Beta-cell autophagy under the scope of hypoglycemic drugs; possible mechanism as a novel therapeutic target

Physiologically, autophagy is a major protective mechanism of β-cells from apoptosis, through can reserve normal β- cell mass and inhibit the progression of β-cells destruction. Beta-cell mass can be affected by differentiation from progenitors and de-differentiation as well as self-renewal and apoptosis. Shred evidence indicated that hypoglycemic drugs can induce β-cell proliferation capacity and neogenesis via autophagy stimulation. However, prolonged use of selective hypoglycemic drugs has induced pancreatitis besides several other factors that contribute to β-cell destruction and apoptosis initiation. Interestingly, some nonhypoglycemic medications possess the same effects on β-cells but depending on the combination of these drugs and the duration of exposure to β-cells. The paper comprehensively illustrates the role of the hypoglycemic drugs on the insulin-producing cells and the pathogeneses of β-cell destruction in type 2 diabetes mellitus, in addition to the regulation mechanisms of β-cells division in norm and pathology. The grasping of the hypoglycemic drug’s role in beta-cell is clinically crucial to evaluate novel therapeutic targets such as new signaling pathways. The present paper addresses a new strategy for diabetes mellitus management via targeting specific autophagy inducer factors (transcription factors, genes, lipid molecules, etc.).

1. DeVries JH, Rosenstock J. DPP-4 Inhibitor-Related Pancreatitis: Rare but Real! Diabetes Care. 2017;40:161-163. doi: https://doi.org/10.2337/dci16-0035

2. Sada K, Nishikawa T, Kukidome D, et al. Hyperglycemia induces cellular hypoxia through production of mitochondrial ROS followed by suppression of aquaporin-1. PLoS One. 2016;11. doi: https://doi.org/10.1371/journal.pone.0158619

3. Marzoog B. Lipid behavior in metabolic syndrome pathophysiology. Curr Diabetes Rev. 2021;17. doi: https://doi.org/10.2174/1573399817666210915101321

4. Lim S, Bae JH, Kwon H-S, Nauck MA. COVID-19 and diabetes mellitus: from pathophysiology to clinical management. Nat Rev Endocrinol. 2021;17:11-30. doi: https://doi.org/10.1038/s41574-020-00435-4

5. Rubino F, Amiel SA, Zimmet P, et al. New-Onset Diabetes in Covid-19. N Engl J Med. 2020;383(8):789-790. doi: https://doi.org/10.1056/NEJMc2018688

6. Brereton MF, Iberl M, Shimomura K, et al. Reversible changes in pancreatic islet structure and function produced by elevated blood glucose. Nat Commun. 2014;5:4639. doi: https://doi.org/10.1038/ncomms5639

7. Cinti F, Bouchi R, Kim-Muller JY, et al. Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes. J Clin Endocrinol Metab. 2016;101:1044-1054. doi: https://doi.org/10.1210/jc.2015-2860

8. Cheng STW, Li SYT, Leung PS. Fibroblast Growth Factor 21 Stimulates Pancreatic Islet Autophagy via Inhibition of AMPK-mTOR Signaling. Int J Mol Sci. 2019;20:2517. doi: https://doi.org/10.3390/ijms20102517.

9. Talchai C, Xuan S, Lin HV, et al. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell. 2012;150:1223-1234. doi: https://doi.org/10.1016/j.cell.2012.07.029.

10. Bensellam M, Jonas JC, Laybutt DR. Mechanisms of β-cell dedifferentiation in diabetes: Recent findings and future research directions. J Endocrinol. 2018;236:109-143. doi: https://doi.org/10.1530/JOE-17-0516.

11. DiNicolantonio JJ, McCarty M. Autophagy-induced degradation of Notch1, achieved through intermittent fasting, may promote beta cell neogenesis: implications for reversal of type 2 diabetes. Open Hear. 2019;6(1):e001028. doi: https://doi.org/10.1136/openhrt-2019-001028

12. Lambelet M, Terra LF, Fukaya M, et al. Dysfunctional autophagy following exposure to pro-inflammatory cytokines contributes to pancreatic β-cell apoptosis. Cell Death Dis. 2018;9:96. doi: https://doi.org/10.1038/s41419-017-0121-5

13. Hu M, Yang S, Yang L, et al. Interleukin-22 Alleviated Palmitate-Induced Endoplasmic Reticulum Stress in INS-1 Cells through Activation of Autophagy. PLoS One. 2016;11(1):e0146818. doi: https://doi.org/10.1371/journal.pone.0146818

14. Linnemann AK, Blumer J, Marasco MR, et al. Interleukin 6 protects pancreatic b cells from apoptosis by stimulation of autophagy. FASEB J. 2017;31:4140-4152. doi: https://doi.org/10.1096/fj.201700061RR

15. Butler PC, Meier JJ, Butler AE, Bhushan A. The replication of β cells in normal physiology, in disease and for therapy. Nat Clin Pract Endocrinol Metab. 2007;3:758-768. doi: https://doi.org/10.1038/ncpendmet0647

16. Talchai C, Lin HV, Kitamura T, Accili D. Genetic and biochemical pathways of β-cell failure in type 2 diabetes. Diabetes, Obes Metab. 2009;11:38-45. doi: https://doi.org/10.1111/j.1463-1326.2009.01115.x

17. Marasco MR, Linnemann AK. B-Cell autophagy in diabetes pathogenesis. Endocrinology. 2018;159:2127-2141. doi: https://doi.org/10.1210/en.2017-03273

18. Riahi Y, Wikstrom JD, Bachar-Wikstrom E, et al. Autophagy is a major regulator of beta cell insulin homeostasis. Diabetologia. 2016;59:1480-1491. doi: https://doi.org/10.1007/s00125-016-3868-9

19. Ren L, Yang H, Cui Y, et al. Autophagy is essential for the differentiation of porcine PSCs into insulin-producing cells. Biochem Biophys Res Commun. 2017;488:471-476. doi: https://doi.org/10.1016/j.bbrc.2017.05.058

20. Choi SE, Lee SM, Lee YJ, et al. Protective role of autophagy in palmitate-induced INS-1 β-cell death. Endocrinology. 2009;150:126-134. doi: https://doi.org/10.1210/en.2008-0483

21. Wu J, Kong F, Pan Q, et al. Autophagy protects against cholesterol-induced apoptosis in pancreatic β-cells. Biochem Biophys Res Commun. 2017;482:678-685. doi: https://doi.org/10.1016/j.bbrc.2016.11.093

22. Sheng Q, Xiao X, Prasadan K, 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(1):16348. doi: https://doi.org/10.1038/s41598-017-16485-0

23. Goginashvili A, Zhang Z, Erbs E, et al. Insulin secretory granules control autophagy in Pancreatic β cells. Science (80-). 2015;347:878-882. doi: https://doi.org/10.1126/science.aaa2628.

24. Li C, Li X, Han H, et al. Effect of probiotics on metabolic profiles in type 2 diabetes mellitus. Medicine (Baltimore). 2016;95(26):e4088. doi: https://doi.org/10.1097/MD.0000000000004088

25. Patti M-E, Corvera S. The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes. Endocr Rev. 2010;31(3):364-395. doi: https://doi.org/10.1210/er.2009-0027

26. Xu S, Sun F, Ren L, Yang H, Tian N, Peng S. Resveratrol controlled the fate of porcine pancreatic stem cells through the Wnt/β-catenin signaling pathway mediated by Sirt1. PLoS One. 2017;12(10):e0187159. doi: https://doi.org/10.1371/journal.pone.0187159

27. Kuma A, Hatano M, Matsui M, et al. The role of autophagy during the early neonatal starvation period. Nature. 2004;432(7020):1032-1036. doi: https://doi.org/10.1038/nature03029

28. Mizukami H, Takahashi K, Inaba W, et al. Involvement of oxidative stress-induced DNA damage, endoplasmic reticulum stress, and autophagy deficits in the decline of β-cell mass in Japanese type 2 diabetic patients. Diabetes Care. 2014;37:1966-1974. doi: https://doi.org/10.2337/DC13-2018.

29. Murphy R, Carroll RW, Krebs JD. Pathogenesis of the metabolic syndrome: insights from monogenic disorders. Mediators Inflamm. 2013;2013:920214. doi: https://doi.org/10.1155/2013/920214.

30. Nica AC, Ongen H, Irminger J-C, et al. Cell-type, allelic, and genetic signatures in the human pancreatic beta cell transcriptome. Genome Res. 2013;23:1554-1562. doi: https://doi.org/10.1101/gr.150706.112

31. Brunetti A, Chiefari E, Foti D. Perspectives on the contribution of genetics to the pathogenesis of type 2 diabetes mellitus. Recenti Prog Med. 2011;102:468-475. doi: https://doi.org/10.1701/998.10858.

32. Kalin MF, Goncalves M, John-Kalarickal J, Fonseca V. Pathogenesis of type 2 diabetes mellitus. Princ. Diabetes Mellit. 2017. doi: https://doi.org/10.1007/978-3-319-18741-9_13

33. Raimondo A, Thomsen SK, Hastoy B, et al. Type 2 Diabetes Risk Alleles Reveal a Role for Peptidylglycine Alpha-amidating Monooxygenase in Beta Cell Function. bioRxiv. 2017. doi: https://doi.org/10.1101/158642

34. Cnop M, Welsh N, Jonas JC, et al. Mechanisms of pancreatic β-cell death in type 1 and type 2 diabetes: Many differences, few similarities. Diabetes. 2005;54:S97-107. doi: https://doi.org/10.2337/diabetes.54.suppl_2.S97.

35. Ozougwu O. The pathogenesis and pathophysiology of type 1 and type 2 diabetes mellitus. J Physiol Pathophysiol. 2013;4:46-57. doi: https://doi.org/10.5897/JPAP2013.0001

36. Ashcroft FM, Rorsman P. Molecular defects in insulin secretion in type-2 diabetes. Rev Endocr Metab Disord. 2004;5:135-142. doi: https://doi.org/10.1023/B:REMD.0000021435.87776.a7.

37. Butler AE, Janson J, Bonner-Weir S, et al. β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102-110. doi: https://doi.org/10.2337/diabetes.52.1.102.

38. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia. 2003;46:3-19. doi: https://doi.org/10.1007/s00125-002-1009-0

39. Abdel-Moneim A, Bakery HH, Allam G. The potential pathogenic role of IL-17/Th17 cells in both type 1 and type 2 diabetes mellitus. Biomed Pharmacother. 2018;101:287-292. doi: https://doi.org/10.1016/j.biopha.2018.02.103

40. Marzoog BA, Vlasova TI. Transcription Factors in Deriving β Cell Regeneration; A Potential Novel Therapeutic Target. Curr Mol Med. 2021;21. doi: https://doi.org/10.2174/1566524021666210712144638

41. Dalle S, Burcelin R, Gourdy P. Specific actions of GLP-1 receptor agonists and DPP4 inhibitors for the treatment of pancreatic β-cell impairments in type 2 diabetes. Cell Signal. 2013;25:570-579. doi: https://doi.org/10.1016/j.cellsig.2012.11.009

42. Jiang Y, Huang W, Wang J, et al. Metformin Plays a Dual Role in MIN6 Pancreatic β Cell Function through AMPK-dependent Autophagy. Int J Biol Sci. 2014;10:268-277. doi: https://doi.org/10.7150/ijbs.7929

43. Wu J, Wu JJ, Yang LJ, et al. Rosiglitazone protects against palmitate-induced pancreatic beta-cell death by activation of autophagy via 5′-AMP-activated protein kinase modulation. Endocrine. 2013;44:87-98. doi: https://doi.org/10.1007/s12020-012-9826-5

44. Diaz A, Romero M, Vazquez T, et al. Metformin improves in vivo and in vitro B cell function in individuals with obesity and Type-2 Diabetes. Vaccine. 2017;35:2694-2700. doi: https://doi.org/10.1016/j.vaccine.2017.03.078

45. Janzen KM, Steuber TD, Nisly SA. GLP-1 Agonists in Type 1 Diabetes Mellitus. Ann Pharmacother. 2016;50:656-665. doi: https://doi.org/10.1177/1060028016651279

46. Wajchenberg BL. β-Cell Failure in Diabetes and Preservation by Clinical Treatment. Endocr Rev. 2007;28(2):187-218. doi: https://doi.org/10.1210/10.1210/er.2006-0038

47. Jones B, Buenaventura T, Kanda N, et al. Targeting GLP-1 receptor trafficking to improve agonist efficacy. Nat Commun. 2018;9(1):1602. doi: https://doi.org/10.1038/s41467-018-03941-2

48. Donnelly D. The structure and function of the glucagon-like peptide-1 receptor and its ligands. Br J Pharmacol. 2012;166:27-41. doi: https://doi.org/10.1111/j.1476-5381.2011.01687.x

49. Shyangdan DS, Royle P, Clar C, et al. Glucagon-like peptide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2011. doi: https://doi.org/10.1002/14651858.CD006423.pub2

50. Piya MK, Tahrani AA, Barnett AH. Emerging treatment options for type 2 diabetes. Br J Clin Pharmacol. 2010;70(5):631-644. doi: https://doi.org/10.1111/j.1365-2125.2010.03711.x

51. Doyle ME, Egan JM. Mechanisms of action of glucagon-like peptide 1 in the pancreas. Pharmacol Ther. 2007;113:546-593. doi: https://doi.org/10.1016/j.pharmthera.2006.11.007

52. Lee Y-S, Jun H-S. Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control. Mediators Inflamm. 2016;2016:1-11. doi: https://doi.org/10.1155/2016/3094642.

53. Lee Y-S, Jun H-S. Anti-diabetic actions of glucagon-like peptide-1 on pancreatic beta-cells. Metabolism. 2014;63(1):9-19. doi: https://doi.org/10.1016/j.metabol.2013.09.010

54. Vilsbøll T. The effects of glucagon-like peptide-1 on the beta cell. Diabetes, Obes Metab. 2009;11:11-18. doi: https://doi.org/10.1111/j.1463-1326.2009.01073.x

55. Pratley RE, Nauck M, Bailey T, et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial. Lancet. 2010;375:1447-1456. doi: https://doi.org/10.1016/S0140-6736(10)60307-8.

56. Bergenstal RM, Wysham C, MacConell L, et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): A randomised trial. Lancet. 2010;376:431-439. doi: https://doi.org/10.1016/S0140-6736(10)60590-9.

57. Omar BA, Vikman J, Winzell MS, et al. Enhanced beta cell function and anti-inflammatory effect after chronic treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin in an advanced-aged diet-induced obesity mouse model. Diabetologia. 2013;56(8):1752-1760. doi: https://doi.org/10.1007/s00125-013-2927-8

58. Yang L, Yuan J, Zhou Z. Emerging Roles of Dipeptidyl Peptidase 4 Inhibitors: Anti-Inflammatory and Immunomodulatory Effect and Its Application in Diabetes Mellitus. Can J Diabetes. 2014;38(6):473-479. doi: https://doi.org/10.1016/j.jcjd.2014.01.008

59. Tanemura M, Ohmura Y, Deguchi T, et al. Rapamycin causes upregulation of autophagy and impairs islets function both in vitro and in vivo. Am J Transplant. 2012;12:102-114. doi: https://doi.org/10.1111/j.1600-6143.2011.03771.x

60. Zhou Z, Wu S, Li X, et al. Rapamycin induces autophagy and exacerbates metabolism associated complications in a mouse model of type 1 diabetes. Indian J Exp Biol. 2010;48:31-38.

61. Chang G-R, Wu Y-Y, Chiu Y-S, et al. Long-term administration of rapamycin reduces adiposity, but impairs glucose tolerance in high-fat diet-fed KK/HlJ mice. Basic Clin Pharmacol Toxicol. 2009;105:188-198. doi: https://doi.org/10.1111/j.1742-7843.2009.00427.x

62. Chang G-R, Chiu Y-S, Wu Y-Y, et al. Rapamycin protects against high fat diet-induced obesity in C57BL/6J mice. J Pharmacol Sci. 2009;109:496-503. doi: https://doi.org/10.1254/jphs.08215fp.

63. Gong F-H, Ye Y-N, Li J-M, et al. Rapamycin-ameliorated diabetic symptoms involved in increasing adiponectin expression in diabetic mice on a high-fat diet. Kaohsiung J Med Sci. 2017;33:321-326. doi: https://doi.org/10.1016/j.kjms.2017.05.008

64. Reifsnyder PC, Flurkey K, Te A, Harrison DE. Rapamycin treatment benefits glucose metabolism in mouse models of type 2 diabetes. Aging (Albany NY). 2016;8:3120-3130. doi: https://doi.org/10.18632/aging.101117

65. Fang Y, Westbrook R, Hill C, et al. Duration of rapamycin treatment has differential effects on metabolism in mice. Cell Metab. 2013;17:456-462. doi: https://doi.org/10.1016/j.cmet.2013.02.008

66. Lupi R, Del Prato S. Beta-cell apoptosis in type 2 diabetes: quantitative and functional consequences. Diabetes Metab. 2008;34(S2):56-64. doi: https://doi.org/10.1016/S1262-3636(08)73396-2

67. Barlow AD, Nicholson ML, Herbert TP. Evidence for Rapamycin Toxicity in Pancreatic β-Cells and a Review of the Underlying Molecular Mechanisms. Diabetes. 2013;62:2674-2682. doi: https://doi.org/10.2337/db13-0106

68. Schindler CE, Partap U, Patchen BK, Swoap SJ. Chronic rapamycin treatment causes diabetes in male mice. Am J Physiol Regul Integr Comp Physiol. 2014;307:R434-43. doi: https://doi.org/10.1152/ajpregu.00123.2014.

69. Lamming DW, Ye L, Astle CM, et al. Young and old genetically heterogeneous HET3 mice on a rapamycin diet are glucose intolerant but insulin sensitive. Aging Cell. 2013;12:712-718. doi: https://doi.org/10.1111/acel.12097

70. Lamming DW, Ye L, Katajisto P, et al. Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity. Science (80- ). 2012;335:1638-1643. doi: https://doi.org/10.1126/science.1215135

71. Okauchi S, Shimoda M, Obata A, et al. Protective effects of SGLT2 inhibitor luseogliflozin on pancreatic β-cells in obese type 2 diabetic db/db mice. Biochem Biophys Res Commun. 2016;470:772-782. doi: https://doi.org/10.1016/J.BBRC.2015.10.109

72. Lalloyer F, Vandewalle B, Percevault F, et al. Peroxisome proliferator-activated receptor α improves pancreatic adaptation to insulin resistance in obese mice and reduces lipotoxicity in human islets. Diabetes. 2006;55:1605-1613. doi: https://doi.org/10.2337/DB06-0016

73. Zhou J, Kang X, Luo Y, et al. Glibenclamide-Induced Autophagy Inhibits Its Insulin Secretion-Improving Function in β Cells. Int J Endocrinol. 2019;2019:1-8. doi: https://doi.org/10.1155/2019/1265175.

74. Ganesan K, Rana MBM, Sultan S. Oral Hypoglycemic Medications. StatPearls Publishing; 2020.

75. Bugliani M, Mossuto S, Grano F, 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. doi: https://doi.org/10.3389/fendo.2019.00052

76. Chen Z, Li Y-B, Han J, et al. The double-edged effect of autophagy in pancreatic beta cells and diabetes. Autophagy. 2011;7:12-16. doi: https://doi.org/10.4161/auto.7.1.13607

77. Capozzi ME, DiMarchi RD, Tschöp MH, et al. Targeting the Incretin/Glucagon System With Triagonists to Treat Diabetes. Endocr Rev. 2018;39(5):719-738. doi: https://doi.org/10.1210/er.2018-00117

78. Churchill AJ, Gutiérrez GD, Singer RA, et al. Genetic evidence that Nkx2.2 acts primarily downstream of Neurog3 in pancreatic endocrine lineage development. Elife. 2017;6. doi: https://doi.org/10.7554/eLife.20010

79. Zhu Y, Liu Q, Zhou Z, Ikeda Y. PDX1, Neurogenin-3, and MAFA: critical transcription regulators for beta cell development and regeneration. Stem Cell Res Ther. 2017;8(1):240. doi: https://doi.org/10.1186/s13287-017-0694-z

80. Donelan W, Li S, Wang H, et al. Pancreatic and duodenal homeobox gene 1 (Pdx1) down-regulates hepatic transcription factor 1 alpha (hnf1α) expression during reprogramming of human hepatic cells into insulin-producing cells. Am J Transl Res. 2015;7(6):995-1008.