Top

Current Diabetes Reports

Published in:

01-08-2019 | Insulins | Pathogenesis of Type 1 Diabetes (A Pugliese and SJ Richardson, Section Editors)

How, When, and Where Do Human β-Cells Regenerate?

Authors: Giorgio Basile, Rohit N. Kulkarni, Noel G. Morgan

Published in: Current Diabetes Reports | Issue 8/2019

Abstract

Purpose of Review

Pancreatic β-cells play a critical role in whole-body glucose homeostasis by regulating the release of insulin in response to minute by minute alterations in metabolic demand. As such, β-cells are staunchly resilient but there are circumstances where they can become functionally compromised or physically lost due to pathophysiological changes which culminate in overt hyperglycemia and diabetes.

Recent Findings

In humans, β-cell mass appears to be largely defined in the postnatal period and this early replicative and generative phase is followed by a refractory state which persists throughout life. Despite this, efforts to identify physiological and pharmacological factors which might re-initiate β-cell replication (or cause the replenishment of β-cells by neogenesis or transdifferentiation) are beginning to bear fruit.

Summary

Controlled manipulation of β-cell mass in humans still represents a holy grail for therapeutic intervention in diabetes, but progress is being made which may lead to ultimate success.

Shields BM, Freathy RM, Hattersley AT. Genetic influences on the association between fetal growth and susceptibility to type 2 diabetes. J Dev Orig Health Dis. 2010;1(2):96–105.PubMed

Spyer G, Macleod KM, Shepherd M, Ellard S, Hattersley AT. Pregnancy outcome in patients with raised blood glucose due to a heterozygous glucokinase gene mutation. Diabet Med. 2009;26(1):14–8.PubMed

Jennings RE, Berry AA, Strutt JP, Gerrard DT, Hanley NA. Human pancreas development. Development. 2015;142(18):3126–37.PubMed

Bonner-Weir S, Aguayo-Mazzucato C, Weir GC. Dynamic development of the pancreas from birth to adulthood. Ups J Med Sci. 2016;121(2):155–8.PubMedPubMedCentral

Cnop M, Igoillo-Esteve M, Hughes SJ, Walker JN, Cnop I, Clark A. Longevity of human islet alpha and beta cells. Diabetes Obes Metab. 2011;13(Suppl 1):39–46.PubMed

Butler AE, Cao-Minh L, Galasso R, Rizza RA, Corradin A, Cobelli C, et al. Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy. Diabetologia. 2010;53(10):2167–76.PubMedPubMedCentral

Genevay M, Pontes H, Meda P. Beta cell adaptation in pregnancy: a major difference between humans and rodents? Diabetologia. 2010;53(10):2089–92.PubMed

Wang YJ, Golson ML, Schug J, Traum D, Liu C, Vivek K, et al. Single-cell mass cytometry analysis of the human endocrine pancreas. Cell Metab. 2016;24(4):616–26.PubMedPubMedCentral

Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell. 2012;150(6):1223–34.PubMedPubMedCentral

10.

Cinti F, Bouchi R, Kim-Muller JY, Ohmura Y, Sandoval PR, Masini M, et al. Evidence of beta-cell dedifferentiation in human type 2 diabetes. J Clin Endocrinol Metab. 2016;101(3):1044–54.PubMed

11.

Aguayo-Mazzucato C, Bonner-Weir S. Pancreatic beta cell regeneration as a possible therapy for diabetes. Cell Metab. 2018;27(1):57–67.PubMed

12.

Morgan NG, Richardson SJ. Fifty years of pancreatic islet pathology in human type 1 diabetes: insights gained and progress made. Diabetologia. 2018;61(12):2499–506.PubMedPubMedCentral

13.

Lam CJ, Jacobson DR, Rankin MM, Cox AR, Kushner JA. Beta cells persist in T1D pancreata without evidence of ongoing β-cell turnover or neogenesis. J Clin Endocrinol Metab. 2017;102(8):2647–59.

14.

Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG. Evidence of increased islet cell proliferation in patients with recent-onset type 1 diabetes. Diabetologia. 2010;53(9):2020–8.PubMed

15.

Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG. Immunohistochemical analysis of the relationship between islet cell proliferation and the production of the enteroviral capsid protein, VP1, in the islets of patients with recent-onset type 1 diabetes. Diabetologia. 2011;54(9):2417–20.PubMed

16.

Dirice E, Kahraman S, Jiang W, El Ouaamari A, De Jesus DF, Teo AK, et al. Soluble factors secreted by T cells promote beta-cell proliferation. Diabetes. 2014;63(1):188–202.PubMed

17.

Fiaschi-Taesch NM, Kleinberger JW, Salim FG, Troxell R, Wills R, Tanwir M, et al. Human pancreatic beta-cell G1/S molecule cell cycle atlas. Diabetes. 2013;62(7):2450–9.PubMedPubMedCentral

18.

Fiaschi-Taesch NM, Kleinberger JW, Salim FG, Troxell R, Wills R, Tanwir M, et al. Cytoplasmic-nuclear trafficking of G1/S cell cycle molecules and adult human beta-cell replication: a revised model of human beta-cell G1/S control. Diabetes. 2013;62(7):2460–70.PubMedPubMedCentral

19.

Taniguchi K, Russell MA, Richardson SJ, Morgan NG. The subcellular distribution of cyclin-D1 and cyclin-D3 within human islet cells varies according to the status of the pancreas donor. Diabetologia. 2015;58(9):2056–63.PubMed

20.

Caballero F, Siniakowicz K, Hollister-Lock J, Duran L, Katsuta H, Yamada T, et al. Birth and death of human beta-cells in pancreases from cadaver donors, autopsies, surgical specimens, and islets transplanted into mice. Cell Transplant. 2014;23(2):139–51.PubMed

21.

• Sullivan BA, Hollister-Lock J, Bonner-Weir S, Weir GC. Reduced Ki67 staining in the postmortem state calls into question past conclusions about the lack of turnover of adult human beta-cells. Diabetes. 2015;64(5):1698–702. An important study which suggests that estimates of Ki67 immunopositivity may not correlate fully with beta cell replication in post mortem tissues.PubMedPubMedCentral

22.

Ferber S, Halkin A, Cohen H, Ber I, Einav Y, Goldberg I, et al. Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat Med. 2000;6(5):568–72.PubMed

23.

Ber I, Shternhall K, Perl S, Ohanuna Z, Goldberg I, Barshack I, et al. Functional, persistent, and extended liver to pancreas transdifferentiation. J Biol Chem. 2003;278(34):31950–7.PubMed

24.

Kojima H, Fujimiya M, Matsumura K, Younan P, Imaeda H, Maeda M, et al. NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nat Med. 2003;9(5):596–603.PubMed

25.

Tang DQ, Shun L, Koya V, Sun Y, Wang Q, Wang H, et al. Genetically reprogrammed, liver-derived insulin-producing cells are glucose-responsive, but susceptible to autoimmune destruction in settings of murine model of type 1 diabetes. Am J Transl Res. 2013;5(2):184–99.PubMedPubMedCentral

26.

Nagasaki H, Katsumata T, Oishi H, Tai PH, Sekiguchi Y, Koshida R, et al. Generation of insulin-producing cells from the mouse liver using beta cell-related gene transfer including Mafa and Mafb. PLoS One. 2014;14;9(11):e113022.

27.

Zalzman M, Gupta S, Giri RK, Berkovich I, Sappal BS, Karnieli O, et al. Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells. Proc Natl Acad Sci U S A. 2003;100(12):7253–8.PubMedPubMedCentral

28.

Zalzman M, Anker-Kitai L, Efrat S. Differentiation of human liver-derived, insulin-producing cells toward the beta-cell phenotype. Diabetes. 2005;54(9):2568–75.PubMed

29.

Sapir T, Shternhall K, Meivar-Levy I, Blumenfeld T, Cohen H, Skutelsky E, 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(22):7964–9.PubMedPubMedCentral

30.

Chen YJ, Finkbeiner SR, Weinblatt D, Emmett MJ, Tameire F, Yousefi M, et al. De novo formation of insulin-producing “neo-β cell islets” from intestinal crypts. Cell Rep. 2014;6(6):1046–58.PubMed

31.

Suzuki A, Nakauchi H, Taniguchi H. Glucagon-like peptide 1 (1-37) converts intestinal epithelial cells into insulin-producing cells. Proc Natl Acad Sci U S A. 2003;100(9):5034–9.PubMedPubMedCentral

32.

Talchai C, Xuan S, Kitamura T, DePinho RA, Accili D. Generation of functional insulin-producing cells in the gut by Foxo1 ablation. Nat Genet 2012; 44(4):406–12, S1.PubMedPubMedCentral

33.

Bouchi R, Foo KS, Hua H, Tsuchiya K, Ohmura Y, Sandoval PR, et al. FOXO1 inhibition yields functional insulin-producing cells in human gut organoid cultures. Nat Commun. 2014;5:4242.PubMed

34.

Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature. 2008;455(7213):627–32.PubMedPubMedCentral

35.

Baeyens L, Lemper M, Leuckx G, De Groef S, Bonfanti P, StangÃ G, Shemer R, Nord C, Scheel DW, Pan FC, Ahlgren U, Gu G, Stoffers DA, Dor Y, Ferrer J, Gradwohl G, Wright CV, Van de Casteele M, German MS, Bouwens L, Heimberg H. Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice. Nat Biotechnol 2014; 32(1):76–83.PubMedPubMedCentral

36.

Rooman I, Bouwens L. Combined gastrin and epidermal growth factor treatment induces islet regeneration and restores normoglycaemia in C57Bl6/J mice treated with alloxan. Diabetologia. 2004;47(2):259–65.PubMed

37.

Lemper M, De Groef S, Stangé G, Baeyens L, Heimberg H. A combination of cytokines EGF and CNTF protects the functional beta cell mass in mice with short-term hyperglycaemia. Diabetologia. 2016;59(9):1948–58.PubMed

38.

Klein D, Álvarez-Cubela S, Lanzoni G, Vargas N, Prabakar KR, Boulina M, et al. BMP-7 induces adult human pancreatic exocrine-to-endocrine conversion. Diabetes. 2015;64(12):4123–34.PubMedPubMedCentral

39.

Noguchi H, Kaneto H, Weir GC, Bonner-Weir S. PDX-1 protein containing its own antennapedia-like protein transduction domain can transduce pancreatic duct and islet cells. Diabetes. 2003;52(7):1732–7.PubMed

40.

Valdez IA, Dirice E, Gupta MK, Shirakawa J, Teo AKK, Kulkarni RN. Proinflammatory cytokines induce endocrine differentiation in pancreatic ductal cells via STAT3-dependent NGN3 activation. Cell Rep. 2016;15(3):460–70.PubMedPubMedCentral

41.

Collombat P, Xu X, Ravassard P, Sosa-Pineda B, Dussaud S, Billestrup N, et al. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells. Cell. 2009;138(3):449–62.PubMedPubMedCentral

42.

Courtney M, Gjernes E, Druelle N, Ravaud C, Vieira A, Ben-Othman N, et al. The inactivation of Arx in pancreatic α-cells triggers their neogenesis and conversion into functional beta-like cells. PLoS Genet. 2013;9(10):e1003934.PubMedPubMedCentral

43.

Chakravarthy H, Gu X, Enge M, Dai X, Wang Y, Damond N, et al. Converting adult pancreatic islet α cells into β cells by targeting both Dnmt1 and Arx. Cell Metab. 2017;25(3):622–34.PubMedPubMedCentral

44.

Thorel F, Napote V, Avril I, Kohno K, Desgraz R, Chera S, et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature. 2010;464(7292):1149–54.PubMedPubMedCentral

45.

Chung CH, Hao E, Piran R, Keinan E, Levine F. Pancreatic beta-cell neogenesis by direct conversion from mature alpha-cells. Stem Cells. 2010;28:1630–8.PubMed

46.

Piran R, Lee SH, Kuss P, Hao E, Newlin R, Millán JL, et al. PAR2 regulates regeneration, transdifferentiation, and death. Cell Death Dis. 2016;7(11):e2452.

47.

Ben-Othman N, Vieira A, Courtney M, Record F, Gjernes E, Avolio F, et al. Long-term GABA administration Induces alpha cell-mediated beta-like cell neogenesis. Cell. 2017;168(1–2):73–85.e11.PubMed

48.

• Li J, Casteels T, Frogne T, Ingvorsen C, Honora C, Courtney M, Huber KVM, Schmitner N, Kimmel RA, Romanov RA, Sturtzel C, Lardeau CH, Klughammer J, Farlik M, Sdelci S, Vieira A, Avolio F, Briand F, Baburin I, Májek P, Pauler FM, Penz T, Stukalov A, Gridling M, Parapatics K, Barbieux C, Berishvili E, Spittler A, Colinge J, Bennett KL, Hering S, Sulpice T, Bock C, Distel M, Harkany T, Meyer D, Superti-Furga G, Collombat P, Hecksher S, Rensen J, Kubicek S. Artemisinins target GABA(A) receptor signaling and impair alpha cell identity. Cell. 2017; 168(1–2):86–100.e15. Presents opposing sides in the important debate about the role of artemisinins as regulators of islet cell transdifferentation PubMedPubMedCentral

49.

Xiao X, Guo P, Shiota C, Zhang T, Coudriet GM, Fischbach S, et al. Endogenous reprogramming of alpha cells into beta cells, induced by viral gene therapy, reverses autoimmune diabetes. Cell Stem Cell. 2018;22(1):78–90.e4.PubMedPubMedCentral

50.

Furuyama K, Chera S, van Gurp L, Oropeza D, Ghila L, Damond N, Vethe H, Paulo JA, Joosten AM, Berney T, Bosco D, Dorrell C, Grompe M, Ræder H, Roep BO, Thorel F, Herrera PL. Diabetes relief in mice by glucose-sensing insulin-secreting human beta-cells. Nature. 2019; 567(7746):43–48.PubMedPubMedCentral

51.

De Lisle RC, Logsdon CD. Pancreatic acinar cells in culture: expression of acinar and ductal antigens in a growth-related manner. Eur J Cell Biol. 1990;51(1):64–75.PubMed

52.

Hall PA, Lemoine NR. Rapid acinar to ductal transdifferentiation in cultured human exocrine pancreas. J Pathol. 1992;166(2):97–103.PubMed

53.

Furuyama K, Kawaguchi Y, Akiyama H, Horiguchi M, Kodama S, Kuhara T, et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet. 2011;43(1):34–41.PubMed

54.

Masini M, Marselli L, Himpe E, Martino L, Bugliani M, Suleiman M, et al. Co-localization of acinar markers and insulin in pancreatic cells of subjects with type 2 diabetes. PLoS One. 2017;12(6):e0179398.PubMedPubMedCentral

55.

Roy N, Hebrok M. Regulation of cellular identity in cancer. Dev Cell. 2015;35(6):674–84.PubMedPubMedCentral

56.

Solar M, Cardalda C, Houbracken I, Martan M, Maestro MA, De Medts N, et al. Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth. Dev Cell. 2017;17(6):849–60.

57.

Bogdani M, Lefebvre V, Buelens N, Bock T, Pipeleers-Marichal M, In't Veld P, et al. Formation of insulin-positive cells in implants of human pancreatic duct cell preparations from young donors. Diabetologia. 2003;46(6):830–8.PubMed

58.

Meier JJ, Butler AE, Galasso R, Butler PC. Hyperinsulinemic hypoglycemia after gastric bypass surgery is not accompanied by islet hyperplasia or increased beta-cell turnover. Diabetes Care. 2006;29(7):1554–9.PubMed

59.

Bonner-Weir S, Toschi E, Inada A, Reitz P, Fonseca SY, Aye T, et al. The pancreatic ductal epithelium serves as a potential pool of progenitor cells. Pediatr Diabetes. 2004;5(Suppl 2):16–22.PubMed

60.

Bonner-Weir S, Guo L, Li WC, Ouziel-Yahalom L, Lysy PA, Weir GC, et al. Islet neogenesis: a possible pathway for beta-cell replenishment. Rev Diabet Stud. 2012;9(4):407–16.PubMed

61.

Alidjinou EK, Sana F, Bertin A, Caloone D, Hober D. Persistent infection of human pancreatic cells with Coxsackievirus B4 is cured by fluoxetine. Antivir Res. 2015;116:51–4.PubMed

62.

Dunne JL, Richardson SJ, Atkinson MA, Craig ME, Dahl-Jorgensen K, Flodstrom-Tullberg M, et al. Rationale for enteroviral vaccination and antiviral therapies in human type 1 diabetes. Diabetologia. 2019 Jan 23;62:744–53. https://doi.org/10.1007/s00125-019-4811-7.CrossRefPubMedPubMedCentral

63.

Martin-Pagola A, Sisino G, Allende G, Dominguez-Bendala J, Gianani R, Reijonen H, 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(10):1803–13.PubMedPubMedCentral

64.

Dirice E, De Jesus DF, Kahraman S, Basile G, Ng RW, El Ouaamari A, Teo AKK, Bhatt S, Hu J, Kulkarni RN. Human duct cells contribute to β cell compensation in insulin resistance. JCI Insight. 2019; 4(8): pii: 99576.

65.

Rall LB, Pictet RL, Williams RH, Rutter WJ. Early differentiation of glucagon-producing cells in embryonic pancreas: a possible developmental role for glucagon. Proc Natl Acad Sci U S A. 1973;70(12):3478–82.PubMedPubMedCentral

66.

Teitelman G, Alpert S, Polak JM, Martinez A, Hanahan D. Precursor cells of mouse endocrine pancreas coexpress insulin, glucagon and the neuronal proteins tyrosine hydroxylase and neuropeptide Y, but not pancreatic polypeptide. Development. 1993;118(4):1031–9.PubMed

67.

Johansson KA, Dursun U, Jordan N, Gu G, Beermann F, Gradwohl G, et al. Temporal control of neurogenin3 activity in pancreas progenitors reveals competence windows for the generation of different endocrine cell types. Dev Cell. 2007;12(3):457–65.PubMed

68.

Sharon N, Chawla R, Mueller J, Vanderhooft J, Whitehorn LJ, Rosenthal B, et al. A peninsular structure coordinates asynchronous differentiation with morphogenesis to generate pancreatic islets. Cell. 2019;176(4):790–804.e13.PubMedPubMedCentral

69.

Hancock AS, Du A, Liu J, Miller M, May CL. Glucagon deficiency reduces hepatic glucose production and improves glucose tolerance in adult mice. Mol Endocrinol. 2010;24(8):1605–14.PubMedPubMedCentral

70.

Thorel F, Damond N, Chera S, Wiederkehr A, Thorens B, Meda P, et al. Normal glucagon signaling and β-cell function after near-total α-cell ablation in adult mice. Diabetes. 2011;60(11):2872–82.PubMedPubMedCentral

71.

• Ackermann AM, Moss NG, Kaestner KH. GABA and artesunate do not induce pancreatic alpha-to-beta cell transdifferentiation in vivo. Cell Metab. 2018;28(5):787–792.e3. Presents opposing sides in the important debate about the role of artemisinins as regulators of islet cell transdifferentation.

72.

Eizirik DL, Gurzov EN. Can GABA turn pancreatic alpha-cells into beta-cells? Nat Rev Endocrinol. 2018;14(11):629–30.PubMed

73.

Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature. 2004;429(6987):41–6.PubMed

74.

Georgia S, Bhushan A. Beta cell replication is the primary mechanism for maintaining postnatal beta cell mass. J Clin Invest. 2004;114(7):963–8.PubMedPubMedCentral

75.

Kulkarni RN, Jhala US, Winnay JN, Krajewski S, Montminy M, Kahn CR. PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. J Clin Invest. 2004;114(6):828–36.PubMedPubMedCentral

76.

Vasavada RC, Gonzalez-Pertusa JA, Fujinaka Y, Fiaschi-Taesch N, Cozar-Castellano I, Garcia-Ocaña A. Growth factors and beta cell replication. Int J Biochem Cell Biol 2006; 38(5–6):931–950.

77.

Heit JJ, Karnik SK, Kim SK. Intrinsic regulators of pancreatic beta-cell proliferation. Annu Rev Cell Dev Biol. 2006;22:311–38.PubMed

78.

Assmann A, Hinault C, Kulkarni RN. Growth factor control of pancreatic islet regeneration and function. Pediatr Diabetes. 2009;10(1):14–32.PubMed

79.

Jiang WJ, Peng YC, Yang KM. Cellular signaling pathways regulating beta-cell proliferation as a promising therapeutic target in the treatment of diabetes. Exp Ther Med. 2018;16(4):3275–85.PubMedPubMedCentral

80.

Kulkarni RN, Mizrachi EB, Ocana AG, Stewart AF. Human beta-cell proliferation and intracellular signaling: driving in the dark without a road map. Diabetes. 2012;61(9):2205–13.PubMedPubMedCentral

81.

Bernal-Mizrachi E, Kulkarni RN, Scott DK, Mauvais-Jarvis F, Stewart AF, Garcia-Ocaña A. Human beta-cell proliferation and intracellular signaling part 2: still driving in the dark without a road map. Diabetes. 2014;63(3):819–31.PubMedPubMedCentral

82.

Stewart AF, Hussain MA, Garcia-Ocaña A, Vasavada RC, Bhushan A, Bernal-Mizrachi E, et al. Human beta-cell proliferation and intracellular signaling: part 3. Diabetes. 2015;64(6):1872–85.PubMedPubMedCentral

83.

Shen W, Tremblay MS, Deshmukh VA, Wang W, Filippi CM, Harb G, et al. Small-molecule inducer of beta cell proliferation identified by high-throughput screening. J Am Chem Soc. 2013;135(5):1669–72.PubMed

84.

Boerner BP, George NM, Mir SU, Sarvetnick NE. WS6 induces both alpha and beta cell proliferation without affecting differentiation or viability. Endocr J. 2015;62(4):379–86.PubMedPubMedCentral

85.

•• Wang P, Alvarez-Perez JC, Felsenfeld DP, Liu H, Sivendran S, Bender A, et al. A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat Med. 2015;21(4):383–8. Provides convincing evidence that harmine may be capable of promoting beta cell profilferation via its ability to inhibit DYRK1A.PubMedPubMedCentral

86.

•• Dirice E, Walpita D, Vetere A, Meier BC, Kahraman S, Hu J, et al. Inhibition of DYRK1A stimulates human beta-cell proliferation. Diabetes. 2016;65(6):1660–71. Critical evidence that inhibitors of a key kinase may be mediators of beta cell proliferation.PubMedPubMedCentral

87.

Walpita D, Hasaka T, Spoonamore J, Vetere A, Takane KK, Fomina-Yadlin D, et al. A human islet cell culture system for high-throughput screening. J Biomol Screen. 2012;17(4):509–18.PubMed

88.

Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003;425(6958):577–84.PubMed

89.

Massague J. TGF-beta signalling in context. Nat Rev Mol Cell Biol. 2012;13(10):616–30.PubMedPubMedCentral

90.

Dhawan S, Dirice E, Kulkarni RN, Bhushan A. Inhibition of TGF-beta signaling promotes human pancreatic beta-cell replication. Diabetes. 2016;65(5):1208–18.PubMedPubMedCentral

91.

•• Wang P, Karakose E, Liu H, Swartz E, Ackeifi C, Zlatanic V, et al. Combined inhibition of DYRK1A, SMAD, and trithorax pathways synergizes to induce robust replication in adult human beta cells. Cell Metab. 2019;29(3):638–652.e5. Offers a new therapeutic route to achieve beta cell proliferation by application of exogenous small molecules.

92.

Liu Z, Tanabe K, Bernal-Mizrachi E, Permutt MA. Mice with beta cell overexpression of glycogen synthase kinase-3beta have reduced beta cell mass and proliferation. Diabetologia. 2008;51(4):623–31.PubMed

93.

Tanabe K, Liu Z, Patel S, Doble BW, Li L, Cras-Méneur C, et al. Genetic deficiency of glycogen synthase kinase-3beta corrects diabetes in mouse models of insulin resistance. PLoS Biol. 2008;6(2):e37.PubMedPubMedCentral

94.

Liu Y, Tanabe K, Baronnier D, Patel S, Woodgett J, Cras-Méneur C, Permutt MA. Conditional ablation of Gsk-β in islet beta cells results in expanded mass and resistance to fat feeding-induced diabetes in mice. Diabetologia. 2010; 53(12):2600–2610.PubMedPubMedCentral

95.

Liu H, Remedi MS, Pappan KL, Kwon G, Rohatgi N, Marshall CA, et al. Glycogen synthase kinase-3 and mammalian target of rapamycin pathways contribute to DNA synthesis, cell cycle progression, and proliferation in human islets. Diabetes. 2009;58(3):663–72.PubMedPubMedCentral

96.

Shen W, Taylor B, Jin Q, Nguyen-Tran V, Meeusen S, Zhang YQ, et al. Inhibition of DYRK1A and GSK3B induces human beta-cell proliferation. Nat Commun. 2015;6:8372.

97.

Rieck S, Kaestner KH. Expansion of beta-cell mass in response to pregnancy. Trends Endocrinol Metab. 2010;21:151–8.PubMed

98.

Zhang H, Zhang J, Pope CF, Crawford LA, Vasavada RC, Jagasia SM, 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(1):143–52.PubMed

99.

Karnik SK, Chen H, McLean GW, Heit JJ, Gu X, Zhang AY, et al. Menin controls growth of pancreatic beta-cells in pregnant mice and promotes gestational diabetes mellitus. Science. 2007;318(5851):806–9.PubMed

100.

Kim H, Toyofuku Y, Lynn FC, Chak E, Uchida T, Mizukami H, et al. Serotonin regulates pancreatic beta cell mass during pregnancy. Nat Med. 2010;16(7):804–8.PubMedPubMedCentral

101.

Shirakawa J, Fernandez M, Takatani T, El Ouaamari A, Jungtrakoon P, Okawa ER, et al. Insulin signaling regulates the FoxM1/PLK1/CENP-A pathway to promote adaptive pancreatic β cell proliferation. Cell Metab. 2017;25(4):868–82.PubMedPubMedCentral

102.

Rieck S, White P, Schug J, Fox AJ, Smirnova O, Gao N, et al. The transcriptional response of the islet to pregnancy in mice. Mol Endocrinol. 2009;23(10):1702–12.PubMedPubMedCentral

103.

Schrader J, Rennekamp W, Niebergall U, Schoppet M, Jahr H, Brendel MD, et al. Cytokine-induced osteoprotegerin expression protects pancreatic beta cells through p38 mitogen-activated protein kinase signalling against cell death. Diabetologia. 2007;50(6):1243–7.PubMed

104.

Walsh MC, Choi Y. Biology of the RANKL-RANK-OPG system in immunity, Bone, and beyond. Front Immunol. 2014;5:511.PubMedPubMedCentral

105.

Kondegowda NG, Fenutria R, Pollack IR, Orthofer M, Garcia-Ocaña A, Penninger JM, et al. Osteoprotegerin and denosumab stimulate human beta cell proliferation through inhibition of the receptor activator of NF-KB ligand pathway. Cell Metab. 2015;22(1):77–85.PubMedPubMedCentral

106.

Jones B, Bloom SR, Buenaventura T, Tomas A, Rutter GA. Control of insulin secretion by GLP-1. Peptides. 2018;100:75–84.PubMed

107.

Lavine JA, Attie AD. Gastrointestinal hormones and the regulation of beta-cell mass. Ann N Y Acad Sci. 2010;1212:41–58.PubMed

108.

Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 2013;17(6):819–37.PubMed

109.

Xie J, El Sayed NM, Qi C, Zhao X, Moore CE, Herbert TP. Exendin-4 stimulates islet cell replication via the IGF1 receptor activation of mTORC1/S6K1. J Mol Endocrinol. 2014;53(1):105–15.PubMed

110.

Friedrichsen BN, Neubauer N, Lee YC, Gram VK, Blume N, Petersen JS, et al. Stimulation of pancreatic beta-cell replication by incretins involves transcriptional induction of cyclin D1 via multiple signalling pathways. J Endocrinol. 2006;188(3):481–92.PubMed

111.

Tschen SI, Georgia S, Dhawan S, Bhushan A. Skp2 is required for incretin hormone-mediated beta-cell proliferation. Mol Endocrinol. 2011;25(12):2134–43.PubMedPubMedCentral

112.

Tian L, Gao J, Weng G, Yi H, Tian B, O'Brien TD, et al. Comparison of exendin-4 on beta-cell replication in mouse and human islet grafts. Transpl Int. 2011;24(8):856–64.PubMed

113.

Saisho Y, Butler AE, Manesso E, Elashoff D, Rizza RA, Butler PC. Beta-cell mass and turnover in humans: effects of obesity and aging. Diabetes Care. 2013;36(1):111–7.PubMed

114.

Shirakawa J, Kulkarni RN. Novel factors modulating human beta-cell proliferation. Diabetes Obes Metab. 2016;18(Suppl 1):71–7.PubMedPubMedCentral

115.

El Ouaamari A, Dirice E, Gedeon N, Hu J, Zhou JY, Shirakawa J, et al. SerpinB1 promotes pancreatic beta cell proliferation. Cell Metab. 2016;23(1):194–205.PubMed

116.

El Ouaamari A, O-Sullivan I, Shirakawa J, Basile G, Zhang W, Roger S, et al. Forkhead box protein O1 (FoxO1) regulates hepatic serine protease inhibitor B1 (serpinB1) expression in a non-cell-autonomous fashion. J Biol Chem. 2019;294(3):1059–69.PubMed

117.

Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, et al. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell. 2000l;6(1):87–97.PubMed

118.

Takebayashi K, Hara K, Terasawa T, Naruse R, Suetsugu M, Tsuchiya T, et al. Circulating SerpinB1 levels and clinical features in patients with type 2 diabetes. BMJ Open Diabetes Res Care. 2016;4(1):e000274.

119.

Sugimori T, Cooley J, Hoidal JR, Remold-O'Donnell E. Inhibitory properties of recombinant human monocyte/neutrophil elastase inhibitor. Am J Respir Cell Mol Biol. 1995;13(3):314–22.PubMed

120.

Leete P, Willcox A, Krogvold L, Dahl-Jørgensen K, Foulis AK, Richardson SJ, Morgan NG. Differential insulitic profiles determine the extent of beta-cell destruction and the age at onset of type 1 diabetes. Diabetes. 2016; 65(5):1362–1369.PubMed

121.

Keenan HA, Sun JK, Levine J, Doria A, Aiello LP, Eisenbarth G, Bonner-Weir S, King GL. Residual insulin production and pancreatic β-cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes. 2010; 59(11):2846–2853.PubMedPubMedCentral

122.

• Shields BM, TJ MD, Oram R, Hill A, Hudson M, Leete P, et al. TIGI Consortium. C-Peptide decline in type 1 diabetes has two phases: an initial exponential fall and a subsequent stable phase. Diabetes Care. 2018;41(7):1486–92. Provides important evidence that beta-cell death may be arrested after the initial phase of loss during the normal progression of type 1 diabetes.PubMed

123.

Oram RA, Jones AG, Besser RE, Knight BA, Shields BM, Brown RJ, et al. The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells. Diabetologia. 2014;57(1):187–91.PubMed

124.

Krogvold L, Skog O, Sundstrom G, Edwin B, Buanes T, Hanssen KF, et al. Function of isolated pancreatic islets from patients at onset of type 1 diabetes: insulin secretion can be restored after some days in a nondiabetogenic environment in vitro: results from the DiViD study. Diabetes. 2015;64(7):2506–12.PubMed

Title: How, When, and Where Do Human β-Cells Regenerate?
Authors: Giorgio Basile
Rohit N. Kulkarni
Noel G. Morgan
Publication date: 01-08-2019
Publisher: Springer US
Keywords: Insulins
Insulins
Published in: Current Diabetes Reports / Issue 8/2019
Print ISSN: 1534-4827
Electronic ISSN: 1539-0829
DOI: https://doi.org/10.1007/s11892-019-1176-8

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose of Review

Recent Findings

Summary

Please log in to get access to this content

Other articles of this Issue 8/2019

Fecal Microbiota Transplantation: a Future Therapeutic Option for Obesity/Diabetes?

Epigenetics and Type 2 Diabetes Risk

Advanced Technology in the Management of Diabetes: Which Comes First—Continuous Glucose Monitor or Insulin Pump?

GPR44 as a Target for Imaging Pancreatic Beta-Cell Mass

Machine Perfusion and the Pancreas: Will It Increase the Donor Pool?

Barriers and Facilitators Influencing Parental Transition of College-Bound Youth with Type 1 Diabetes Mellitus: An Integrative Review

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials