Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 1.736
5-Year Impact Factor – 2.135
Index Copernicus  – 168.52
MEiN – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

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Advances in Clinical and Experimental Medicine

2018, vol. 27, nr 9, September, p. 1309–1315

doi: 10.17219/acem/74452

Publication type: review article

Language: English

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Increasing beta cell mass to treat diabetes mellitus

Shakila Sabir1,A,B,D,F, Ammara Saleem1,A,E,F, Muhammad Furqan Akhtar1,A,B,D,F, Muhammad Saleem1,A,E,F, Moosa Raza2,A,E,F

1 Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Pakistan

2 Faculty of Pharmacy, University of Lahore, Lahore, Pakistan

Abstract

Finding a radical cure for diabetes has reached paramount importance in medicine due to the widespread prevalence of the disease. A substantial reduction in insulin-secreting beta cells is evident in diabetes. The failure of cyclin-dependent kinases (CDKs) and cyclins to access the nucleus is responsible for quiescence or senescence in human and rodent beta cells. The augmentation of beta cell proliferation is supposed to reverse diabetes. This concept has inspired the discovery of newer drugs that encourage the proliferation of beta cells. Although it is a rational step towards a cure for diabetes, the differences in biochemical pathways in rodents and human beta cells pose difficulty in promoting the proliferation of human beta cells. Primarily, it is mandatory to clearly understand the intracellular pathways involved in the proliferation of beta cells so as to pave the way for therapeutic interventions. There are several intrinsic factors that trigger the proliferation of beta cells. Furthermore, it is also obvious that the early death of beta cells due to oxidative stress-related upregulation of pro-apoptotic genes also predisposes individuals to diabetes mellitus. Polyphenols, exendin 4, histone deacetylase inhibitors, glucagon-like peptide 1, phenyl pyruvic acid glucoside, and several flavonoids reduce the early apoptosis of beta cells partly through their role in the reduction of oxidative stress. A better understanding of intracellular pathways, the identification of specific mitogens, the induction of beta cell proliferation, and the inhibition of apoptosis may help us treat diabetes mellitus through an increase in beta cell mass.

Key words

diabetes mellitus, apoptosis, cell proliferation, rodent beta cells, human beta cells

References (60)

  1. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: Perspectives on the past, present, and future. Lancet. 2014;383(9922):1068–1083.
  2. Roizen JD, Bradfield JP, Hakonarson H. Progress in understanding type 1 diabetes through its genetic overlap with other autoimmune diseases. Curr Diabetes Rep. 2015;15(11):1–7.
  3. Dupuis J, Langenberg C, Prokopenko I, et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nature Genet. 2010;42(2):105–116.
  4. Marques-Vidal P, Bastardot F, Kanel R, et al. Association between circulating cytokine levels, diabetes and insulin resistance in a population-based sample (CoLaus study). J Clin Endocrinol. 2013;78(2):232–241.
  5. Weir GC, Bonner-Weir S. Islet β cell mass in diabetes and how it relates to function, birth, and death. Ann NY Acad Sci. 2013;1281(1):92–105.
  6. Rahier J, Guiot Y, Goebbels R, et al. Pancreatic β-cell mass in European subjects with type 2 diabetes. Diabet Obes Metab. 2008;10(s4): 32–42.
  7. Niclauss N, Meier R, Bedat B, et al. Beta-cell replacement: Pancreas and islet cell transplantation. In: Novelties in Diabetes. Switzerland: Karger Publishers; 2016:146–162.
  8. Avrahami D, Li C, Yu M, et al. Targeting the cell cycle inhibitor p57 Kip2 promotes adult human β cell replication. J Clin Invest. 2014;124(2): 660–664.
  9. Bernal-Mizrachi E, Kulkarni RN, Scott DK, et al. Human β-cell proliferation and intracellular signaling part 2: Still driving in the dark without a road map. Diabetes. 2014;63(3):819–831.
  10. Fiaschi-Taesch NM, Kleinberger JW, Salim FG, et al. Human pancreatic β-cell G1/S molecule cell cycle atlas. Diabetes. 2013;62(7):2450–2459.
  11. Fiaschi-Taesch NM, Kleinberger JW, Salim FG, et al. Cytoplasmic-nuclear trafficking of G1/S cell cycle molecules and adult human β-cell replication a revised model of human β-cell G1/S control. Diabetes. 2013;62(7):2460–2470.
  12. Lavine JA, Raess PW, Davis DB, et al. Overexpression of pre-pro-cholecystokinin stimulates β-cell proliferation in mouse and human islets with retention of islet function. Mol Endocrinol. 2008;22(12):2716–2728.
  13. Fiaschi-Taesch NM, Salim F, Kleinberger J, et al. Induction of human β-cell proliferation and engraftment using a single G1/S regulatory molecule, CDK6. Diabetes. 2010;59(8):1926–1936.
  14. Agarwal SK, Mateo CM, Marx SJ. Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J Clin Endocrinol Metabol. 2009;94(5):1826–1834.
  15. Kulkarni RN, Mizrachi EB, Ocana AG, et al. Human β-cell proliferation and intracellular signaling. Diabetes. 2012;61(9):2205–2213.
  16. Demozay D, Tsunekawa S, Briaud I, et al. Specific glucose-induced control of insulin receptor substrate-2 expression is mediated via Ca2+-dependent calcineurin/NFAT signaling in primary pancreatic islet β-cells. Diabetes. 2011;60(11):2892–2902.
  17. Liu H, Remedi MS, Pappan KL, 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):663–672.
  18. Rhodes CJ, White MF, Leahy JL, et al. Direct autocrine action of insulin on β-cells: Does it make physiological sense? Diabetes. 2013;62(7): 2157–2163.
  19. Conrad E, Stein R, Hunter CS. Revealing transcription factors during human pancreatic β cell development. Trend Endocrinol Metab. 2014;25(8):407–414.
  20. De Vos A, Heimberg H, Quartier E, et al. Human and rat beta cells differ in glucose transporter but not in glucokinase gene expression. J Clin Invest. 1995;96(5):2489.
  21. Gradwohl G, Dierich A, LeMeur M, et al. Neurogenin 3 is required for the development of the four endocrine cell lineages of the pancreas. Proceed Nat Acad of Sci. 2000;97(4):1607–1611.
  22. Rubio-Cabezas O, Codner E, Flanagan SE, et al. Neurogenin 3 is important but not essential for pancreatic islet development in humans. Diabetologia. 2014;57(11):2421–2424.
  23. Dai C, Brissova M, Hang Y, et al. Islet-enriched gene expression and glucose-induced insulin secretion in human and mouse islets. Diabetologia. 2012;55(3):707–718.
  24. Gregg BE, Moore PC, Demozay D, et al. Formation of a human β-cell population within pancreatic islets is set early in life. J Clin Endocrinol Met. 2012;97(9):3197–3206.
  25. Mezza T, Muscogiuri G, Sorice GP, et al. Insulin resistance alters islet morphology in nondiabetic humans. Diabetes. 2014;63(3):994–1007.
  26. Teta M, Long SY, Wartschow LM, et al. Very slow turnover of β-cells in aged adult mice. Diabetes. 2005;54(9):2557–2567.
  27. Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metabol. 2013;17(6):819–837.
  28. Griffin KJ, Thompson PA, Gottschalk M, et al. Combination therapy with sitagliptin and lansoprazole in patients with recent-onset type 1 diabetes (REPAIR-T1D): 12-month results of a multicentre, randomised, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol. 2014;2(9):710–718.
  29. Tchkonia T, Zhu Y, Van Deursen J, et al. Cellular senescence and the senescent secretory phenotype: Therapeutic opportunities. J Clin Invest. 2013;123(3):966–972.
  30. Chen H, Gu X, Liu Y, et al. PDGF signaling controls age-dependent proliferation in pancreatic [bgr]-cells. Nature. 2011;478(7369):349–355.
  31. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132(6):2131–2157.
  32. Alonso LC, Yokoe T, Zhang P, et al. Glucose infusion in mice a new model to induce β-cell replication. Diabetes. 2007;56(7):1792–1801.
  33. Porat S, Weinberg-Corem N, Tornovsky-Babaey S, et al. Control of pancreatic β cell regeneration by glucose metabolism. Cell Metab. 2011;13(4):440–449.
  34. Futamura M, Yao J, Li X, et al. Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat. Diabetologia. 2012;55(4):1071–1080.
  35. Wang W, Walker JR, Wang X, et al. Identification of small-molecule inducers of pancreatic β-cell expansion. Proceed Nat Acad Sci. 2009; 106(5):1427–1432.
  36. Andersson O, Adams BA, Yoo D, et al. Adenosine signaling promotes regeneration of pancreatic β cells in vivo. Cell Metab. 2012;15(6):885–894.
  37. Xu X, D’Hoker J, Stange G, et al. β cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell. 2008;132(2): 197–207.
  38. Annes JP, Ryu JH, Lam K, et al. Adenosine kinase inhibition selectively promotes rodent and porcine islet β-cell replication. Proceed Nat Acad Sci. 2012;109(10):3915–3920.
  39. Vasavada RC, Gonzalez-Pertusa JA, Fujinaka Y, et al. Growth factors and beta cell replication. Int J Biochem Cell Biol. 2006;38(5):931–950.
  40. Ding L, Gysemans C, Mathieu C. β-cell differentiation and regeneration in type 1 diabetes. Diabetes Obes Metab. 2013;15(3):98–104.
  41. Butler AE, Campbell-Thompson M, Gurlo T, et al. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes. 2013;62(7): 2595–2604.
  42. Brelje TC, Bhagroo NV, Stout LE, et al. Beneficial effects of lipids and prolactin on insulin secretion and β-cell proliferation: A role for lipids in the adaptation of islets to pregnancy. J Endocrinol. 2008;197(2): 265–276.
  43. Kim H, Toyofuku Y, Lynn FC, et al. Serotonin regulates pancreatic beta cell mass during pregnancy. Nat Med. 2010;16(7):804–808.
  44. Karnik SK, Chen H, McLean GW, et al. Menin controls growth of pancreatic ß-cells in pregnant mice and promotes gestational diabetes mellitus. Science. 2007;318(5851):806–809.
  45. Donath MY, Ehses JA, Maedler K, et al. Mechanisms of β-cell death in type 2 diabetes. Diabetes. 2005;54(Suppl 2):108–113.
  46. Cunha DA, Igoillo-Esteve M, Gurzov EN, et al. Death protein 5 and p53-upregulated modulator of apoptosis mediate the endoplasmic reticulum stress-mitochondrial dialog triggering lipotoxic rodent and human β-cell apoptosis. Diabetes. 2012;61(11):2763–2775.
  47. Mahadevan J, Parazzoli S, Oseid E, et al. Ebselen treatment prevents islet apoptosis, maintains intranuclear Pdx-1 and MafA levels, and preserves β-cell mass and function in ZDF rats. Diabetes. 2013;62(10): 3582–3588.
  48. Gilbert ER, Liu D. Anti-diabetic functions of soy isoflavone genistein: Mechanisms underlying its effects on pancreatic β-cell function. Food Funct. 2013;4(2):200–212.
  49. Mathijs I, Cunha DA, Himpe E, et al. Phenylpropenoic acid glucoside augments pancreatic beta cell mass in high-fat diet-fed mice and protects beta cells from ER stress-induced apoptosis. Mol Nutr Food Res. 2014;58(10):1980–1990.
  50. Wang C, Guan Y, Yang J. Cytokines in the progression of pancreatic β-cell dysfunction. Int J Endocrinol. 2010;13:34–42
  51. Banerjee M, Saxena M. Interleukin-1 (IL-1) family of cytokines: Role in type 2 diabetes. Clini Chim Acta. 2012;413(15):1163–1170.
  52. Ku CR, Lee HJ, Kim SK, et al. Resveratrol prevents streptozotocin-induced diabetes by inhibiting the apoptosis of pancreatic β-cell and the cleavage of poly (ADP-ribose) polymerase. Endocr J. 2012;59(2): 103–109.
  53. Lewis EC, Blaabjerg L, Storling J, et al. The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet beta cells in vivo and in vitro. Mol Med. 2011;17:369–377.
  54. Liu X-H, Remedi MS, Pappan KL, et al. Exendin-4 protects murine MIN6 pancreatic β-cells from interleukin-1β-induced apoptosis via the NF-κB pathway. J Endocrinol Invest. 2013;36(10):803–811.
  55. Kwon DY, Kim YS, Ahn IS, et al. Exendin-4 potentiates insulinotropic action partly via increasing beta-cell proliferation and neogenesis and decreasing apoptosis in association with the attenuation of endoplasmic reticulum stress in islets of diabetic rats. J Pharmacol Sci. 2009;111(4):361–371.
  56. Shimoda M, Kanda Y, Hamamoto S, et al. The human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells via regulation of cell kinetics and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes. Diabetologia. 2011;54(5):1098–1108.
  57. Farilla L, Bulotta A, Hirshberg B, et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinol. 2003;144(12):5149–5158.
  58. Tiano JP, Mauvais-Jarvis F. Importance of oestrogen receptors to preserve functional β-cell mass in diabetes. Nat Rev Endocrinol. 2012; 8(6):342–351.
  59. Le-May C, Chu K, Hu M, et al. Estrogens protect pancreatic β-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice. Proc Nat Acad Sci. 2006;103(24):9232–9237.
  60. Verga FC, Panacchia L, Bucci B, et al. 3,5,3′-triiodothyronine (T3) is a survival factor for pancreatic β-cells undergoing apoptosis. J Cell Physiol. 2006;206(2):309–321.
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