drucker, 2013), is largely due to differences in the regulatory networks that control glucose metabolism in teleost fish and mammals (Mommsen et al., 1987, Plisetskaya and Mommsen, 1996). In contrast to mammals, duplicated proglucagon (gcg) genes have been found in many fish (Lund et al., 1982, Lund et al., 1983, Irwin and Wong, 1995, Irwin, 2001, Busby and Mommsen, 2016, Cardoso et al., 2018). While vertebrates descended from an ancestor that experienced two genome duplications (Panopoulou and Poustka, 2005), teleost fish, of Superclass Osteichthyes, have experienced a third genome duplication, which resulted in two copies of some genes that are single-copy in the genomes of other vertebrates such as humans (Meyer and Van de Peer, 2005, Glasauer and Neuhauss, 2014). Indeed, gcg was first described as a pair of genes in the American anglerfish (Lund et al., 1982, Lund et al., 1983), but later found as a single-copy gene in mammals (Bell et al., 1983a, Bell et al., 1983b). The first gcg cDNAs isolated from the anglerfish predicted coding sequences encoding glucagon and a GLP-1 (initially called glucagon-like peptide) (Lund et al., 1982, Lund et al., 1983), with subsequent work showing that one of these genes, named gcga, is alternatively spliced with one transcript also encoding GLP-2 (Irwin and Wong, 1995, Zhou and Irwin, 2004, Busby and Mommsen, 2016). Why teleost fish have multiple glucagon and GLP-1 peptides is currently unclear.