Diabetes Metab J.  2022 Jul;46(4):533-542. 10.4093/dmj.2022.0070.

Endoplasmic Reticulum Stress and Dysregulated Autophagy in Human Pancreatic Beta Cells

• Moon S
• Jung HS

• KMID: 2531957
• DOI: http://doi.org/10.4093/dmj.2022.0070

Abstract

Pancreatic beta cell homeostasis is crucial for the synthesis and secretion of insulin; disruption of homeostasis causes diabetes, and is a treatment target. Adaptation to endoplasmic reticulum (ER) stress through the unfolded protein response (UPR) and adequate regulation of autophagy, which are closely linked, play essential roles in this homeostasis. In diabetes, the UPR and autophagy are dysregulated, which leads to beta cell failure and death. Various studies have explored methods to preserve pancreatic beta cell function and mass by relieving ER stress and regulating autophagic activity. To promote clinical translation of these research results to potential therapeutics for diabetes, we summarize the current knowledge on ER stress and autophagy in human insulin-secreting cells.

Keyword

Autophagy; Diabetes mellitus; Endoplasmic reticulum stress; Humans; Insulin-secreting cells; Insulin secretion; Unfolded protein response

Figure

• 

  Fig. 1 Endoplasmic reticulum (ER) stress in pancreatic beta cells. In vitro, ex vivo, and in vivo human findings are depicted in red, along with the references. TIDM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; MODY, maturity onset diabetes of the young; IL, interleukin; WFS1, wolframin ER transmembrane glycoprotein; BIP, binding immunoglobulin protein; IRE1, inositol-requiring protein-1; PERK, protein kinase R-like ER kinase; ATF6, activating transcription factor-6; EIF2B1, eukaryotic translation initiation factor 2B subunit alpha; eIF2A, eukaryotic translation initiation factor 2-alpha; XBP1, X-box binding protein 1; ATF4, activating transcription factor-4; UPR, unfolded protein response; CHOP, C/EBP homologous protein; ATF6f, cytoplasmic fragment of activating transcription factor-6; TUDCA, tauroursodeoxycholic acid.

• 

  Fig. 2 Autophagic process in pancreatic beta cells. In vitro and ex vivo human findings are depicted in red, along with the references. TFEB, transcription factor EB; mTORC1, mTOR complex I; T2DM, type 2 diabetes mellitus; MSL-7, autophagy enhancer; ATG7, autophagy-related 7; LC3, microtubule-associated protein 1 light chain 3; FFA, free fatty acid; PE, phosphatidylethanolamine; T1DM, type 1 diabetes mellitus; IAPP, islet amyloid polypeptide.

Reference

1. Steiner DJ, Kim A, Miller K, Hara M. Pancreatic islet plasticity: interspecies comparison of islet architecture and composition. Islets. 2010; 2:135–45.

2. MacDonald MJ, Longacre MJ, Stoker SW, Kendrick M, Thonpho A, Brown LJ, et al. Differences between human and rodent pancreatic islets: low pyruvate carboxylase, atp citrate lyase, and pyruvate carboxylation and high glucose-stimulated acetoacetate in human pancreatic islets. J Biol Chem. 2011; 286:18383–96.

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

4. Xu X, D’Hoker J, Stange G, Bonne S, De Leu N, Xiao X, et al. Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell. 2008; 132:197–207.

5. Perl S, Kushner JA, Buchholz BA, Meeker AK, Stein GM, Hsieh M, 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:E234–9.

6. Levetan CS, Pierce SM. Distinctions between the islets of mice and men: implications for new therapies for type 1 and 2 diabetes. Endocr Pract. 2013; 19:301–12.

7. Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nat Biotechnol. 2014; 32:40–51.

8. Ravassard P, Hazhouz Y, Pechberty S, Bricout-Neveu E, Armanet M, Czernichow P, et al. A genetically engineered human pancreatic β cell line exhibiting glucose-inducible insulin secretion. J Clin Invest. 2011; 121:3589–97.

9. McCluskey JT, Hamid M, Guo-Parke H, McClenaghan NH, Gomis R, Flatt PR. Development and functional characterization of insulin-releasing human pancreatic beta cell lines produced by electrofusion. J Biol Chem. 2011; 286:21982–92.

10. Siehler J, Blochinger AK, Meier M, Lickert H. Engineering islets from stem cells for advanced therapies of diabetes. Nat Rev Drug Discov. 2021; 20:920–40.

11. Bilekova S, Sachs S, Lickert H. Pharmacological targeting of endoplasmic reticulum stress in pancreatic beta cells. Trends Pharmacol Sci. 2021; 42:85–95.

12. Yong J, Johnson JD, Arvan P, Han J, Kaufman RJ. Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus. Nat Rev Endocrinol. 2021; 17:455–67.

13. Vivot K, Pasquier A, Goginashvili A, Ricci R. Breaking bad and breaking good: β-cell autophagy pathways in diabetes. J Mol Biol. 2020; 432:1494–513.

14. Lee YH, Kim J, Park K, Lee MS. β-Cell autophagy: mechanism and role in β-cell dysfunction. Mol Metab. 2019; 27S(Suppl):S92–103.

15. Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol. 2020; 21:421–38.

16. Oakes SA, Papa FR. The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol. 2015; 10:173–94.

17. Arunagiri A, Haataja L, Pottekat A, Pamenan F, Kim S, Zeltser LM, et al. Proinsulin misfolding is an early event in the progression to type 2 diabetes. Elife. 2019; 8:e44532.

18. Burgos-Moron E, Abad-Jimenez Z, Maranon AM, Iannantuoni F, Escribano-Lopez I, Lopez-Domenech S, et al. Relationship between oxidative stress, ER stress, and inflammation in type 2 diabetes: the battle continues. J Clin Med. 2019; 8:1385.

19. Biden TJ, Boslem E, Chu KY, Sue N. Lipotoxic endoplasmic reticulum stress, β cell failure, and type 2 diabetes mellitus. Trends Endocrinol Metab. 2014; 25:389–98.

20. Han J, Kaufman RJ. The role of ER stress in lipid metabolism and lipotoxicity. J Lipid Res. 2016; 57:1329–38.

21. Axten JM, Medina JR, Feng Y, Shu A, Romeril SP, Grant SW, et al. Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]ac etyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J Med Chem. 2012; 55:7193–207.

22. Moreno JA, Halliday M, Molloy C, Radford H, Verity N, Axten JM, et al. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med. 2013; 5:206ra138.

23. Wang R, McGrath BC, Kopp RF, Roe MW, Tang X, Chen G, et al. Insulin secretion and Ca2+ dynamics in β-cells are regulated by PERK (EIF2AK3) in concert with calcineurin. J Biol Chem. 2013; 288:33824–36.

24. Harding HP, Zyryanova AF, Ron D. Uncoupling proteostasis and development in vitro with a small molecule inhibitor of the pancreatic endoplasmic reticulum kinase, PERK. J Biol Chem. 2012; 287:44338–44.

25. Ghosh R, Wang L, Wang ES, Perera BG, Igbaria A, Morita S, et al. Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress. Cell. 2014; 158:534–48.

26. Morita S, Villalta SA, Feldman HC, Register AC, Rosenthal W, Hoffmann-Petersen IT, et al. Targeting ABL-IRE1α signaling spares ER-stressed pancreatic β cells to reverse autoimmune diabetes. Cell Metab. 2017; 25:883–97.

27. Sharma RB, Landa-Galvan HV, Alonso LC. Living dangerously: protective and harmful ER stress responses in pancreatic β-cells. Diabetes. 2021; 70:2431–43.

28. Sahin GS, Lee H, Engin F. An accomplice more than a mere victim: The impact of β-cell ER stress on type 1 diabetes pathogenesis. Mol Metab. 2021; 54:101365.

29. Delepine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet. 2000; 25:406–9.

30. De Franco E, Caswell R, Johnson MB, Wakeling MN, Zung A, Dung VC, et al. De novo mutations in EIF2B1 affecting eIF2 signaling cause neonatal/early-onset diabetes and transient hepatic dysfunction. Diabetes. 2020; 69:477–83.

31. Hofmann S, Philbrook C, Gerbitz KD, Bauer MF. Wolfram syndrome: structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product. Hum Mol Genet. 2003; 12:2003–12.

32. Liu M, Hodish I, Haataja L, Lara-Lemus R, Rajpal G, Wright J, et al. Proinsulin misfolding and diabetes: mutant INS gene-induced diabetes of youth. Trends Endocrinol Metab. 2010; 21:652–9.

33. Ma S, Viola R, Sui L, Cherubini V, Barbetti F, Egli D. β Cell replacement after gene editing of a neonatal diabetes-causing mutation at the insulin locus. Stem Cell Reports. 2018; 11:1407–15.

34. Eizirik DL, Pasquali L, Cnop M. Pancreatic β-cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nat Rev Endocrinol. 2020; 16:349–62.

35. Marhfour I, Lopez XM, Lefkaditis D, Salmon I, Allagnat F, Richardson SJ, et al. Expression of endoplasmic reticulum stress markers in the islets of patients with type 1 diabetes. Diabetologia. 2012; 55:2417–20.

36. Sims EK, Bahnson HT, Nyalwidhe J, Haataja L, Davis AK, Speake C, et al. Proinsulin secretion is a persistent feature of type 1 diabetes. Diabetes Care. 2019; 42:258–64.

37. Brozzi F, Nardelli TR, Lopes M, Millard I, Barthson J, Igoillo-Esteve M, et al. Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms. Diabetologia. 2015; 58:2307–16.

38. Ramzy A, Kieffer TJ. Altered islet prohormone processing: a cause or consequence of diabetes? Physiol Rev. 2022; 102:155–208.

39. Lytrivi M, Castell AL, Poitout V, Cnop M. Recent insights into mechanisms of β-cell lipo- and glucolipotoxicity in type 2 diabetes. J Mol Biol. 2020; 432:1514–34.

40. Weir GC. Glucolipotoxicity, β-cells, and diabetes: the emperor has no clothes. Diabetes. 2020; 69:273–8.

41. Hall E, Dekker Nitert M, Volkov P, Malmgren S, Mulder H, Bacos K, et al. The effects of high glucose exposure on global gene expression and DNA methylation in human pancreatic islets. Mol Cell Endocrinol. 2018; 472:57–67.

42. Schrimpe-Rutledge AC, Fontes G, Gritsenko MA, Norbeck AD, Anderson DJ, Waters KM, et al. Discovery of novel glucose-regulated proteins in isolated human pancreatic islets using LC-MS/MS-based proteomics. J Proteome Res. 2012; 11:3520–32.

43. Sargsyan E, Cen J, Roomp K, Schneider R, Bergsten P. Identification of early biological changes in palmitate-treated isolated human islets. BMC Genomics. 2018; 19:629.

44. Roomp K, Kristinsson H, Schvartz D, Ubhayasekera K, Sargsyan E, Manukyan L, et al. Combined lipidomic and proteomic analysis of isolated human islets exposed to palmitate reveals time-dependent changes in insulin secretion and lipid metabolism. PLoS One. 2017; 12:e0176391.

45. Hall E, Jonsson J, Ofori JK, Volkov P, Perfilyev A, Dekker Nitert M, et al. Glucolipotoxicity alters insulin secretion via epigenetic changes in human islets. Diabetes. 2019; 68:1965–74.

46. Zhou YP, Grill V. Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans. J Clin Endocrinol Metab. 1995; 80:1584–90.

47. Cnop M, Abdulkarim B, Bottu G, Cunha DA, Igoillo-Esteve M, Masini M, et al. RNA sequencing identifies dysregulation of the human pancreatic islet transcriptome by the saturated fatty acid palmitate. Diabetes. 2014; 63:1978–93.

48. Westermark P, Andersson A, Westermark GT. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol Rev. 2011; 91:795–826.

49. Krizhanovskii C, Fred RG, Oskarsson ME, Westermark GT, Welsh N. Addition of exogenous sodium palmitate increases the IAPP/insulin mRNA ratio via GPR40 in human EndoC-βH1 cells. Ups J Med Sci. 2017; 122:149–59.

50. Sharma RB, O’Donnell AC, Stamateris RE, Ha B, McCloskey KM, Reynolds PR, et al. Insulin demand regulates β cell number via the unfolded protein response. J Clin Invest. 2015; 125:3831–46.

51. Hasnain SZ, Borg DJ, Harcourt BE, Tong H, Sheng YH, Ng CP, et al. Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress. Nat Med. 2014; 20:1417–26.

52. Gitelman SE, Bundy BN, Ferrannini E, Lim N, Blanchfield JL, DiMeglio LA, et al. Imatinib therapy for patients with recent-onset type 1 diabetes: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol. 2021; 9:502–14.

53. Ohsumi Y. Molecular dissection of autophagy: two ubiquitin-like systems. Nat Rev Mol Cell Biol. 2001; 2:211–6.

54. Noguchi M, Hirata N, Tanaka T, Suizu F, Nakajima H, Chiorini JA. Autophagy as a modulator of cell death machinery. Cell Death Dis. 2020; 11:517.

55. Sheng Q, Xiao X, Prasadan K, Chen C, Ming Y, Fusco J, et al. Autophagy protects pancreatic beta cell mass and function in the setting of a high-fat and high-glucose diet. Sci Rep. 2017; 7:16348.

56. Jung HS, Chung KW, Won Kim J, Kim J, Komatsu M, Tanaka K, et al. Loss of autophagy diminishes pancreatic beta cell mass and function with resultant hyperglycemia. Cell Metab. 2008; 8:318–24.

57. Kim J, Cheon H, Jeong YT, Quan W, Kim KH, Cho JM, et al. Amyloidogenic peptide oligomer accumulation in autophagy-deficient β cells induces diabetes. J Clin Invest. 2014; 124:3311–24.

58. Rivera JF, Costes S, Gurlo T, Glabe CG, Butler PC. Autophagy defends pancreatic β cells from human islet amyloid polypeptide-induced toxicity. J Clin Invest. 2014; 124:3489–500.

59. Shigihara N, Fukunaka A, Hara A, Komiya K, Honda A, Uchida T, et al. Human IAPP-induced pancreatic β cell toxicity and its regulation by autophagy. J Clin Invest. 2014; 124:3634–44.

60. Lim H, Lim YM, Kim KH, Jeon YE, Park K, Kim J, et al. A novel autophagy enhancer as a therapeutic agent against metabolic syndrome and diabetes. Nat Commun. 2018; 9:1438.

61. Kim J, Park K, Kim MJ, Lim H, Kim KH, Kim SW, et al. An autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer. Nat Commun. 2021; 12:183.

62. Yao RQ, Ren C, Xia ZF, Yao YM. Organelle-specific autophagy in inflammatory diseases: a potential therapeutic target underlying the quality control of multiple organelles. Autophagy. 2021; 17:385–401.

63. Smith MD, Harley ME, Kemp AJ, Wills J, Lee M, Arends M, et al. CCPG1 is a non-canonical autophagy cargo receptor essential for ER-phagy and pancreatic ER proteostasis. Dev Cell. 2018; 44:217–32.

64. Cunningham CN, Williams JM, Knupp J, Arunagiri A, Arvan P, Tsai B. Cells deploy a two-pronged strategy to rectify misfolded proinsulin aggregates. Mol Cell. 2019; 75:442–56.

65. Muralidharan C, Linnemann AK. β-Cell autophagy in the pathogenesis of type 1 diabetes. Am J Physiol Endocrinol Metab. 2021; 321:E410–6.

66. Muralidharan C, Conteh AM, Marasco MR, Crowder JJ, Kuipers J, de Boer P, et al. Pancreatic beta cell autophagy is impaired in type 1 diabetes. Diabetologia. 2021; 64:865–77.

67. Masini M, Bugliani M, Lupi R, del Guerra S, Boggi U, Filipponi F, et al. Autophagy in human type 2 diabetes pancreatic beta cells. Diabetologia. 2009; 52:1083–6.

68. Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016; 12:1–222.

69. Ji J, Petropavlovskaia M, Khatchadourian A, Patapas J, Makhlin J, Rosenberg L, et al. Type 2 diabetes is associated with suppression of autophagy and lipid accumulation in β-cells. J Cell Mol Med. 2019; 23:2890–900.

70. Abe H, Uchida T, Hara A, Mizukami H, Komiya K, Koike M, et al. Exendin-4 improves β-cell function in autophagy-deficient β-cells. Endocrinology. 2013; 154:4512–24.

71. Mir SU, George NM, Zahoor L, Harms R, Guinn Z, Sarvetnick NE. Inhibition of autophagic turnover in β-cells by fatty acids and glucose leads to apoptotic cell death. J Biol Chem. 2015; 290:6071–85.

72. King BC, Kulak K, Krus U, Rosberg R, Golec E, Wozniak K, et al. Complement component C3 is highly expressed in human pancreatic islets and prevents β cell death via ATG16L1 interaction and autophagy regulation. Cell Metab. 2019; 29:202–10.

73. Bugliani M, Mossuto S, Grano F, Suleiman M, Marselli L, Boggi U, et al. Modulation of autophagy influences the function and survival of human pancreatic beta cells under endoplasmic reticulum stress conditions and in type 2 diabetes. Front Endocrinol (Lausanne). 2019; 10:52.

74. Lombardi A, Gambardella J, Du XL, Sorriento D, Mauro M, Iaccarino G, et al. Sirolimus induces depletion of intracellular calcium stores and mitochondrial dysfunction in pancreatic beta cells. Sci Rep. 2017; 7:15823.

75. Kim MJ, Kim MN, Min SH, Ham DS, Kim JW, Yoon KH, et al. Specific PERK inhibitors enhanced glucose-stimulated insulin secretion in a mouse model of type 2 diabetes. Metabolism. 2019; 97:87–91.

76. Moon S, Lim J, Kim H, Kwon W, Jang JY, Park K, et al. A PERK inhibitor enhanced insulin synthesis in beta cells under metabolic stress by regulation of autophagy activity with an Atg7-dependent manner. In : The 9th Seoul International Congress of Endocrinology and Metabolism; 2021 Oct 28–30; Busan (KR).

77. Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The pancreas cancer microenvironment. Clin Cancer Res. 2012; 18:4266–76.

78. Barovic M, Distler M, Schoniger E, Radisch N, Aust D, Weitz J, et al. Metabolically phenotyped pancreatectomized patients as living donors for the study of islets in health and diabetes. Mol Metab. 2019; 27S(Suppl):S1–6.