Miyatsuka T (2016) Chronology of endocrine differentiation and beta-cell neogenesis. Endocr J 63(3):205–211. https://doi.org/10.1507/endocrj.EJ15-0601

Article  CAS  PubMed  Google Scholar 

Gradwohl G, Dierich A, LeMeur M, Guillemot F (2000) neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci U S A 97(4):1607–1611. https://doi.org/10.1073/pnas.97.4.1607

Article  CAS  PubMed  PubMed Central  Google Scholar 

Miyatsuka T, Li Z, German MS (2009) Chronology of islet differentiation revealed by temporal cell labeling. Diabetes 58(8):1863–1868. https://doi.org/10.2337/db09-0390

Article  CAS  PubMed  PubMed Central  Google Scholar 

Raskin P, Unger RH (1978) Hyperglucagonemia and its suppression. Importance in the metabolic control of diabetes. N Engl J Med 299(9):433–436. https://doi.org/10.1056/nejm197808312990901

Article  CAS  PubMed  Google Scholar 

D’Alessio D (2011) The role of dysregulated glucagon secretion in type 2 diabetes. Diabetes Obes Metab 13(Suppl 1):126–132. https://doi.org/10.1111/j.1463-1326.2011.01449.x

Article  CAS  PubMed  Google Scholar 

Unger RH, Cherrington AD (2012) Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest 122(1):4–12. https://doi.org/10.1172/JCI60016

Article  CAS  PubMed  PubMed Central  Google Scholar 

Thorel F, Nepote V, Avril I et al (2010) Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 464(7292):1149–1154. https://doi.org/10.1038/nature08894

Article  CAS  PubMed  PubMed Central  Google Scholar 

Matsuoka TA, Kawashima S, Miyatsuka T et al (2017) Mafa enables Pdx1 to effectively convert pancreatic islet progenitors and committed islet alpha-cells into beta-cells in vivo. Diabetes 66(5):1293–1300. https://doi.org/10.2337/db16-0887

Article  CAS  PubMed  PubMed Central  Google Scholar 

Xiao X, Guo P, Shiota C et al (2018) Endogenous reprogramming of alpha cells into beta cells, induced by viral gene therapy, reverses autoimmune diabetes. Cell Stem Cell 22(1):78-90.e74. https://doi.org/10.1016/j.stem.2017.11.020

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cigliola V, Ghila L, Thorel F et al (2018) Pancreatic islet-autonomous insulin and smoothened-mediated signalling modulate identity changes of glucagon+ α-cells. Nat Cell Biol 20(11):1267–1277. https://doi.org/10.1038/s41556-018-0216-y

Article  CAS  PubMed  PubMed Central  Google Scholar 

Furuyama K, Chera S, van Gurp L et al (2019) Diabetes relief in mice by glucose-sensing insulin-secreting human α-cells. Nature 567(7746):43–48. https://doi.org/10.1038/s41586-019-0942-8

Article  CAS  PubMed  PubMed Central  Google Scholar 

Aida T, Chiyo K, Usami T et al (2015) Cloning-free CRISPR/Cas system facilitates functional cassette knock-in in mice. Genome Biol 16(1):87. https://doi.org/10.1186/s13059-015-0653-x

Article  CAS  PubMed  PubMed Central  Google Scholar 

Shiota C, Prasadan K, Guo P, Fusco J, Xiao X, Gittes GK (2017) Gcg CreERT2 knockin mice as a tool for genetic manipulation in pancreatic alpha cells. Diabetologia 60(12):2399–2408. https://doi.org/10.1007/s00125-017-4425-x

Article  CAS  PubMed  PubMed Central  Google Scholar 

Muzumdar MD, Tasic B, Miyamichi K, Li L, Luo L (2007) A global double-fluorescent Cre reporter mouse. Genesis 45(9):593–605. https://doi.org/10.1002/dvg.20335

Article  CAS  PubMed  Google Scholar 

Lee CS, Perreault N, Brestelli JE, Kaestner KH (2002) Neurogenin 3 is essential for the proper specification of gastric enteroendocrine cells and the maintenance of gastric epithelial cell identity. Genes Dev 16(12):1488–1497. https://doi.org/10.1101/gad.985002

Article  CAS  PubMed  PubMed Central  Google Scholar 

Brand CL, Rolin B, Jørgensen PN, Svendsen I, Kristensen JS, Holst JJ (1994) Immunoneutralization of endogenous glucagon with monoclonal glucagon antibody normalizes hyperglycaemia in moderately streptozotocin-diabetic rats. Diabetologia 37(10):985–993. https://doi.org/10.1007/bf00400461

Article  CAS  PubMed  Google Scholar 

Sørensen H, Brand CL, Neschen S et al (2006) Immunoneutralization of endogenous glucagon reduces hepatic glucose output and improves long-term glycemic control in diabetic ob/ob mice. Diabetes 55(10):2843–2848. https://doi.org/10.2337/db06-0222

Article  CAS  PubMed  Google Scholar 

Vajda EG, Logan D, Lasseter K et al (2017) Pharmacokinetics and pharmacodynamics of single and multiple doses of the glucagon receptor antagonist LGD-6972 in healthy subjects and subjects with type 2 diabetes mellitus. Diabetes Obes Metab 19(1):24–32. https://doi.org/10.1111/dom.12752

Article  CAS  PubMed  Google Scholar 

Pettus JH, D’Alessio D, Frias JP et al (2020) Efficacy and safety of the glucagon receptor antagonist RVT-1502 in type 2 diabetes uncontrolled on metformin monotherapy: a 12-week dose-ranging study. Diabetes Care 43(1):161–168. https://doi.org/10.2337/dc19-1328

Article  CAS  PubMed  Google Scholar 

Hayashi Y, Yamamoto M, Mizoguchi H et al (2009) Mice deficient for glucagon gene-derived peptides display normoglycemia and hyperplasia of islet -cells but not of intestinal L-cells. Mol Endocrinol 23(12):1990–1999. https://doi.org/10.1210/me.2009-0296

Article  CAS  PubMed  PubMed Central  Google Scholar 

Terskikh A, Fradkov A, Ermakova G et al (2000) “Fluorescent timer”: protein that changes color with time. Science 290(5496):1585–1588. https://doi.org/10.1126/science.290.5496.1585

Article  CAS  PubMed  Google Scholar 

Miyatsuka T, Matsuoka TA, Sasaki S et al (2014) Chronological analysis with fluorescent timer reveals unique features of newly generated β-cells. Diabetes 63:3388–3393. https://doi.org/10.2337/db13-1312/-/DC1

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sasaki S, Lee MYY, Wakabayashi Y et al (2022) Spatial and transcriptional heterogeneity of pancreatic beta cell neogenesis revealed by a time-resolved reporter system. Diabetologia 65(5):811–828. https://doi.org/10.1007/s00125-022-05662-0

Article  CAS  PubMed  Google Scholar 

Zhou J, Lin J, Zhou C, Deng X, Xia B (2011) Cytotoxicity of red fluorescent protein DsRed is associated with the suppression of Bcl-xL translation. FEBS Lett 585(5):821–827. https://doi.org/10.1016/j.febslet.2011.02.013

Article  CAS  PubMed  Google Scholar 

Chen TH, Chen MR, Chen TY et al (2016) Cardiac fibrosis in mouse expressing DsRed tetramers involves chronic autophagy and proteasome degradation insufficiency. Oncotarget 7(34):54274–54289. https://doi.org/10.18632/oncotarget.11026

Article  PubMed  PubMed Central  Google Scholar 

Mizuguchi H, Xu Z, Ishii-Watabe A, Uchida E, Hayakawa T (2000) IRES-dependent second gene expression is significantly lower than cap-dependent first gene expression in a bicistronic vector. Mol Ther 1(4):376–382. https://doi.org/10.1006/mthe.2000.0050

Article  CAS  PubMed  Google Scholar 

Schwitzgebel VM, Scheel DW, Conners JR et al (2000) Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development 127(16):3533–3542. https://doi.org/10.1242/dev.127.16.3533

Article  CAS  PubMed  Google Scholar 

Hussain MA, Lee J, Miller CP, Habener JF (1997) POU domain transcription factor brain 4 confers pancreatic alpha-cell-specific expression of the proglucagon gene through interaction with a novel proximal promoter G1 element. Mol Cell Biol 17(12):7186–7194. https://doi.org/10.1128/mcb.17.12.7186

Article  CAS  PubMed  PubMed Central  Google Scholar 

Collombat P, Mansouri A, Hecksher-Sorensen J et al (2003) Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes Dev 17(20):2591–2603. https://doi.org/10.1101/gad.269003

Article  CAS  PubMed  PubMed Central  Google Scholar 

Artner I, Le Lay J, Hang Y et al (2006) MafB: an activator of the glucagon gene expressed in developing islet alpha- and beta-cells. Diabetes 55(2):297–304. https://doi.org/10.2337/diabetes.55.02.06.db05-0946

Article  CAS  PubMed  Google Scholar 

Petri A, Ahnfelt-Ronne J, Frederiksen KS et al (2006) The effect of neurogenin3 deficiency on pancreatic gene expression in embryonic mice. J Mol Endocrinol 37(2):301–316. https://doi.org/10.1677/jme.1.02096

Article  CAS  PubMed  Google Scholar