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Front Pharmacol. 2016 Apr 06;7:83. doi: 10.3389/fphar.2016.00083. eCollection 2016.

Pancreatic β Cell Mass Death.

Frontiers in pharmacology

Husnia I Marrif, Salma I Al-Sunousi

Affiliations

  1. Department of Pharmacology, Faculty of Medicine, University of Benghazi Benghazi, Libya.
  2. Department of Histology and Anatomy, Faculty of Medicine, University of Benghazi Benghazi, Libya.

PMID: 27092078 PMCID: PMC4821858 DOI: 10.3389/fphar.2016.00083

Abstract

Type two diabetes (T2D) is a challenging metabolic disorder for which a cure has not yet been found. Its etiology is associated with several phenomena, including significant loss of insulin-producing, beta cell (β cell) mass via progressive programmed cell death and disrupted cellular autophagy. In diabetes, the etiology of β cell death and the role of mitochondria are complex and involve several layers of mechanisms. Understanding the dynamics of those mechanisms could permit researchers to develop an intervention for the progressive loss of β cells. Currently, diabetes research has shifted toward rejuvenation and plasticity technology and away from the simplified approach of hormonal compensation. Diabetes research is currently challenged by questions such as how to enhance cell survival, decrease apoptosis and replenish β cell mass in diabetic patients. In this review, we discuss evidence that β cell development and mass formation are guided by specific signaling systems, particularly hormones, transcription factors, and growth factors, all of which could be manipulated to enhance mass growth. There is also strong evidence that β cells are dynamically active cells, which, under specific conditions such as obesity, can increase in size and subsequently increase insulin secretion. In certain cases of aggressive or advanced forms of T2D, β cells become markedly impaired, and the only alternatives for maintaining glucose homeostasis are through partial or complete cell grafting (the Edmonton protocol). In these cases, the harvesting of an enriched population of viable β cells is required for transplantation. This task necessitates a deep understanding of the pharmacological agents that affect β cell survival, mass, and function. The aim of this review is to initiate discussion about the important signals in pancreatic β cell development and mass formation and to highlight the process by which cell death occurs in diabetes. This review also examines the attempts that have been made to recover or increase cell mass in diabetic patients by using various pharmacological agents.

Keywords: apoptosis; autophagy; diabetes; insulin; protein folding; stem cells; β cells

References

  1. Free Radic Biol Med. 2000 Aug;29(3-4):222-30 - PubMed
  2. J Biol Chem. 2014 May 2;289(18):12435-45 - PubMed
  3. Diabetes. 2011 Mar;60(3):890-8 - PubMed
  4. Nat Clin Pract Endocrinol Metab. 2007 Nov;3(11):758-68 - PubMed
  5. Cold Spring Harb Perspect Biol. 2013 Apr 01;5(4):a008656 - PubMed
  6. Diabetologia. 1982 Dec;23(6):525-8 - PubMed
  7. Diabetologia. 2008 Jan;51(1):91-100 - PubMed
  8. Mol Cell Biol. 2005 May;25(9):3752-62 - PubMed
  9. J Pharmacol Exp Ther. 2014 Sep;350(3):657-64 - PubMed
  10. BMJ Open. 2015 Oct 07;5(10):e007235 - PubMed
  11. Nature. 2003 Dec 18;426(6968):884-90 - PubMed
  12. Diabetes. 2005 Feb;54(2):452-61 - PubMed
  13. Methods Mol Biol. 2012;810:165-82 - PubMed
  14. Cell Physiol Biochem. 2011;28(5):873-86 - PubMed
  15. Lab Invest. 2010 Nov;90(11):1661-75 - PubMed
  16. Science. 2006 Dec 1;314(5804):1414-5 - PubMed
  17. PLoS One. 2013;8(3):e58655 - PubMed
  18. EBioMedicine. 2015 Mar 17;2(5):378-85 - PubMed
  19. Diabetes Care. 2009 Nov;32 Suppl 2:S151-6 - PubMed
  20. J Biol Chem. 2015 Mar 6;290(10 ):6071-85 - PubMed
  21. Diabetes Care. 2002 Feb;25(2):370-5 - PubMed
  22. Dev Cell. 2013 Jul 15;26(1):3-7 - PubMed
  23. Endocrinology. 2000 Jul;141(7):2350-60 - PubMed
  24. Transplant Proc. 2005 Mar;37(2):1305-8 - PubMed
  25. Front Biosci. 2008 May 01;13:5824-37 - PubMed
  26. Horm Res. 2008;70(3):165-73 - PubMed
  27. Am J Transplant. 2012 Jan;12(1):102-14 - PubMed
  28. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1607-11 - PubMed
  29. Diabetes. 2002 Mar;51(3):686-90 - PubMed
  30. Endocrinology. 2006 Jul;147(7):3398-407 - PubMed
  31. Diabetes. 2005 Sep;54(9):2602-11 - PubMed
  32. Essays Biochem. 2010;47:53-67 - PubMed
  33. Cell. 2009 Aug 7;138(3):449-62 - PubMed
  34. Oxid Med Cell Longev. 2015;2015:639191 - PubMed
  35. Obes Rev. 2014 Oct;15 Suppl 4:107-24 - PubMed
  36. Diabetes. 2006 Dec;55(12):3289-98 - PubMed
  37. Clin Pharmacol Ther. 2015 Aug;98(2):162-9 - PubMed
  38. Am J Kidney Dis. 2015 Apr;65(4):634-6 - PubMed
  39. Diabetologia. 2007 Apr;50(4):752-63 - PubMed
  40. Invest Ophthalmol Vis Sci. 2013 Mar 11;54(3):1750-7 - PubMed
  41. J Clin Invest. 1983 Jun;71(6):1544-53 - PubMed
  42. Mol Cell Endocrinol. 2011 Mar 30;335(2):104-9 - PubMed
  43. Nature. 2006 Oct 19;443(7113):787-95 - PubMed
  44. Mol Cell Neurosci. 1996;8(4):221-41 - PubMed
  45. J Biol Chem. 1996 Jan 12;271(2):1200-8 - PubMed
  46. Annu Rev Physiol. 2013;75:155-79 - PubMed
  47. Arq Bras Endocrinol Metabol. 2007 Mar;51(2):212-21 - PubMed
  48. Nature. 2003 Dec 18;426(6968):905-9 - PubMed
  49. Diabetologia. 1995 Dec;38(12):1405-11 - PubMed
  50. Dev Cell. 2010 Jun 15;18(6):1022-9 - PubMed
  51. PLoS One. 2013;8(1):e54173 - PubMed
  52. Trends Endocrinol Metab. 2011 Jul;22(7):266-74 - PubMed
  53. Biochem Soc Trans. 2008 Jun;36(Pt 3):353-6 - PubMed
  54. PLoS One. 2011;6(5):e20151 - PubMed
  55. Diabetologia. 1998 Jun;41(6):629-33 - PubMed
  56. J Histochem Cytochem. 2010 Apr;58(4):369-76 - PubMed
  57. Am J Physiol Endocrinol Metab. 2013 Nov 15;305(10):E1309-18 - PubMed
  58. Nat Protoc. 2014 Dec;9(12):2719-24 - PubMed
  59. Cell. 2006 Aug 25;126(4):663-76 - PubMed
  60. Physiol Rev. 2007 Jan;87(1):315-424 - PubMed
  61. N Engl J Med. 2015 Oct 29;373(18):1720-32 - PubMed
  62. Br J Pharmacol. 2012 Jun;166(3):877-94 - PubMed
  63. Diabetes Care. 2015 Aug;38(8):1441-8 - PubMed
  64. Physiol Res. 2001;50(6):537-46 - PubMed
  65. Dev Dyn. 2007 Dec;236(12):3451-8 - PubMed
  66. N Engl J Med. 1993 Sep 30;329(14):977-86 - PubMed
  67. Sci Rep. 2012;2:279 - PubMed
  68. Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29 - PubMed
  69. Cell Biochem Biophys. 2007;48(2-3):127-37 - PubMed
  70. Islets. 2010 May-Jun;2(3):135-45 - PubMed
  71. Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2334-9 - PubMed
  72. Nat Rev Drug Discov. 2012 Dec;11(12):937-57 - PubMed
  73. Biochem Biophys Res Commun. 2015 Apr 17;459(4):561-7 - PubMed
  74. J Ethnopharmacol. 1995 Nov 17;49(1):51-5 - PubMed
  75. Vitam Horm. 2009;80:409-71 - PubMed
  76. Dev Cell. 2002 Nov;3(5):631-43 - PubMed
  77. Mol Cancer Res. 2007 Jun;5(6):523-30 - PubMed
  78. Ann Intern Med. 1998 Apr 1;128(7):517-23 - PubMed
  79. Transpl Int. 2003 Jul;16(7):537-42 - PubMed
  80. Diabetes. 2003 Apr;52(4):991-7 - PubMed
  81. Diabetologia. 2013 Mar;56(3):542-52 - PubMed
  82. Biochem Biophys Res Commun. 2013 Nov 8;441(1):133-8 - PubMed
  83. Diabetol Metab Syndr. 2014 Aug 24;6(1):91 - PubMed
  84. Diabetes. 2003 Jan;52(1):102-10 - PubMed
  85. Pediatr Res. 2000 Jan;47(1):136-42 - PubMed
  86. J Biol Chem. 2009 Oct 2;284(40):27664-73 - PubMed
  87. Mol Endocrinol. 1989 Jan;3(1):165-73 - PubMed
  88. Diabetologia. 1996 May;39(5):548-57 - PubMed
  89. Nature. 2004 May 6;429(6987):41-6 - PubMed
  90. Mitochondrion. 2012 Jan;12(1):77-85 - PubMed
  91. Curr Neurovasc Res. 2015;12(4):404-13 - PubMed
  92. Cells. 2013 Apr 26;2(2):266-83 - PubMed
  93. Islets. 2009 Nov-Dec;1(3):177-84 - PubMed
  94. Eur J Endocrinol. 2002 Feb;146(2):129-41 - PubMed
  95. N Engl J Med. 2000 Jul 27;343(4):230-8 - PubMed
  96. Diabetes. 2009 Sep;58(9):2059-69 - PubMed
  97. Am J Physiol Endocrinol Metab. 2007 Apr;292(4):E1052-61 - PubMed
  98. Nat Genet. 1999 Sep;23(1):67-70 - PubMed
  99. Mol Ther. 2013 Jan;21(1):228-39 - PubMed
  100. Mol Cell Biol. 1999 Dec;19(12):8272-80 - PubMed
  101. Dev Biol. 2009 Feb 1;326(1):4-35 - PubMed
  102. J Biol Chem. 1999 Feb 26;274(9):5654-8 - PubMed
  103. Diabetes Metab J. 2013 Oct;37(5):375-84 - PubMed
  104. J Cell Physiol. 2010 Aug;224(2):501-8 - PubMed
  105. Acta Gastroenterol Latinoam. 2000;30(2):107-13 - PubMed
  106. Diabetes. 2002 Jun;51(6):1834-41 - PubMed
  107. Curr Diabetes Rev. 2011 Mar;7(2):106-25 - PubMed
  108. Trends Endocrinol Metab. 2015 Jul;26(7):337-8 - PubMed
  109. Cell Cycle. 2012 Jul 1;11(13):2431-42 - PubMed
  110. Int J Environ Res Public Health. 2015 Sep 10;12(9):11304-27 - PubMed
  111. Cell Transplant. 2013;22(8):1463-76 - PubMed
  112. Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):14920-5 - PubMed
  113. Cells Tissues Organs. 2014;199(5-6):329-41 - PubMed
  114. Cold Spring Harb Perspect Med. 2012 Sep 01;2(9):a007666 - PubMed
  115. Genes Dev. 2008 Dec 15;22(24):3435-48 - PubMed
  116. Histol Histopathol. 2008 Jul;23(7):883-95 - PubMed
  117. Curr Biol. 2009 Dec 1;19(22):R1046-52 - PubMed
  118. J Intern Med. 2013 Jun;273(6):529-43 - PubMed
  119. J Histochem Cytochem. 1998 Jun;46(6):707-15 - PubMed
  120. Rev Diabet Stud. 2014 Summer;11(2):181-9 - PubMed
  121. Exp Diabetes Res. 2012;2012:509437 - PubMed
  122. Surv Synth Pathol Res. 1985;4(2):110-25 - PubMed
  123. Diabetes. 1999 Apr;48(4):927-32 - PubMed
  124. Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5407-12 - PubMed
  125. Regul Pept. 2006 Sep 11;136(1-3):78-84 - PubMed
  126. Cell. 1996 Oct 4;87(1):43-52 - PubMed
  127. Diabetes. 1999 Dec;48(12):2398-406 - PubMed
  128. Toxicol Pathol. 2007 Jun;35(4):495-516 - PubMed
  129. Diabetes. 2004 Dec;53(12):3107-14 - PubMed
  130. J Biol Chem. 2015 Aug 21;290(34):20687-99 - PubMed
  131. Oncogene. 2003 Aug 14;22(34):5261-9 - PubMed
  132. Diabetes Care. 2015 Jan;38 Suppl:S8-S16 - PubMed
  133. Bioinformation. 2013 Dec 27;9(20):1040-3 - PubMed
  134. PLoS One. 2012;7(2):e30555 - PubMed
  135. Diabetes. 2004 Dec;53 Suppl 3:S26-33 - PubMed
  136. Biochem J. 2012 Jan 15;441(2):523-40 - PubMed
  137. PLoS One. 2011;6(12):e28828 - PubMed
  138. Exp Clin Transplant. 2015 Feb;13(1):68-75 - PubMed
  139. Adv Chronic Kidney Dis. 2014 Mar;21(2):121-33 - PubMed
  140. Biochem Biophys Res Commun. 2013 Apr 12;433(3):292-7 - PubMed
  141. Clin Ther. 2005 Aug;27(8):1164-80 - PubMed
  142. Nat Genet. 2000 Jan;24(1):36-44 - PubMed
  143. Curr Mol Med. 2014;14(9):1103-25 - PubMed
  144. Physiol Rev. 2005 Oct;85(4):1255-70 - PubMed
  145. Biochem Biophys Res Commun. 2004 Apr 16;316(4):1094-100 - PubMed
  146. Nature. 2003 Dec 18;426(6968):891-4 - PubMed
  147. Diabetologia. 2012 Feb;55(2):392-403 - PubMed
  148. J Gerontol A Biol Sci Med Sci. 1999 Nov;54(11):M541-5 - PubMed
  149. Pancreas. 2004 Aug;29(2):e51-8 - PubMed
  150. J Clin Invest. 2006 Jul;116(7):1802-12 - PubMed
  151. PLoS One. 2014 Aug 07;9(8):e102843 - PubMed
  152. ILAR J. 2006;47(3):225-33 - PubMed
  153. Physiol Rev. 2014 Jul;94(3):909-50 - PubMed
  154. Endocrinology. 2009 Nov;150(11):4855-62 - PubMed
  155. Nan Fang Yi Ke Da Xue Xue Bao. 2010 Jul;30(7):1530-3 - PubMed
  156. World J Diabetes. 2011 Jul 15;2(7):114-8 - PubMed
  157. Mol Genet Metab. 2011 Dec;104(4):648-53 - PubMed
  158. J Pharmacol Exp Ther. 2015 Sep;354(3):279-89 - PubMed
  159. J Cell Biol. 2001 Nov 12;155(4):519-30 - PubMed
  160. Diabetes. 2003 Jan;52(1):124-32 - PubMed
  161. Diabetes. 2002 Dec;51 Suppl 3:S455-61 - PubMed
  162. Endocrinology. 1999 Aug;140(8):3422-8 - PubMed
  163. J Clin Invest. 2002 Nov;110(10 ):1389-98 - PubMed
  164. Diabetes Obes Metab. 2011 Oct;13 Suppl 1:126-32 - PubMed
  165. Diabetes. 2010 Oct;59(10):2340-8 - PubMed
  166. Biochem Biophys Res Commun. 2002 Mar 1;291(3):649-54 - PubMed
  167. J Am Soc Nephrol. 2003 Aug;14(8 Suppl 3):S250-3 - PubMed
  168. Free Radic Biol Med. 1996;20(3):463-6 - PubMed

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