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01-02-2022 | Insulins | Review

Regenerative approaches to preserve pancreatic β-cell mass and function in diabetes pathogenesis

Author: Maria Fernanda Desentis-Desentis

Published in: Endocrine | Issue 2/2022

Abstract

In both type 1 diabetes (T1D) and type 2 diabetes (T2D), there is a substantial β-cell mass loss. Residual β-cell mass is susceptible to cellular damage because of specific pancreatic β-cell characteristics. β cells have a low proliferation rate, being in human adults almost zero and a low antioxidant system that makes β cells susceptible to oxidative stress and increases their vulnerability to cell destruction. Different strategies have been addressed to preserve pancreatic β-cell residual mass and function in patients with diabetes. However, the effect of many compounds proposed in rodent models to trigger β-cell replication has different results in human β cells. In this review, scientific evidence of β-cell of two major regenerative approaches has been gathered. Regeneration proceedings for pancreatic β cells are promising and could improve β-cell proliferation capacity and contribute to the conservation of mature β-cell phenotypic characteristics. This evidence supports the notion that regenerative medicine could be a helpful strategy to yield amelioration of T1D and T2D pathogenesis.

A. Pisania, G.C. Weir, J.J. O’Neil, A. Omer, V. Tchipashvili, J. Lei et al. Quantitative analysis of cell composition and purity of human pancreatic islet preparations. Lab. Investig. 90, 1661–75 (2011). https://doi.org/10.1038/labinvest.2010.124.QuantitativeCrossRef

H.I. Marrif, S.I. Al-Sunousi, Pancreatic β cell mass death. Front. Pharmacol. 7, 83 (2016). https://doi.org/10.3389/fphar.2016.00083CrossRefPubMedPubMedCentral

B.E. Gregg, P.C. Moore, D. Demozay, B.A. Hall, M. Li, A. Husain et al. Formation of a human β-cell population within pancreatic islets is set early in life. J. Clin. Endocrinol. Metab. 97, 3197–206 (2012). https://doi.org/10.1210/jc.2012-1206CrossRefPubMedPubMedCentral

I. Cozar-Castellano, N. Fiaschi-Taesch, T.A. Bigatel, K.K. Takane, A. García-Ocaña, R. Vasavada et al. Molecular control of cell cycle progression in the pancreatic β-cell. Endocr. Rev. 27, 356–70 (2006). https://doi.org/10.1210/er.2006-0004CrossRefPubMed

Y. Dor, J. Brown, O.I. Martinez, D.A. Melton, Adult pancreatic β-cell are formed by self-duplication rather than stem-cell differentiation. Nature 429, 41–6 (2004)CrossRef

I. Swenne, Effects of aging on the regenerative capacity of the pancreatic β-cell of the rat. Diabetes 32, 14–9 (1983)CrossRef

R.N. Kulkarni, E.-B. Mizrachi, A. García-Ocaña, A.F. Stewart, Human β-cell proliferation and intracellular signaling driving in the dark without a road map. Diabetes 61, 2205–13 (2012). https://doi.org/10.2337/db12-0018CrossRefPubMedPubMedCentral

T. Mezza, R.N. Kulkarni, The regulation of pre- and post-maturational plasticity of mammalian islet cell mass. Diabetologia 57, 1291–303 (2014). https://doi.org/10.1007/s00125-014-3251-7CrossRefPubMed

N. Fiaschi-Taesch, T.A. Bigatel, B. Sicari, K.K. Takane, F. Salim, S. Velazquez-Garcia et al. Survey of the human pancreatic β-cell G1/S proteome reveals a potential therapeutic role for Cdk-6 and cyclin D1 in enhancing human β-cell replication and function in vivo. Diabetes 58, 882–93 (2009). https://doi.org/10.2337/db08-0631.N.F.-TCrossRefPubMedPubMedCentral

10.

L.U.C. Bouwens, I. Rooman, Regulation of pancreatic beta-cell mass. Physiol. Rev. 85, 1255–70 (2005). https://doi.org/10.1152/physrev.00025.2004CrossRefPubMed

11.

B. Reusens, C. Remacle, Programming of the endocrine pancreas by the early nutritional environment. Int J. Biochem Cell Biol. 38, 913–22 (2006). https://doi.org/10.1016/j.biocel.2005.10.012CrossRefPubMed

12.

D.J. Hill, Development of the endocrine pancreas. Rev. Endocr. Metab. Disord. 6, 229–38 (2005). https://doi.org/10.1016/B978-0-323-18907-1.00030-5CrossRefPubMed

13.

Q. Zhou, D.A. Melton, Pancreas regeneration. Nature 557, 351–8 (2018). https://doi.org/10.1038/s41586-018-0088-0CrossRefPubMedPubMedCentral

14.

T.M. Nordmann, E. Dror, F. Schulze, S. Traub, E. Berishvili, C. Barbie et al. The role of inflammation in β-cell dedifferentiation. Sci. Rep. 2017:6285. https://doi.org/10.1038/s41598-017-06731-w.

15.

C. Ackeifi, P. Wang, E. Karakose, J.E.M. Fox, B.J. González, H. Liu et al. GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human β-cell regeneration. Sci. Transl. Med 12, eaaw9996 (2020)CrossRef

16.

D. Saunders, A.C. Powers, Replicative capacity of β-cells and type 1 diabetes. J. Autoimmun. 71, 59–68 (2016). https://doi.org/10.1016/j.jaut.2016.03.014CrossRefPubMedPubMedCentral

17.

E. Dirice, D. Walpita, A. Vetere, B.C. Meier, S. Kahraman, J. Hu et al. Inhibition of DYRK1A stimulates human β-cell proliferation. Diabetes 65, 1660–71 (2016). https://doi.org/10.2337/db15-1127CrossRefPubMedPubMedCentral

18.

C. Ackeifi, E. Swartz, K. Kumar, H. Liu, S. Chalada, E. Karakose et al. Pharmacologic and genetic approaches define human pancreatic β cell mitogenic targets of DYRK1A inhibitors. JCI Insight 5, e132594 (2020)CrossRef

19.

P. Wang, E. Karakose, H. Liu, E. Swartz, V. Zlatanic, J. Wilson et al. Combined inhibition of DYRK1A, SMAD and trithorax pathways synergizes to induce robust replication in adult human beta cells. Cell Metab. 29, 638–52 (2020). https://doi.org/10.1016/j.cmet.2018.12.005.CombinedCrossRef

20.

P. Wang, J. Alvarez-Perez, D.P. Felsenfeld, S. Sivendran, A. Bender, A. Kumar et al. Induction of human pancreatic beta cell replication by inhibitors of dual specificity tyrosine regulated kinase. Nat. Med. 21, 383–8 (2015). https://doi.org/10.1038/nm.3820.InductionCrossRefPubMedPubMedCentral

21.

E. Karakose, C. Ackeifi, P. Wang, A.F. Stewart, Advances in drug discovery for human beta cell regeneration. Diabetologia 61, 1693–9 (2018). https://doi.org/10.1007/s00125-018-4639-6CrossRefPubMedPubMedCentral

22.

Y. Gwack, S. Sharma, J. Nardone, B. Tanasa, A. Iuga, S. Srikanth et al. A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature 441, 646–50 (2006). https://doi.org/10.1038/nature04631CrossRefPubMed

23.

J. Shirakawa, R.N. Kulkarni, Novel factors modulating human β-cell proliferation. Diabetes Obes. Metab. 18, 71–7 (2017). https://doi.org/10.1111/dom.12731.NovelCrossRef

24.

W.R. Goodyer, X. Gu, Y. Liu, R. Bottino, G.R. Crabtree, S.K. Kim, Neonatal β cell development in mice and humans is regulated by calcineurin/NFAT. Dev. Cell 23, 21–34 (2012). https://doi.org/10.1016/j.devcel.2012.05.014.NeonatalCrossRefPubMedPubMedCentral

25.

W. Shen, B. Taylor, Q. Jin, S. Meeusen, Y. Zhang, A. Kamireddy et al. Inhibition of DYRK1A and GSK3B induces human β-cell proliferation. Nat. Commun. 6, 8372 (2015). https://doi.org/10.1038/ncomms9372CrossRefPubMed

26.

K.I. Aamodt, R. Aramandla, J.J. Brown, N. Fiaschi-Taesch, P. Wang, A.F. Stewart et al. Development of a reliable automated screening system to identify small molecules and biologics that promote human β-cell regeneration. Am. J. Physiol. Endocrinol. Metab. 311, E859–68 (2016). https://doi.org/10.1152/ajpendo.00515.2015CrossRefPubMedPubMedCentral

27.

S. Dhawan, E. Dirice, R.N. Kulkarni, A. Bhushan, Inhibition of TGF-β signaling promotes human pancreatic β-cell replication. Diabetes 65, 1208–18 (2016). https://doi.org/10.2337/db15-1331CrossRefPubMedPubMedCentral

28.

G. Basile, R.N. Kulkarni, N.G. Morgan, How, when, and where do human β-cells regenerate? Curr. Diab Rep. 19, 48 (2020). https://doi.org/10.1007/s11892-019-1176-8.HowCrossRef

29.

Y. Nakagawa, T. Suzuki, H. Ishii, A. Ogata, D. Nakae, Mitochondrial dysfunction and biotransformation of β-carboline alkaloids, harmine and harmaline, on isolated rat hepatocytes. Chem. Biol. Interact. 188, 393–403 (2010). https://doi.org/10.1016/j.cbi.2010.09.004CrossRefPubMed

30.

H. Waki, K.W. Park, N. Mitro, L. Pei, R. Damoiseaux, D.C. Wilpitz et al. The small molecule harmine is an antidiabetic cell-type-specific regulator of PPAR g expression. Cell Metab. 5, 357–70 (2007). https://doi.org/10.1016/j.cmet.2007.03.010CrossRefPubMed

31.

B. Khor, J.D. Gagnon, G. Goel, M.I. Roche, K.L. Conway, K. Tran et al. The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells. Elife 4, e05920 (2015). https://doi.org/10.7554/eLife.05920CrossRefPubMedCentral

32.

D. Kondoh, S. Yamamoto, T. Tomita, K. Miyazaki, N. Itoh, Y. Yasumoto et al. Harmine lengthens circadian period of the mammalian molecular clock in the suprachiasmatic nucleus. Biol. Pharm. Bull. 37, 1422–7 (2014)CrossRef

33.

H.E. Hohmeier, L. Zhang, B. Taylor, S. Stephens, D. Lu, P. Mcnamara et al. Identification of a small molecule that stimulates human β-cell proliferation and insulin secretion, and protects against cytotoxic stress in rat insulinoma cells. PLoS ONE 15, e0224344 (2020). https://doi.org/10.1371/journal.pone.0224344CrossRefPubMedPubMedCentral

34.

Y. Li, B. Hao, Structural basis of dimerization-dependent ubiquitination by the SCF Fbx4 ubiquitin ligase. J. Biol. Chem. 285, 13896–906 (2010). https://doi.org/10.1074/jbc.M110.111518CrossRefPubMedPubMedCentral

35.

S. Tiwari, C. Roel, T. Mansoor, R. Wills, N. Perianayagam, P. Wang et al. Definition of a Skp2-c-Myc Pathway to Expand Human Beta-cells. Sci. Rep. 6, 28461 (2016). https://doi.org/10.1038/srep28461CrossRefPubMedPubMedCentral

36.

P.P. Khin, J.H. Lee, H.S. Jun, A brief review of the mechanisms of β-cell dedifferentiation in type 2 diabetes. Nutrients 2021;13. https://doi.org/10.3390/nu13051593.

37.

O. Friedman-Mazursky, R. Elkon, S. Efrat, Redifferentiation of expanded human islet β cells by inhibition of ARX. Sci. Rep. 6, 20698 (2016). https://doi.org/10.1038/srep20698CrossRefPubMedPubMedCentral

38.

J. Zhang, F. Liu, The De-, Re-, and trans-differentiation of β-cells: Regulation and function. Semin Cell Dev. Biol. 103, 68–75 (2020). https://doi.org/10.1016/j.semcdb.2020.01.003CrossRefPubMed

39.

G. Domínguez Gutiérrez, A.S. Bender, V. Cirulli, T.L. Mastracci, S.M. Kelly, A. Tsirigos et al. Pancreatic β cell identity requires continual repression of non–β cell programs. J. Clin. Investig 127, 244–59 (2017). https://doi.org/10.1172/JCI88017.NEUROD1CrossRef

40.

M. Bensellam, J.C. Jonas, D.R. Laybutt, Mechanisms of β-cell dedifferentiation in diabetes: Recent findings and future research directions. J. Endocrinol. 236, R109–43 (2018). https://doi.org/10.1530/JOE-17-0516CrossRefPubMed

41.

Sachs S., Bastidas-Ponce A., Tritschler S., Bakhti M., Böttcher A., Sánchez-Garrido M.A., et al. Targeted Pharmacological Therapy Restores β-Cell Function for Diabetes Remission. 2 (Springer US, 2020). https://doi.org/10.1038/s42255-020-0171-3.

42.

W. Zhiyu, N.W. York, C.G. Nichols, M.S. Remedi, Pancreatic β-cell dedifferentiation in diabetes and re-differentiation following insulin therapy. Cell Metab. 19, 872–82 (2014). https://doi.org/10.1016/j.cmet.2014.03.010.PancreaticCrossRef

43.

X.N. Téllez, M. Vilaseca, Y. Martí, A. Pla, E. Montanya, β-Cell dedifferentiation, reduced duct cell plasticity, and impaired β-cell mass regeneration in middle-aged rats. Am. J. Physiol. Endocrinol. Metab. 311, E554–63 (2016). https://doi.org/10.1152/ajpendo.00502.2015CrossRefPubMed

44.

C. Talchai, S. Xuan, H.V. Lin, L. Sussel, D. Accili, Pancreatic β-cell dedifferentiation as mechanism of diabetic β-cell failure. Cell 150, 1223–34 (2012). https://doi.org/10.1016/j.cell.2012.07.029.PancreaticCrossRefPubMedPubMedCentral

45.

Y. Bar, H.A. Russ, S. Knoller, L. Ouziel-Yahalom, E. Shimon, HES-1 is involved in adaptation of adult human β-cells to proliferation in vitro. Diabetes 57, 2413–20 (2008). https://doi.org/10.2337/db07-1323CrossRefPubMedPubMedCentral

46.

S. Efrat, Mechanisms of adult human β-cell in vitro dedifferentiation and redifferentiation. Diabetes Obes. Metab. 18, 97–101 (2016). https://doi.org/10.1111/dom.12724CrossRefPubMed

47.

A. Lenz, G. Toren-Haritan, S. Efrat, Redifferentiation of adult human β cells expanded in vitro by inhibition of the WNT pathway. PLoS ONE 9, e112914 (2014). https://doi.org/10.1371/journal.pone.0112914CrossRefPubMedPubMedCentral

48.

M. Bakhti, A. Böttcher, H. Lickert, Modelling the endocrine pancreas in health and disease. Nat. Rev. Endocrinol. 15, 155–71 (2019). https://doi.org/10.1038/s41574-018-0132-zCrossRefPubMed

49.

W.L. Qiu, Y.W. Zhang, Y. Feng, L.C. Li, L. Yang, C.R. Xu, Deciphering pancreatic islet β cell and α cell maturation pathways and characteristic features at the single-cell level. Cell Metab. 25, 1194–1205.e4 (2017). https://doi.org/10.1016/j.cmet.2017.04.003CrossRefPubMed

50.

C. Zeng, F. Mulas, Y. Sui, T. Guan, N. Miller, F. Liu et al. Pseudotemporal ordering of single cells reveals metabolic control of postnatal beta-cell proliferation. Cell Metab. 25, 1160–75 (2017).https://doi.org/10.1016/j.cmet.2017.04.014.PseudotemporalCrossRefPubMedPubMedCentral

51.

J. Sun, Q. Ni, J. Xie, M. Xu, J. Zhang, J. Kuang et al. β-cell dedifferentiation in patients With T2D With adequate glucose control and nondiabetic chronic pancreatitis. J. Clin. Endocrinol. Metab. 104, 83–94 (2019). https://doi.org/10.1210/jc.2018-00968CrossRefPubMed

52.

W. Ying, Y.S. Lee, Y. Dong, J.S. Seidman, M. Yang, R. Isaac et al. Expansion of islet-resident macrophages leads to inflammation affecting β cell proliferation and function in obesity. Cell Metab. 29, 457–474.e5 (2019). https://doi.org/10.1016/j.cmet.2018.12.003CrossRefPubMed

53.

W. He, T. Yuan, K. Maedler, Macrophage-associated pro-inflammatory state in human islets from obese individuals. Nutr. Diabetes 9, 36 (2019). https://doi.org/10.1038/s41387-019-0103-zCrossRefPubMedPubMedCentral

54.

M. Ghodsi, B. Larijani, A.A. Keshtkar, E. Nasli-Esfahani, S. Alatab, M.R. Mohajeri-Tehrani, Mechanisms involved in altered bone metabolism in diabetes: a narrative review. J. Diabetes Metab. Disord. 15, 52 (2016). https://doi.org/10.1186/s40200-016-0275-1CrossRefPubMedPubMedCentral

55.

R.A. DeFronzo, E. Ferrannini, L. Groop, R.R. Henry, W.H. Herman, J.J. Holst et al. Type 2 diabetes mellitus. Nat. Rev. Dis. Prim. 1, 1–22 (2015). https://doi.org/10.1038/s41574-019-0286-3CrossRef

56.

S. Efrat, Beta-cell dedifferentiation in type 2 diabetes: concise review. Transl. Clin. Res. 37, 1267–72 (2019). https://doi.org/10.1002/stem.3059CrossRef

57.

F. Han, X. Li, J. Yang, H. Liu, Y. Zhang, X. Yang et al. Salsalate prevents β-cell dedifferentiation in OLETF rats with type 2 diabetes through Notch1 pathway. Aging Dis. 10, 719–30 (2019). https://doi.org/10.14336/AD.2018.1221CrossRefPubMedPubMedCentral

58.

Y.S. Oh, S. Shin, Y.J. Lee, E.H. Kim, H.S. Jun, Betacellulin-induced beta cell proliferation and regeneration is mediated by activation of ErbB-1 and ErbB-2 receptors. PLoS ONE. 2011;6. https://doi.org/10.1371/journal.pone.0023894.

59.

S. Shin, N. Li, N. Kobayashi, J.W. Yoon, H.S. Jun, Remission of diabetes by β-cell regeneration in diabetic mice treated with a recombinant adenovirus expressing Betacellulin. Mol. Ther. 16, 854–61 (2008). https://doi.org/10.1038/mt.2008.22CrossRefPubMed

60.

H. Kojima, M. Fujimiya, K. Matsumura, P. Younan, H. Imaeda, M. Maeda et al. NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nat. Med. 9, 596–603 (2003). https://doi.org/10.1038/nm867CrossRefPubMed

61.

L. Li, M. Seno, H. Yamada, I. Kojima, Betacellulin improves glucose metabolism by promoting conversion of intraislet precursor cells to β-cells in streptozotocin-treated mice. Am. J. Physiol. Endocrinol. Metab. 285, 577–83 (2003). https://doi.org/10.1152/ajpendo.00120.2003CrossRef

62.

L. Ouziel-Yahalom, M. Zalzman, L. Anker-kitai, S. Knoller, Y. Bar, M. Glandt et al. Expansion and redifferentiation of adult human pancreatic islet cells. Biochem. Biophys. Res. Commun. 341, 291–8 (2006). https://doi.org/10.1016/j.bbrc.2005.12.187CrossRefPubMed

63.

Y.S. Lee, G.J. Song, H.S. Jun, Betacellulin-induced α-cell proliferation is mediated by ErbB3 and ErbB4, and may contribute to β-cell regeneration. Front Cell Dev. Biol. 8, 1–11 (2021). https://doi.org/10.3389/fcell.2020.605110CrossRef

64.

M.Y. Song, U.J. Bae, K.Y. Jang, B.H. Park, Transplantation of betacellulin-transduced islets improves glucose intolerance in diabetic mice. Exp. Mol. Med. 46, e98–8 (2014). https://doi.org/10.1038/emm.2014.24CrossRefPubMedPubMedCentral

65.

H.A. Russ, E. Sintov, L. Anker-Kitai, O. Friedman, A. Lenz, G. Toren et al. Insulin-producing cells generated from dedifferentiated human pancreatic beta cells expanded in vitro. PLoS ONE 6, e25566 (2011). https://doi.org/10.1371/journal.pone.0025566CrossRefPubMedPubMedCentral

66.

R.P. Robertson, L.K. Olson, H.-J. Zhang, Differentiating glucose toxicity from glucose desensitization: A new message from the insulin gene. Diabetes 43, 1085–9 (1994). https://doi.org/10.2337/diab.43.9.1085CrossRefPubMed

67.

E. Sintov, G. Nathan, S. Knoller, M. Pasmanik-Chor, H.A. Russ, E. Shimon, Inhibition of ZEB1 expression induces redifferentiation of adult human β cells expanded in vitro. Sci. Rep. 5, 13024 (2015). https://doi.org/10.1038/srep13024CrossRefPubMedPubMedCentral

68.

B. Finan, B. Yang, N. Ottaway, K. Stemmer, T.D. Müller, C.-X. Yi et al. Targeted estrogen delivery reverses the metabolic syndrome. Nat. Med. 18, 1847–56 (2012). https://doi.org/10.1038/nm.3009.TargetedCrossRefPubMedPubMedCentral

69.

F. Mauvais-Jarvis, C. Le May, J.P. Tiano, S. Liu, G. Kilic-Berkmen, J.H. Kim, The role of estrogens in pancreatic islet physiopathology. Adv. Exp. Med Biol. 1043, 385–99 (2017). https://doi.org/10.1007/978-3-319-70178-3_18CrossRefPubMed

Title: Regenerative approaches to preserve pancreatic β-cell mass and function in diabetes pathogenesis
Author: Maria Fernanda Desentis-Desentis
Publication date: 01-02-2022
Publisher: Springer US
Keywords: Insulins
Insulins
Type 2 Diabetes
Published in: Endocrine / Issue 2/2022
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI: https://doi.org/10.1007/s12020-021-02941-5

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