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Adult tissue sources for new β cells

Published:December 02, 2013DOI:https://doi.org/10.1016/j.trsl.2013.11.012
      The diabetes pandemic incurs extraordinary public health and financial costs that are projected to expand for the foreseeable future. Consequently, the development of definitive therapies for diabetes is a priority. Currently, a wide spectrum of therapeutic strategies—from implantable insulin delivery devices to transplantation-based cell replacement therapy, to β-cell regeneration—focus on replacing the lost insulin-producing capacity of individuals with diabetes. Among these, β-cell regeneration remains promising but heretofore unproved. Indeed, recent experimental work has uncovered surprising biology that underscores the potential therapeutic benefit of β-cell regeneration. These studies have elucidated a variety of sources for the endogenous production of new β cells from existing cells. First, β cells, long thought to be postmitotic, have demonstrated the potential for regenerative capacity. Second, the presence of pancreatic facultative endocrine progenitor cells has been established. Third, the malleability of cellular identity has availed the possibility of generating β cells from other differentiated cell types. Here, we review the exciting developments surrounding endogenous sources of β-cell production and consider the potential of realizing a regenerative therapy for diabetes from adult tissues.

      Abbreviations:

      ADKi (adenosine kinase inhibitor), CAII (carbonic anhydrase II), LIRKO (liver insulin receptor knockout), Neurog3 (neurogenin 3), OCN (osteocalcin), PDL (pancreatic duct ligation), PMP (pancreas-derived multipotent precursor), PPY (partial pancreatectomy), T1DM (type 1 diabetes mellitus), T2DM (type 2 diabetes mellitus), EMT (epithelial to mesenchymal transition), BrdU (bromodeoxyuridine)
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      References

        • Vehik K.
        • Hamman R.F.
        • Lezotte D.
        • et al.
        Increasing incidence of type 1 diabetes in 0- to 17-year-old Colorado youth.
        Diabetes Care. 2007; 30: 503-509
        • Onkamo P.
        • Vaananen S.
        • Karvonen M.
        • Tuomilehto J.
        Worldwide increase in incidence of type I diabetes: the analysis of the data on published incidence trends.
        Diabetologia. 1999; 42: 1395-1403
        • Huang E.S.
        • Basu A.
        • O'Grady M.
        • Capretta J.C.
        Projecting the future diabetes population size and related costs for the U.S.
        Diabetes Care. 2009; 32: 2225-2229
        • Boyle J.P.
        • Thompson T.J.
        • Gregg E.W.
        • Barker L.E.
        • Williamson D.F.
        Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence.
        Population Health Metrics. 2011; 8: 29
        • Olshansky S.J.
        • Passaro D.J.
        • Hershow R.C.
        • et al.
        A potential decline in life expectancy in the United States in the 21st century.
        N Engl J Med. 2005; 352: 1138-1145
        • Miller R.G.
        • Secrest A.M.
        • Sharma R.K.
        • Songer T.J.
        • Orchard T.J.
        Improvements in the life expectancy of type 1 diabetes: the Pittsburgh Epidemiology of Diabetes Complications Study cohort.
        Diabetes. 2012; 61: 2987-2992
        • Harlan D.M.
        • Kenyon N.S.
        • Korsgren O.
        • Roep B.O.
        Current advances and travails in islet transplantation.
        Diabetes. 2009; 58: 2175-2184
        • Nath D.S.
        • Gruessner A.C.
        • Kandaswamy R.
        • Gruessner R.W.
        • Sutherland D.E.
        • Humar A.
        Outcomes of pancreas transplants for patients with type 2 diabetes mellitus.
        Clin Transplant. 2005; 19: 792-797
        • Pagliuca F.W.
        • Melton D.A.
        How to make a functional beta-cell.
        Development. 2013; 140: 2472-2483
        • Warren S.
        Adenomas of the islands of Langerhans.
        Am J Pathol. 1926; 2: 335-340.3
        • Wilder R.M.
        • Allan F.N.
        • Power M.H.
        • Robertson H.E.
        Carcinoma of the islands of the pancreas: hyperinsulinism and hypoglycemia.
        JAMA. 1927; 89: 348-355
        • Green I.C.
        • Taylor K.W.
        Effects of pregnancy in the rat on the size and insulin secretory response of the islets of Langerhans.
        J Endocrinol. 1972; 54: 317-325
        • Van Assche F.A.
        • Aerts L.
        • De Prins F.
        A morphological study of the endocrine pancreas in human pregnancy.
        Br J Obstet Gynaecol. 1978; 85: 818-820
        • Sorenson R.L.
        • Brelje T.C.
        Adaptation of islets of Langerhans to pregnancy: beta-cell growth, enhanced insulin secretion and the role of lactogenic hormones.
        Hormone Metab Res. 1997; 29: 301-307
        • Bonner-Weir S.
        Islet growth and development in the adult.
        J Mol Endocrinol. 2000; 24: 297-302
        • Kloppel G.
        • Lohr M.
        • Habich K.
        • Oberholzer M.
        • Heitz P.U.
        Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited.
        Survey Synthesis Pathol Res. 1985; 4: 110-125
        • Rahier J.
        • Guiot Y.
        • Goebbels R.M.
        • Sempoux C.
        • Henquin J.C.
        Pancreatic beta-cell mass in European subjects with type 2 diabetes.
        Diabetes Obes Metab. 2008; 10: 32-42
        • Ritzel R.A.
        • Butler A.E.
        • Rizza R.A.
        • Veldhuis J.D.
        • Butler P.C.
        Relationship between beta-cell mass and fasting blood glucose concentration in humans.
        Diabetes Care. 2006; 29: 717-718
        • Meier J.J.
        • Butler A.E.
        • Saisho Y.
        • et al.
        Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans.
        Diabetes. 2008; 57: 1584-1594
        • Saisho Y.
        • Butler A.E.
        • Manesso E.
        • Elashoff D.
        • Rizza R.A.
        • Butler P.C.
        Beta-cell mass and turnover in humans: effects of obesity and aging.
        Diabetes Care. 2013; 36: 111-117
        • Bruning J.C.
        • Winnay J.
        • Bonner-Weir S.
        • Taylor S.I.
        • Accili D.
        • Kahn C.R.
        Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles.
        Cell. 1997; 88: 561-572
        • Okada T.
        • Liew C.W.
        • Hu J.
        • et al.
        Insulin receptors in beta-cells are critical for islet compensatory growth response to insulin resistance.
        Proc Natl Acad Sci U S A. 2007; 104: 8977-8982
        • Nir T.
        • Melton D.A.
        • Dor Y.
        Recovery from diabetes in mice by beta cell regeneration.
        J Clin Invest. 2007; 117: 2553-2561
        • Stolovich-Rain M.
        • Hija A.
        • Grimsby J.
        • Glaser B.
        • Dor Y.
        Pancreatic beta cells in very old mice retain capacity for compensatory proliferation.
        J Biol Chem. 2012; 287: 27407-27414
        • Cano D.A.
        • Rulifson I.C.
        • Heiser P.W.
        • et al.
        Regulated beta-cell regeneration in the adult mouse pancreas.
        Diabetes. 2008; 57: 958-966
        • Thorel F.
        • Nepote V.
        • Avril I.
        • et al.
        Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss.
        Nature. 2010; 464: 1149-1154
        • Xu X.
        • D'Hoker J.
        • Stange G.
        • et al.
        Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas.
        Cell. 2008; 132: 197-207
        • Perl S.
        • Kushner J.A.
        • Buchholz B.A.
        • et al.
        Significant human beta-cell turnover is limited to the first three decades of life as determined by in vivo thymidine analog incorporation and radiocarbon dating.
        J Clin Endocrinol Metab. 2010; 95: E234-E239
        • In't Veld P.
        • De Munck N.
        • Van Belle K.
        • et al.
        Beta-cell replication is increased in donor organs from young patients after prolonged life support.
        Diabetes. 2010; 59: 1702-1708
        • Reers C.
        • Erbel S.
        • Esposito I.
        • et al.
        Impaired islet turnover in human donor pancreata with aging.
        Eur J Endocrinol. 2009; 160: 185-191
        • Gregg B.E.
        • Moore P.C.
        • Demozay D.
        • et al.
        Formation of a human beta-cell population within pancreatic islets is set early in life.
        J Clin Endocrinol Metab. 2012; 97: 3197-3206
        • Tyrberg B.
        • Eizirik D.L.
        • Hellerstrom C.
        • Pipeleers D.G.
        • Andersson A.
        Human pancreatic beta-cell deoxyribonucleic acid-synthesis in islet grafts decreases with increasing organ donor age but increases in response to glucose stimulation in vitro.
        Endocrinology. 1996; 137: 5694-5699
        • Tyrberg B.
        • Ustinov J.
        • Otonkoski T.
        • Andersson A.
        Stimulated endocrine cell proliferation and differentiation in transplanted human pancreatic islets: effects of the ob gene and compensatory growth of the implantation organ.
        Diabetes. 2001; 50: 301-307
        • Levitt H.E.
        • Cyphert T.J.
        • Pascoe J.L.
        • et al.
        Glucose stimulates human beta cell replication in vivo in islets transplanted into NOD-severe combined immunodeficiency (SCID) mice.
        Diabetologia. 2011; 54: 572-582
        • Takane K.K.
        • Kleinberger J.W.
        • Salim F.G.
        • Fiaschi-Taesch N.M.
        • Stewart A.F.
        Regulated and reversible induction of adult human beta-cell replication.
        Diabetes. 2012; 61: 418-424
        • Karslioglu E.
        • Kleinberger J.W.
        • Salim F.G.
        • et al.
        cMyc is a principal upstream driver of beta-cell proliferation in rat insulinoma cell lines and is an effective mediator of human beta-cell replication.
        Mol Endocrinol. 2011; 25: 1760-1772
        • Metukuri M.R.
        • Zhang P.
        • Basantani M.K.
        • et al.
        ChREBP mediates glucose-stimulated pancreatic beta-cell proliferation.
        Diabetes. 2012; 61: 2004-2015
        • Schisler J.C.
        • Fueger P.T.
        • Babu D.A.
        • et al.
        Stimulation of human and rat islet beta-cell proliferation with retention of function by the homeodomain transcription factor Nkx6.1.
        Mol Cell Biol. 2008; 28: 3465-3476
        • Davis D.B.
        • Lavine J.A.
        • Suhonen J.I.
        • et al.
        FoxM1 is up-regulated by obesity and stimulates beta-cell proliferation.
        Mol Endocrinol. 2010; 24: 1822-1834
        • Rieck S.
        • Zhang J.
        • Li Z.
        • et al.
        Overexpression of hepatocyte nuclear factor-4alpha initiates cell cycle entry, but is not sufficient to promote beta-cell expansion in human islets.
        Mol Endocrinol. 2012; 26: 1590-1602
        • Dor Y.
        • Brown J.
        • Martinez O.I.
        • Melton D.A.
        Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation.
        Nature. 2004; 429: 41-46
        • Chick W.L.
        • Lauris V.
        • Flewelling J.H.
        • Andrews K.A.
        • Woodruff J.M.
        Effects of glucose on beta cells in pancreatic monolayer cultures.
        Endocrinology. 1973; 92: 212-218
        • Bonner-Weir S.
        • Deery D.
        • Leahy J.L.
        • Weir G.C.
        Compensatory growth of pancreatic beta-cells in adult rats after short-term glucose infusion.
        Diabetes. 1989; 38: 49-53
        • Yi P.
        • Park J.S.
        • Melton D.A.
        Betatrophin: a hormone that controls pancreatic beta cell proliferation.
        Cell. 2013; 153: 747-758
        • Kim H.
        • Toyofuku Y.
        • Lynn F.C.
        • et al.
        Serotonin regulates pancreatic beta cell mass during pregnancy.
        Nat Med. 2010; 16: 804-808
        • Vasavada R.C.
        • Garcia-Ocana A.
        • Zawalich W.S.
        • et al.
        Targeted expression of placental lactogen in the beta cells of transgenic mice results in beta cell proliferation, islet mass augmentation, and hypoglycemia.
        J Biol Chem. 2000; 275: 15399-15406
        • Freemark M.
        • Avril I.
        • Fleenor D.
        • et al.
        Targeted deletion of the PRL receptor: effects on islet development, insulin production, and glucose tolerance.
        Endocrinology. 2002; 143: 1378-1385
        • Karnik S.K.
        • Chen H.
        • McLean G.W.
        • et al.
        Menin controls growth of pancreatic beta-cells in pregnant mice and promotes gestational diabetes mellitus.
        Science. 2007; 318: 806-809
        • Zhang H.
        • Zhang J.
        • Pope C.F.
        • et al.
        Gestational diabetes mellitus resulting from impaired beta-cell compensation in the absence of FoxM1, a novel downstream effector of placental lactogen.
        Diabetes. 2010; 59: 143-152
        • Porat S.
        • Weinberg-Corem N.
        • Tornovsky-Babaey S.
        • et al.
        Control of pancreatic beta cell regeneration by glucose metabolism.
        Cell Metab. 2011; 13: 440-449
        • Wang W.
        • Walker J.R.
        • Wang X.
        • et al.
        Identification of small-molecule inducers of pancreatic beta-cell expansion.
        Proc Natl Acad Sci U S A. 2009; 106: 1427-1432
        • Shen W.
        • Tremblay M.S.
        • Deshmukh V.A.
        • et al.
        Small-molecule inducer of beta cell proliferation identified by high-throughput screening.
        J Am Chem Soc. 2013; 135: 1669-1672
        • Andersson O.
        • Adams B.A.
        • Yoo D.
        • et al.
        Adenosine signaling promotes regeneration of pancreatic beta cells in vivo.
        Cell Metab. 2012; 15: 885-894
        • Annes J.P.
        • Ryu J.H.
        • Lam K.
        • et al.
        Adenosine kinase inhibition selectively promotes rodent and porcine islet beta-cell replication.
        Proc Natl Acad Sci U S A. 2012; 109: 3915-3920
        • Bonner-Weir S.
        • Li W.C.
        • Ouziel-Yahalom L.
        • Guo L.
        • Weir G.C.
        • Sharma A.
        Beta-cell growth and regeneration: replication is only part of the story.
        Diabetes. 2010; 59: 2340-2348
        • Bonner-Weir S.
        • Baxter L.A.
        • Schuppin G.T.
        • Smith F.E.
        A second pathway for regeneration of adult exocrine and endocrine pancreas: a possible recapitulation of embryonic development.
        Diabetes. 1993; 42: 1715-1720
        • Butler A.E.
        • Galasso R.
        • Matveyenko A.
        • Rizza R.A.
        • Dry S.
        • Butler P.C.
        Pancreatic duct replication is increased with obesity and type 2 diabetes in humans.
        Diabetologia. 2010; 53: 21-26
        • Martin-Pagola A.
        • Sisino G.
        • Allende G.
        • et al.
        Insulin protein and proliferation in ductal cells in the transplanted pancreas of patients with type 1 diabetes and recurrence of autoimmunity.
        Diabetologia. 2008; 51: 1803-1813
        • Li W.C.
        • Rukstalis J.M.
        • Nishimura W.
        • et al.
        Activation of pancreatic-duct-derived progenitor cells during pancreas regeneration in adult rats.
        J Cell Sci. 2010; 123: 2792-2802
        • Inada A.
        • Nienaber C.
        • Katsuta H.
        • et al.
        Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth.
        Proc Natl Acad Sci U S A. 2008; 105: 19915-19919
        • Van de Casteele M.
        • Leuckx G.
        • Baeyens L.
        • et al.
        Neurogenin 3+ cells contribute to beta-cell neogenesis and proliferation in injured adult mouse pancreas.
        Cell Death Dis. 2013; 4: e523
        • Pan F.C.
        • Bankaitis E.D.
        • Boyer D.
        • et al.
        Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration.
        Development. 2013; 140: 751-764
        • Al-Hasani K.
        • Pfeifer A.
        • Courtney M.
        • et al.
        Adult duct-lining cells can reprogram into beta-like cells able to counter repeated cycles of toxin-induced diabetes.
        Dev Cell. 2013; 26: 86-100
        • Solar M.
        • Cardalda C.
        • Houbracken I.
        • et al.
        Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth.
        Dev Cell. 2009; 17: 849-860
        • Chung C.H.
        • Hao E.
        • Piran R.
        • Keinan E.
        • Levine F.
        Pancreatic beta-cell neogenesis by direct conversion from mature alpha-cells.
        Stem Cells. 2010; 28: 1630-1638
        • Ferber S.
        • Halkin A.
        • Cohen H.
        • et al.
        Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia.
        Nat Med. 2000; 6: 568-572
        • Kojima H.
        • Fujimiya M.
        • Matsumura K.
        • et al.
        NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice.
        Nat Med. 2003; 9: 596-603
        • Kaneto H.
        • Nakatani Y.
        • Miyatsuka T.
        • et al.
        PDX-1/VP16 fusion protein, together with NeuroD or NGN3, markedly induces insulin gene transcription and ameliorates glucose tolerance.
        Diabetes. 2005; 54: 1009-1022
        • Zhou Q.
        • Brown J.
        • Kanarek A.
        • Rajagopal J.
        • Melton D.A.
        In vivo reprogramming of adult pancreatic exocrine cells to beta-cells.
        Nature. 2008; 455: 627-632
        • Lima M.J.
        • Muir K.R.
        • Docherty H.M.
        • et al.
        Suppression of epithelial-to-mesenchymal transitioning enhances ex vivo reprogramming of human exocrine pancreatic tissue toward functional insulin-producing beta-like cells.
        Diabetes. 2013; 62: 2821-2833
        • Fomina-Yadlin D.
        • Kubicek S.
        • Walpita D.
        • et al.
        Small-molecule inducers of insulin expression in pancreatic alpha-cells.
        Proc Natl Acad Sci U S A. 2010; 107: 15099-15104
        • Weinberg N.
        • Ouziel-Yahalom L.
        • Knoller S.
        • Efrat S.
        • Dor Y.
        Lineage tracing evidence for in vitro dedifferentiation but rare proliferation of mouse pancreatic beta-cells.
        Diabetes. 2007; 56: 1299-1304
        • Liu Y.
        • Suckale J.
        • Masjkur J.
        • et al.
        Tamoxifen-independent recombination in the RIP-CreER mouse.
        PLoS One. 2010; 5: e13533
        • Teta M.
        • Rankin M.M.
        • Long S.Y.
        • Stein G.M.
        • Kushner J.A.
        Growth and regeneration of adult beta cells does not involve specialized progenitors.
        Dev Cell. 2007; 12: 817-826
        • Morris A.P.
        • Voight B.F.
        • Teslovich T.M.
        • et al.
        Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes.
        Nat Genet. 2012; 44: 981-990
        • Muoio D.M.
        • Newgard C.B.
        Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes.
        Nat Rev Mol Cell Biol. 2008; 9: 193-205
        • Michael M.D.
        • Kulkarni R.N.
        • Postic C.
        • et al.
        Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction.
        Mol Cell. 2000; 6: 87-97
        • Flier S.N.
        • Kulkarni R.N.
        • Kahn C.R.
        Evidence for a circulating islet cell growth factor in insulin-resistant states.
        Proc Natl Acad Sci U S A. 2001; 98: 7475-7480
        • Heit J.J.
        • Apelqvist A.A.
        • Gu X.
        • et al.
        Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function.
        Nature. 2006; 443: 345-349
        • El Ouaamari A.
        • Kawamori D.
        • Dirice E.
        • et al.
        Liver-derived systemic factors drive beta cell hyperplasia in insulin-resistant states.
        Cell Rep. 2013; 3: 401-410
        • Lee N.K.
        • Sowa H.
        • Hinoi E.
        • et al.
        Endocrine regulation of energy metabolism by the skeleton.
        Cell. 2007; 130: 456-469
        • Wei J.
        • Hanna T.
        • Suda N.
        • Karsenty G.
        • Ducy P.
        Osteocalcin promotes beta-cell proliferation during development and adulthood through Gprc6a.
        Diabetes. 2013;
        • Ferron M.
        • Wei J.
        • Yoshizawa T.
        • et al.
        Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism.
        Cell. 2010; 142: 296-308
        • Fleischer N.
        • Chen C.
        • Surana M.
        • et al.
        Functional analysis of a conditionally transformed pancreatic beta-cell line.
        Diabetes. 1998; 47: 1419-1425
        • Walpita D.
        • Hasaka T.
        • Spoonamore J.
        • et al.
        A human islet cell culture system for high-throughput screening.
        J Biomol Screen. 2012; 17: 509-518
        • Ravassard P.
        • Hazhouz Y.
        • Pechberty S.
        • et al.
        A genetically engineered human pancreatic beta cell line exhibiting glucose-inducible insulin secretion.
        J Clin Invest. 2011; 121: 3589-3597
        • Chen H.
        • Gu X.
        • Liu Y.
        • et al.
        PDGF signalling controls age-dependent proliferation in pancreatic beta-cells.
        Nature. 2011; 478: 349-355
        • Yang Y.
        • Gurung B.
        • Wu T.
        • Wang H.
        • Stoffers D.A.
        • Hua X.
        Reversal of preexisting hyperglycemia in diabetic mice by acute deletion of the Men1 gene.
        Proc Natl Acad Sci U S A. 2010; 107: 20358-20363
        • Service G.J.
        • Thompson G.B.
        • Service F.J.
        • Andrews J.C.
        • Collazo-Clavell M.L.
        • Lloyd R.V.
        Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery.
        N Engl J Med. 2005; 353: 249-254
        • Ziv O.
        • Glaser B.
        • Dor Y.
        The plastic pancreas.
        Dev Cell. 2013; 26: 3-7
        • Jonsson J.
        • Carlsson L.
        • Edlund T.
        • Edlund H.
        Insulin-promoter-factor 1 is required for pancreas development in mice.
        Nature. 1994; 371: 606-609
        • Stoffers D.A.
        • Zinkin N.T.
        • Stanojevic V.
        • Clarke W.L.
        • Habener J.F.
        Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence.
        Nat Genet. 1997; 15: 106-110
        • Gradwohl G.
        • Dierich A.
        • LeMeur M.
        • Guillemot F.
        Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas.
        Proc Natl Acad Sci U S A. 2000; 97: 1607-1611
        • Schwitzgebel V.M.
        • Scheel D.W.
        • Conners J.R.
        • et al.
        Expression of neurogenin3 reveals an islet cell precursor population in the pancreas.
        Development. 2000; 127: 3533-3542
        • Gu G.
        • Dubauskaite J.
        • Melton D.A.
        Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors.
        Development. 2002; 129: 2447-2457
        • Zhou Q.
        • Law A.C.
        • Rajagopal J.
        • Anderson W.J.
        • Gray P.A.
        • Melton D.A.
        A multipotent progenitor domain guides pancreatic organogenesis.
        Dev Cell. 2007; 13: 103-114
        • Rankin M.M.
        • Wilbur C.J.
        • Rak K.
        • Shields E.J.
        • Granger A.
        • Kushner J.A.
        Beta-cells are not generated in pancreatic duct ligation-induced injury in adult mice.
        Diabetes. 2013; 62: 1634-1645
        • Xiao X.
        • Chen Z.
        • Shiota C.
        • et al.
        No evidence for beta cell neogenesis in murine adult pancreas.
        J Clin Invest. 2013; 123: 2207-2217
        • Desai B.M.
        • Oliver-Krasinski J.
        • De Leon D.D.
        • et al.
        Preexisting pancreatic acinar cells contribute to acinar cell, but not islet beta cell, regeneration.
        J Clin Invest. 2007; 117: 971-977
        • Seaberg R.M.
        • Smukler S.R.
        • Kieffer T.J.
        • et al.
        Clonal identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages.
        Nat Biotechnol. 2004; 22: 1115-1124
        • Smukler S.R.
        • Arntfield M.E.
        • Razavi R.
        • et al.
        The adult mouse and human pancreas contain rare multipotent stem cells that express insulin.
        Cell Stem Cell. 2011; 8: 281-293
        • Brennand K.
        • Huangfu D.
        • Melton D.
        All beta cells contribute equally to islet growth and maintenance.
        PLoS Biol. 2007; 5: e163
        • Rovira M.
        • Scott S.G.
        • Liss A.S.
        • Jensen J.
        • Thayer S.P.
        • Leach S.D.
        Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas.
        Proc Natl Acad Sci U S A. 2010; 107: 75-80
        • Hao E.
        • Tyrberg B.
        • Itkin-Ansari P.
        • et al.
        Beta-cell differentiation from nonendocrine epithelial cells of the adult human pancreas.
        Nat Med. 2006; 12: 310-316
        • Yatoh S.
        • Dodge R.
        • Akashi T.
        • et al.
        Differentiation of affinity-purified human pancreatic duct cells to beta-cells.
        Diabetes. 2007; 56: 1802-1809
        • Bonner-Weir S.
        • Taneja M.
        • Weir G.C.
        • et al.
        In vitro cultivation of human islets from expanded ductal tissue.
        Proc Natl Acad Sci U S A. 2000; 97: 7999-8004
        • Takahashi K.
        • Yamanaka S.
        Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.
        Cell. 2006; 126: 663-676
        • Vierbuchen T.
        • Wernig M.
        Direct lineage conversions: unnatural but useful?.
        Nat Biotechnol. 2011; 29: 892-907
        • Banga A.
        • Akinci E.
        • Greder L.V.
        • Dutton J.R.
        • Slack J.M.
        In vivo reprogramming of Sox9+ cells in the liver to insulin-secreting ducts.
        Proc Natl Acad Sci U S A. 2012; 109: 15336-15341
        • Sapir T.
        • Shternhall K.
        • Meivar-Levy I.
        • et al.
        Cell-replacement therapy for diabetes: generating functional insulin-producing tissue from adult human liver cells.
        Proc Natl Acad Sci U S A. 2005; 102: 7964-7969
        • Lu J.
        • Herrera P.L.
        • Carreira C.
        • et al.
        Alpha cell-specific Men1 ablation triggers the transdifferentiation of glucagon-expressing cells and insulinoma development.
        Gastroenterology. 2010; 138: 1954-1965
        • Bramswig N.C.
        • Everett L.J.
        • Schug J.
        • et al.
        Epigenomic plasticity enables human pancreatic alpha to beta cell reprogramming.
        J Clin Invest. 2013; 123: 1275-1284
        • Sosa-Pineda B.
        • Chowdhury K.
        • Torres M.
        • Oliver G.
        • Gruss P.
        The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas.
        Nature. 1997; 386: 399-402
        • Collombat P.
        • Xu X.
        • Ravassard P.
        • et al.
        The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells.
        Cell. 2009; 138: 449-462
        • Collombat P.
        • Mansouri A.
        • Hecksher-Sorensen J.
        • et al.
        Opposing actions of Arx and Pax4 in endocrine pancreas development.
        Genes Dev. 2003; 17: 2591-2603
        • Dhawan S.
        • Georgia S.
        • Tschen S.I.
        • Fan G.
        • Bhushan A.
        Pancreatic beta cell identity is maintained by DNA methylation-mediated repression of Arx.
        Dev Cell. 2011; 20: 419-429
        • Collombat P.
        • Hecksher-Sorensen J.
        • Krull J.
        • et al.
        Embryonic endocrine pancreas and mature beta cells acquire alpha and PP cell phenotypes upon Arx misexpression.
        J Clin Invest. 2007; 117: 961-970
        • Gershengorn M.C.
        • Hardikar A.A.
        • Wei C.
        • Geras-Raaka E.
        • Marcus-Samuels B.
        • Raaka B.M.
        Epithelial-to-mesenchymal transition generates proliferative human islet precursor cells.
        Science. 2004; 306: 2261-2264
        • Russ H.A.
        • Bar Y.
        • Ravassard P.
        • Efrat S.
        In vitro proliferation of cells derived from adult human beta-cells revealed by cell-lineage tracing.
        Diabetes. 2008; 57: 1575-1583
        • Talchai C.
        • Xuan S.
        • Kitamura T.
        • DePinho R.A.
        • Accili D.
        Generation of functional insulin-producing cells in the gut by Foxo1 ablation.
        Nat Genet. 2012; 44: 406-412
        • Weng J.
        • Li Y.
        • Xu W.
        • et al.
        Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial.
        Lancet. 2008; 371: 1753-1760
        • Bar Y.
        • Russ H.A.
        • Sintov E.
        • Anker-Kitai L.
        • Knoller S.
        • Efrat S.
        Redifferentiation of expanded human pancreatic beta-cell-derived cells by inhibition of the NOTCH pathway.
        J Biol Chem. 2012; 287: 17269-17280