Skip to main content
SpringerLink
Log in

Dysfunctions, molecular mechanisms, and therapeutic strategies of pancreatic β-cells in diabetes

  • Review
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Pancreatic beta-cell death has been established as a critical mediator in the progression of type 1 and type 2 diabetes mellitus. Beta-cell death is associated with exacerbating hyperglycemia and insulin resistance and paves the way for the progression of DM and its complications. Apoptosis has been considered the primary mechanism of beta-cell death in diabetes. However, recent pieces of evidence have implicated the substantial involvement of several other novel modes of cell death, including autophagy, pyroptosis, necroptosis, and ferroptosis. These distinct mechanisms are characterized by their unique biochemical features and often precipitate damage through the induction of cellular stressors, including endoplasmic reticulum stress, oxidative stress, and inflammation. Experimental studies were identified from PubMed literature on different modes of beta cell death during the onset of diabetes mellitus. This review summarizes current knowledge on the crucial pathways implicated in pancreatic beta cell death. The article also focuses on applying natural compounds as potential treatment strategies in inhibiting these cell death pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published articles and their supplementary information files.

Abbreviations

AMBRA1:

Autophagy and beclin 1 regulator 1

ATF6:

Activating transcription factor 6

ATG5:

Autophagy related 5

ATG10:

Autophagy related 10

ATG12:

Autophagy related 12

CaMKII:

Calmodulin-dependent protein kinase II

DISC:

Death-inducing signaling complex

DM:

Diabetes mellitus

ER:

Endoplasmic reticulum

GLUD1:

Glutamate dehydrogenase 1

GLUL:

Glutamate-ammonia ligase

Gpx4:

Glutathione peroxidase 4

GSDMD:

Gasdermin D

GSH:

Glutathione

GSIS:

Glucose stimulated insulin secretion

IAPP:

Islet amyloid peptide

IDF:

International Diabetes Federation

iNOS:

Inducible nitric oxide synthase

IRE1:

Inositol-requiring enzyme-1

IRS1:

Insulin receptor substrate 1

JNK:

Jun N-terminal kinase

Lc3ii:

Microtubule-associated protein 1A/1B-light chain

LPS:

Lipopolysaccharide

MLKL:

Mixed lineage kinase domain-like pseudokinase

MMP:

Mitochondrial membrane potential

mPTP:

Mitochondrial transition pore

mTORC1:

Mammalian target of rapamycin

NFκB:

Nuclear factor kappa B

NLRP3:

Nucleotide-binding domain (NOD)-like receptor protein 3

NO:

Nitric oxide

PERK:

Protein kinase RNA- like endoplasmic reticulum kinase

PI3K:

Phosphoinositide 3-Kinase

RIPK:

Receptor interacting protein kinase

ROS:

Reactive oxygen species

SGLT:

Sodium glucose linked transporter

TRADD:

TNFR1-associated death domain protein

ULK1:

Unc-51 like autophagy activating kinase 1

UPR:

Unfolded protein response

WIPI:

WD-repeat protein interacting with phosphoinositide

References

  1. American Diabetes A (2009) Standards of medical care in diabetes–2009. Diabetes Care 32(Suppl 1):S13–S61. https://doi.org/10.2337/dc09-S013

    Article  Google Scholar 

  2. IDF Diabetes Atlas 10th edition scientific committee (2022) IDF DIABETES ATLAS, International Diabetes Federation, Brussels

  3. American Diabetes A (2014) Diagnosis and classification of diabetes mellitus. Diabetes Care 37(Suppl 1):S81-90. https://doi.org/10.2337/dc14-S081

    Article  Google Scholar 

  4. Lee HS, Hwang JS (2019) Genetic aspects of type 1 diabetes. Ann Pediatr Endocrinol Metab 24(3):143–148. https://doi.org/10.6065/apem.2019.24.3.143

    Article  PubMed  PubMed Central  Google Scholar 

  5. Rorsman P, Ashcroft FM (2018) Pancreatic beta-Cell electrical activity and insulin secretion: of mice and men. Physiol Rev 98(1):117–214. https://doi.org/10.1152/physrev.00008.2017

    Article  CAS  PubMed  Google Scholar 

  6. Donath MY, Ehses JA, Maedler K, Schumann DM, Ellingsgaard H, Eppler E et al (2005) Mechanisms of beta-cell death in type 2 diabetes. Diabetes 54(Suppl 2):S108–S113. https://doi.org/10.2337/diabetes.54.suppl_2.s108

    Article  CAS  PubMed  Google Scholar 

  7. Mathis D, Vence L, Benoist C (2001) β-Cell death during progression to diabetes. Nature 414(6865):792–798. https://doi.org/10.1038/414792a

    Article  CAS  PubMed  Google Scholar 

  8. Cnop M, Welsh N, Jonas JC, Jorns A, Lenzen S, Eizirik DL (2005) Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54(Suppl 2):S97–S107. https://doi.org/10.2337/diabetes.54.suppl_2.s97

    Article  CAS  PubMed  Google Scholar 

  9. Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB et al (2020) Pathophysiology of type 2 diabetes mellitus. Int J Mol Sci. https://doi.org/10.3390/ijms21176275

    Article  PubMed  PubMed Central  Google Scholar 

  10. Cerf ME (2013) Beta cell dysfunction and insulin resistance. Front Endocrinol 4:37. https://doi.org/10.3389/fendo.2013.00037

    Article  Google Scholar 

  11. Ikegami H, Babaya N, Noso S (2021) β-Cell failure in diabetes: Common susceptibility and mechanisms shared between type 1 and type 2 diabetes. J Diabetes Investig 12(9):1526–1539. https://doi.org/10.1111/jdi.13576

    Article  PubMed  PubMed Central  Google Scholar 

  12. Chaudhari N, Talwar P, Parimisetty A, Lefebvre d’Hellencourt C, Ravanan P (2014) A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress. Front Cell Neurosci 8:213. https://doi.org/10.3389/fncel.2014.00213

    Article  PubMed  PubMed Central  Google Scholar 

  13. Contreras CJ, Mukherjee N, Branco RCS, Lin L, Hogan MF, Cai EP et al (2022) RIPK1 and RIPK3 regulate TNFalpha-induced beta-cell death in concert with caspase activity. Mol Metab 65:101582. https://doi.org/10.1016/j.molmet.2022.101582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Garcia-Aguilar A, Guillen C (2022) Targeting pancreatic beta cell death in type 2 diabetes by polyphenols. Front Endocrinol 13:1052317. https://doi.org/10.3389/fendo.2022.1052317

    Article  Google Scholar 

  15. Marchetti P, Bugliani M, De Tata V, Suleiman M, Marselli L (2017) Pancreatic beta cell identity in humans and the role of type 2 diabetes. Front Cell Dev Biol 5:55. https://doi.org/10.3389/fcell.2017.00055

    Article  PubMed  PubMed Central  Google Scholar 

  16. Omar-Hmeadi M, Idevall-Hagren O (2021) Insulin granule biogenesis and exocytosis. Cell Mol Life Sci 78(5):1957–1970. https://doi.org/10.1007/s00018-020-03688-4

    Article  CAS  PubMed  Google Scholar 

  17. Hou JC, Min L, Pessin JE (2009) Chapter 16 insulin granule biogenesis, trafficking and exocytosis. In: Hou JC (ed) Insulin and IGFs. Elsevier, Amsterdam, pp 473–506. https://doi.org/10.1016/s0083-6729(08)00616-x

    Chapter  Google Scholar 

  18. Fu Z, Gilbert ER, Liu D (2013) Regulation of insulin synthesis and secretion and pancreatic Beta-cell dysfunction in diabetes. Curr Diabetes Rev 9(1):25–53

    Article  PubMed  PubMed Central  Google Scholar 

  19. Costes S, Bertrand G, Ravier MA (2021) Mechanisms of beta-cell apoptosis in type 2 diabetes-prone situations and potential protection by glp-1-based therapies. Int J Mol Sci. https://doi.org/10.3390/ijms22105303

    Article  PubMed  PubMed Central  Google Scholar 

  20. Chen C, Cohrs CM, Stertmann J, Bozsak R, Speier S (2017) Human beta cell mass and function in diabetes: Recent advances in knowledge and technologies to understand disease pathogenesis. Mol Metab 6(9):943–957. https://doi.org/10.1016/j.molmet.2017.06.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Venugopal SK, Mowery ML, Jialal I (2023) C Peptide. StatPearls, Treasure Island (FL)

    Google Scholar 

  22. Hou JC, Min L, Pessin JE (2009) Insulin granule biogenesis, trafficking and exocytosis. Vitam Horm 80:473–506. https://doi.org/10.1016/S0083-6729(08)00616-X

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Maddaloni E, Bolli GB, Frier BM, Little RR, Leslie RD, Pozzilli P et al (2022) C-peptide determination in the diagnosis of type of diabetes and its management: a clinical perspective. Diabetes Obes Metab 24(10):1912–1926. https://doi.org/10.1111/dom.14785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sokooti S, Kieneker LM, Borst MH, Muller Kobold A, Kootstra-Ros JE, Gloerich J et al (2020) Plasma C-peptide and risk of developing type 2 diabetes in the general population. J Clin Med. https://doi.org/10.3390/jcm9093001

    Article  PubMed  PubMed Central  Google Scholar 

  25. Nepton S (2013) Beta-cell function and failure. In: Nepton S (ed) Type 1 Diabetes. InTech, Houston. https://doi.org/10.5772/52153

    Chapter  Google Scholar 

  26. Boland BB, Rhodes CJ, Grimsby JS (2017) The dynamic plasticity of insulin production in beta-cells. Mol Metab 6(9):958–973. https://doi.org/10.1016/j.molmet.2017.04.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Berger C, Zdzieblo D (2020) Glucose transporters in pancreatic islets. Pflugers Arch 472(9):1249–1272. https://doi.org/10.1007/s00424-020-02383-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jun HS, Yoon JW (2003) A new look at viruses in type 1 diabetes. Diabetes Metab Res Rev 19(1):8–31. https://doi.org/10.1002/dmrr.337

    Article  CAS  PubMed  Google Scholar 

  29. Vincenz L, Szegezdi E, Jager R, Holohan C, Obrien T, Samali A (2011) Cytokine induced cell stress and death in type 1 diabetes mellitus. Type 1 diabetes complications, pathogenesis, and alternative treatments. InTech, Houston. https://doi.org/10.5772/22765

    Chapter  Google Scholar 

  30. Kim S, Kim HS, Chung KW, Oh SH, Yun JW, Im SH et al (2007) Essential role for signal transducer and activator of transcription-1 in pancreatic beta-cell death and autoimmune type 1 diabetes of nonobese diabetic mice. Diabetes 56(10):2561–2568. https://doi.org/10.2337/db06-1372

    Article  CAS  PubMed  Google Scholar 

  31. Turley S, Poirot L, Hattori M, Benoist C, Mathis D (2003) Physiological β cell death triggers priming of self-reactive t cells by dendritic cells in a type-1 diabetes model. J Exp Med 198(10):1527–1537. https://doi.org/10.1084/jem.20030966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52(1):102–110. https://doi.org/10.2337/diabetes.52.1.102

    Article  CAS  PubMed  Google Scholar 

  33. Kim WH, Lee JW, Suh YH, Hong SH, Choi JS, Lim JH et al (2005) Exposure to chronic high glucose induces beta-cell apoptosis through decreased interaction of glucokinase with mitochondria: downregulation of glucokinase in pancreatic beta-cells. Diabetes 54(9):2602–2611. https://doi.org/10.2337/diabetes.54.9.2602

    Article  CAS  PubMed  Google Scholar 

  34. Giri B, Dey S, Das T, Sarkar M, Banerjee J, Dash SK (2018) Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity. Biomed Pharmacother 107:306–328. https://doi.org/10.1016/j.biopha.2018.07.157

    Article  CAS  PubMed  Google Scholar 

  35. Ashcroft FM, Rorsman P (2012) Diabetes mellitus and the beta cell: the last ten years. Cell 148(6):1160–1171. https://doi.org/10.1016/j.cell.2012.02.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rachdaoui N (2020) Insulin: the friend and the foe in the development of type 2 diabetes mellitus. Int J Mol Sci. https://doi.org/10.3390/ijms21051770

    Article  PubMed  PubMed Central  Google Scholar 

  37. Ormazabal V, Nair S, Elfeky O, Aguayo C, Salomon C, Zuniga FA (2018) Association between insulin resistance and the development of cardiovascular disease. Cardiovasc Diabeto 17(1):122. https://doi.org/10.1186/s12933-018-0762-4

    Article  CAS  Google Scholar 

  38. Park YJ, Woo M (2019) Pancreatic beta cells: gatekeepers of type 2 diabetes. J Cell Biol 218(4):1094–1095. https://doi.org/10.1083/jcb.201810097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Laybutt DR, Preston AM, Akerfeldt MC, Kench JG, Busch AK, Biankin AV et al (2007) Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 50(4):752–763. https://doi.org/10.1007/s00125-006-0590-z

    Article  CAS  PubMed  Google Scholar 

  40. Prasad MK, Mohandas S, Ramkumar KM (2022) Role of ER stress inhibitors in the management of diabetes. Eur J Pharmacol 922:174893. https://doi.org/10.1016/j.ejphar.2022.174893

    Article  CAS  Google Scholar 

  41. Hasnain SZ, Prins JB, McGuckin MA (2016) Oxidative and endoplasmic reticulum stress in beta-cell dysfunction in diabetes. J Mol Endocrinol 56(2):R33–R54. https://doi.org/10.1530/JME-15-0232

    Article  CAS  PubMed  Google Scholar 

  42. Maechler P, Wollheim CB (2000) Mitochondrial signals in glucose-stimulated insulin secretion in the beta cell. J Physiol 529(Pt 1):49–56. https://doi.org/10.1111/j.1469-7793.2000.00049.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jitrapakdee S, Wutthisathapornchai A, Wallace JC, MacDonald MJ (2010) Regulation of insulin secretion: role of mitochondrial signalling. Diabetologia 53(6):1019–1032. https://doi.org/10.1007/s00125-010-1685-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Eguchi N, Vaziri ND, Dafoe DC, Ichii H (2021) The role of oxidative stress in pancreatic beta cell dysfunction in diabetes. Int J Mol Sci. https://doi.org/10.3390/ijms22041509

    Article  PubMed  PubMed Central  Google Scholar 

  45. Alejandro EU, Gregg B, Blandino-Rosano M, Cras-Meneur C, Bernal-Mizrachi E (2015) Natural history of beta-cell adaptation and failure in type 2 diabetes. Mol Aspects Med 42:19–41. https://doi.org/10.1016/j.mam.2014.12.002

    Article  CAS  PubMed  Google Scholar 

  46. Donath MY, Dinarello CA, Mandrup-Poulsen T (2019) Targeting innate immune mediators in type 1 and type 2 diabetes. Nat Rev Immunol 19(12):734–746. https://doi.org/10.1038/s41577-019-0213-9

    Article  CAS  PubMed  Google Scholar 

  47. Elouil H, Bensellam M, Guiot Y, Vander Mierde D, Pascal SM, Schuit FC et al (2007) Acute nutrient regulation of the unfolded protein response and integrated stress response in cultured rat pancreatic islets. Diabetologia 50(7):1442–1452. https://doi.org/10.1007/s00125-007-0674-4

    Article  CAS  PubMed  Google Scholar 

  48. Cunha DA, Hekerman P, Ladriere L, Bazarra-Castro A, Ortis F, Wakeham MC et al (2008) Initiation and execution of lipotoxic ER stress in pancreatic beta-cells. J Cell Sci 121(Pt 14):2308–2318. https://doi.org/10.1242/jcs.026062

    Article  CAS  PubMed  Google Scholar 

  49. Marselli L, Piron A, Suleiman M, Colli ML, Yi X, Khamis A et al (2020) Persistent or Transient human beta cell dysfunction induced by metabolic stress: specific signatures and shared gene expression with type 2 diabetes. Cell Rep 33(9):108466. https://doi.org/10.1016/j.celrep.2020.108466

    Article  CAS  PubMed  Google Scholar 

  50. Chan JY, Luzuriaga J, Bensellam M, Biden TJ, Laybutt DR (2013) Failure of the adaptive unfolded protein response in islets of obese mice is linked with abnormalities in beta-cell gene expression and progression to diabetes. Diabetes 62(5):1557–1568. https://doi.org/10.2337/db12-0701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tarabra E, Pelengaris S, Khan M (2012) A simple matter of life and death-the trials of postnatal beta-cell mass regulation. Int J Endocrinol 2012:516718. https://doi.org/10.1155/2012/516718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kasuga M (2006) Insulin resistance and pancreatic beta cell failure. J Clin Investig 116(7):1756–1760. https://doi.org/10.1172/JCI29189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Porat S, Weinberg-Corem N, Tornovsky-Babaey S, Schyr-Ben-Haroush R, Hija A, Stolovich-Rain M et al (2011) Control of pancreatic beta cell regeneration by glucose metabolism. Cell Metab 13(4):440–449. https://doi.org/10.1016/j.cmet.2011.02.012

    Article  CAS  PubMed  Google Scholar 

  54. Liu YQ, Montanya E, Leahy JL (2001) Increased islet DNA synthesis and glucose-derived lipid and amino acid production in association with beta-cell hyperproliferation in normoglycaemic 60 % pancreatectomy rats. Diabetologia 44(8):1026–1033. https://doi.org/10.1007/s001250100597

    Article  CAS  PubMed  Google Scholar 

  55. Sheng Q, Xiao X, Prasadan K, Chen C, Ming Y, Fusco J et al (2017) Autophagy protects pancreatic beta cell mass and function in the setting of a high-fat and high-glucose diet. Sci Rep 7(1):16348. https://doi.org/10.1038/s41598-017-16485-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Masini M, Bugliani M, Lupi R, del Guerra S, Boggi U, Filipponi F et al (2009) Autophagy in human type 2 diabetes pancreatic beta cells. Diabetologia 52(6):1083–1086. https://doi.org/10.1007/s00125-009-1347-2

    Article  CAS  PubMed  Google Scholar 

  57. Rojas J, Bermudez V, Palmar J, Martinez MS, Olivar LC, Nava M et al (2018) Pancreatic beta cell death: novel potential mechanisms in diabetes therapy. J Diabetes Res 2018:9601801. https://doi.org/10.1155/2018/9601801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kim KA, Lee MS (2010) Role and mechanism of pancreatic beta-cell death in diabetes: the emerging role of autophagy. J Diabetes Investig 1(6):232–238. https://doi.org/10.1111/j.2040-1124.2010.00054.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sheng Q, Xiao X, Prasadan K, Chen C, Ming Y, Fusco J et al (2017) Autophagy protects pancreatic beta cell mass and function in the setting of a high-fat and high-glucose diet. Sci Rep. https://doi.org/10.1038/s41598-017-16485-0

    Article  PubMed  PubMed Central  Google Scholar 

  60. Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S et al (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26(24):9220–9231. https://doi.org/10.1128/MCB.01453-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Quan W, Hur KY, Lim Y, Oh SH, Lee JC, Kim KH et al (2012) Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice. Diabetologia 55(2):392–403. https://doi.org/10.1007/s00125-011-2350-y

    Article  CAS  PubMed  Google Scholar 

  62. Ebato C, Uchida T, Arakawa M, Komatsu M, Ueno T, Komiya K et al (2008) Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet. Cell Metab 8(4):325–332. https://doi.org/10.1016/j.cmet.2008.08.009

    Article  PubMed  Google Scholar 

  63. Marasco MR, Linnemann AK (2018) β-cell autophagy in diabetes pathogenesis. Endocrinology 159(5):2127–2141. https://doi.org/10.1210/en.2017-03273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Muralidharan C, Conteh AM, Marasco MR, Crowder JJ, Kuipers J, de Boer P et al (2021) Pancreatic beta cell autophagy is impaired in type 1 diabetes. Diabetologia 64(4):865–877. https://doi.org/10.1007/s00125-021-05387-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Riahi Y, Wikstrom JD, Bachar-Wikstrom E, Polin N, Zucker H, Lee MS et al (2016) Autophagy is a major regulator of beta cell insulin homeostasis. Diabetologia 59(7):1480–1491. https://doi.org/10.1007/s00125-016-3868-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Blandino-Rosano M, Barbaresso R, Jimenez-Palomares M, Bozadjieva N, Werneck-de-Castro JP, Hatanaka M et al (2017) Loss of mTORC1 signalling impairs beta-cell homeostasis and insulin processing. Nat Commun 8:16014. https://doi.org/10.1038/ncomms16014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bugliani M, Mossuto S, Grano F, Suleiman M, Marselli L, Boggi U et al (2019) 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 10:52. https://doi.org/10.3389/fendo.2019.00052

    Article  CAS  Google Scholar 

  68. Bartolome A, Guillen C, Benito M (2012) Autophagy plays a protective role in endoplasmic reticulum stress-mediated pancreatic beta cell death. Autophagy 8(12):1757–1768. https://doi.org/10.4161/auto.21994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yu ZW, Zhang J, Li X, Wang Y, Fu YH, Gao XY (2020) A new research hot spot: the role of NLRP3 inflammasome activation, a key step in pyroptosis, in diabetes and diabetic complications. Life Sci 240:117138. https://doi.org/10.1016/j.lfs.2019.117138

    Article  CAS  PubMed  Google Scholar 

  70. Sharma I, Behl T, Sehgal A, Singh S, Sharma N, Singh H, Hafeez A, Bungau S (2021) Exploring the focal role of pyroptosis in diabetes mellitus. Biointerface Res Appl Chem 11(5):13557–13572. https://doi.org/10.33263/briac115.1355713572

    Article  CAS  Google Scholar 

  71. Shi CS, Shenderov K, Huang NN, Kabat J, Abu-Asab M, Fitzgerald KA et al (2012) Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol 13(3):255–263. https://doi.org/10.1038/ni.2215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. He WT, Wan H, Hu L, Chen P, Wang X, Huang Z et al (2015) Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Res 25(12):1285–1298. https://doi.org/10.1038/cr.2015.139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Mamun AA, Wu Y, Nasrin F, Akter A, Taniya MA, Munir F et al (2021) Role of pyroptosis in diabetes and its therapeutic implications. J Inflamm Res 14:2187–2206. https://doi.org/10.2147/JIR.S291453

    Article  PubMed  PubMed Central  Google Scholar 

  74. Carlos D, Costa FR, Pereira CA, Rocha FA, Yaochite JN, Oliveira GG et al (2017) Mitochondrial DNA activates the NLRP3 inflammasome and predisposes to type 1 diabetes in murine model. Front Immunol 8:164. https://doi.org/10.3389/fimmu.2017.00164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ma H, Jeppesen JF, Jaenisch R (2020) Human T cells expressing a CD19 CAR-T receptor provide insights into mechanisms of human CD19-positive beta cell destruction. Cell Rep Med 1(6):100097. https://doi.org/10.1016/j.xcrm.2020.100097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Lin Y, Hu Y, Hu X, Yang L, Chen X, Li Q et al (2020) Ginsenoside Rb2 improves insulin resistance by inhibiting adipocyte pyroptosis. Adipocyte 9(1):302–312. https://doi.org/10.1080/21623945.2020.1778826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Szpigel A, Hainault I, Carlier A, Venteclef N, Batto AF, Hajduch E et al (2018) Lipid environment induces ER stress, TXNIP expression and inflammation in immune cells of individuals with type 2 diabetes. Diabetologia 61(2):399–412. https://doi.org/10.1007/s00125-017-4462-5

    Article  CAS  PubMed  Google Scholar 

  78. Gharibeh MY, Al Tawallbeh GM, Abboud MM, Radaideh A, Alhader AA, Khabour OF (2010) Correlation of plasma resistin with obesity and insulin resistance in type 2 diabetic patients. Diabetes Metab 36(6 Pt 1):443–449. https://doi.org/10.1016/j.diabet.2010.05.003

    Article  CAS  PubMed  Google Scholar 

  79. Rheinheimer J, de Souza BM, Cardoso NS, Bauer AC, Crispim D (2017) Current role of the NLRP3 inflammasome on obesity and insulin resistance: a systematic review. Metabolism 74:1–9. https://doi.org/10.1016/j.metabol.2017.06.002

    Article  CAS  PubMed  Google Scholar 

  80. Sun X, Hao H, Han Q, Song X, Liu J, Dong L et al (2017) Human umbilical cord-derived mesenchymal stem cells ameliorate insulin resistance by suppressing NLRP3 inflammasome-mediated inflammation in type 2 diabetes rats. Stem Cell Res Ther 8(1):241. https://doi.org/10.1186/s13287-017-0668-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Gerber PA, Rutter GA (2017) The role of oxidative stress and hypoxia in pancreatic beta-cell dysfunction in diabetes mellitus. Antioxid Redox Signal 26(10):501–518. https://doi.org/10.1089/ars.2016.6755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chen C, Ma X, Yang C, Nie W, Zhang J, Li H et al (2018) Hypoxia potentiates LPS-induced inflammatory response and increases cell death by promoting NLRP3 inflammasome activation in pancreatic beta cells. Biochem Biophys Res Commun 495(4):2512–2518. https://doi.org/10.1016/j.bbrc.2017.12.134

    Article  CAS  PubMed  Google Scholar 

  83. Thomas HE, McKenzie MD, Angstetra E, Campbell PD, Kay TW (2009) Beta cell apoptosis in diabetes. Apoptosis 14(12):1389–1404. https://doi.org/10.1007/s10495-009-0339-5

    Article  PubMed  Google Scholar 

  84. Saraste A (2000) Morphologic and biochemical hallmarks of apoptosis. Cardiovasc Res 45(3):528–537. https://doi.org/10.1016/s0008-6363(99)00384-3

    Article  CAS  PubMed  Google Scholar 

  85. Jiang X, Wang X (2004) Cytochrome C-mediated apoptosis. Annu Rev Biochem 73:87–106. https://doi.org/10.1146/annurev.biochem.73.011303.073706

    Article  CAS  PubMed  Google Scholar 

  86. Lee SC, Pervaiz S (2007) Apoptosis in the pathophysiology of diabetes mellitus. Int J Biochem Cell Biol 39(3):497–504. https://doi.org/10.1016/j.biocel.2006.09.007

    Article  CAS  PubMed  Google Scholar 

  87. Kiely A, McClenaghan NH, Flatt PR, Newsholme P (2007) Pro-inflammatory cytokines increase glucose, alanine and triacylglycerol utilization but inhibit insulin secretion in a clonal pancreatic beta-cell line. J Endocrinol 195(1):113–123. https://doi.org/10.1677/JOE-07-0306

    Article  CAS  PubMed  Google Scholar 

  88. Donath MY, Schumann DM, Faulenbach M, Ellingsgaard H, Perren A, Ehses JA (2008) Islet inflammation in type 2 diabetes: from metabolic stress to therapy. Diabetes Care 31(Suppl_2):S161–S1674. https://doi.org/10.2337/dc08-s243

    Article  CAS  PubMed  Google Scholar 

  89. Chandra J, Zhivotovsky B, Zaitsev S, Juntti-Berggren L, Berggren PO, Orrenius S (2001) Role of apoptosis in pancreatic beta-cell death in diabetes. Diabetes 50(Suppl_1):S44–S47. https://doi.org/10.2337/diabetes.50.2007.s44

    Article  CAS  PubMed  Google Scholar 

  90. Nakano M, Matsumoto I, Sawada T, Ansite J, Oberbroeckling J, Zhang HJ et al (2004) Caspase-3 inhibitor prevents apoptosis of human islets immediately after isolation and improves islet graft function. Pancreas 29(2):104–109. https://doi.org/10.1097/00006676-200408000-00004

    Article  CAS  PubMed  Google Scholar 

  91. Brandhorst D, Kumarasamy V, Maatoui A, Alt A, Bretzel RG, Brandhorst H (2006) Porcine islet graft function is affected by pretreatment with a caspase-3 inhibitor. Cell Transplant 15(4):311–317. https://doi.org/10.3727/000000006783981936

    Article  PubMed  Google Scholar 

  92. Gupta K, Phan N, Wang Q, Liu B (2018) Necroptosis in cardiovascular disease—A new therapeutic target. J Mol Cell Cardiol 118:26–35. https://doi.org/10.1016/j.yjmcc.2018.03.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P et al (2018) Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 25(3):486–541. https://doi.org/10.1038/s41418-017-0012-4

    Article  PubMed  PubMed Central  Google Scholar 

  94. Feng N, Anderson ME (2017) CaMKII is a nodal signal for multiple programmed cell death pathways in heart. J Mol Cell Cardiol 103:102–109. https://doi.org/10.1016/j.yjmcc.2016.12.007

    Article  CAS  PubMed  Google Scholar 

  95. Lee EW, Seo J, Jeong M, Lee S, Song J (2012) The roles of FADD in extrinsic apoptosis and necroptosis. BMB Rep 45(9):496–508. https://doi.org/10.5483/bmbrep.2012.45.9.186

    Article  CAS  PubMed  Google Scholar 

  96. Kaczmarek A, Vandenabeele P, Krysko DV (2013) Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 38(2):209–223. https://doi.org/10.1016/j.immuni.2013.02.003

    Article  CAS  PubMed  Google Scholar 

  97. Villalpando-Rodriguez GE, Gibson SB (2021) Reactive Oxygen Species (ROS) regulates different types of cell death by acting as a rheostat. Oxid Med Cell Longev 2021:9912436. https://doi.org/10.1155/2021/9912436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Jain MV, Paczulla AM, Klonisch T, Dimgba FN, Rao SB, Roberg K et al (2013) Interconnections between apoptotic, autophagic and necrotic pathways: implications for cancer therapy development. J Cell Mol Med 17(1):12–29. https://doi.org/10.1111/jcmm.12001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11(10):700–714. https://doi.org/10.1038/nrm2970

    Article  CAS  PubMed  Google Scholar 

  100. Fulda S (2013) Alternative cell death pathways and cell metabolism. Int J Cell Biol. 2013:463637. https://doi.org/10.1155/2013/463637

    Article  PubMed  PubMed Central  Google Scholar 

  101. Yang B, Maddison LA, Zaborska KE, Dai C, Yin L, Tang Z et al (2020) RIPK3-mediated inflammation is a conserved beta cell response to ER stress. Sci Adv. https://doi.org/10.1126/sciadv.abd7272

    Article  PubMed  PubMed Central  Google Scholar 

  102. Bellin MD, Barton FB, Heitman A, Harmon JV, Kandaswamy R, Balamurugan AN et al (2012) Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant 12(6):1576–1583. https://doi.org/10.1111/j.1600-6143.2011.03977.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072. https://doi.org/10.1016/j.cell.2012.03.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Sha W, Hu F, Xi Y, Chu Y, Bu S, G mez Hern ndez A, (2021) Mechanism of ferroptosis and its role in type 2 diabetes mellitus. J Diabetes Res 2021:1–10. https://doi.org/10.1155/2021/9999612

    Article  CAS  Google Scholar 

  105. Dolma S, Lessnick SL, Hahn WC, Stockwell BR (2003) Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 3(3):285–296. https://doi.org/10.1016/s1535-6108(03)00050-3

    Article  CAS  PubMed  Google Scholar 

  106. Chen X, Comish PB, Tang D, Kang R (2021) Characteristics and biomarkers of ferroptosis. Front Cell Dev Biol 9:637162. https://doi.org/10.3389/fcell.2021.637162

    Article  PubMed  PubMed Central  Google Scholar 

  107. Yang WS, Stockwell BR (2008) Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol 15(3):234–245. https://doi.org/10.1016/j.chembiol.2008.02.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Luo EF, Li HX, Qin YH, Qiao Y, Yan GL, Yao YY et al (2021) Role of ferroptosis in the process of diabetes-induced endothelial dysfunction. World J Diabetes 12(2):124–137. https://doi.org/10.4239/wjd.v12.i2.124

    Article  PubMed  PubMed Central  Google Scholar 

  109. Li C, Shi L, Chen D, Ren A, Gao T, Zhao M (2015) Functional analysis of the role of glutathione peroxidase (GPx) in the ROS signaling pathway, hyphal branching and the regulation of ganoderic acid biosynthesis in Ganoderma lucidum. Fungal Genet Biol 82:168–180. https://doi.org/10.1016/j.fgb.2015.07.008

    Article  CAS  PubMed  Google Scholar 

  110. Krummel B, Plotz T, Jorns A, Lenzen S, Mehmeti I (2021) The central role of glutathione peroxidase 4 in the regulation of ferroptosis and its implications for pro-inflammatory cytokine-mediated beta-cell death. Biochim Biophys Acta Mol Basis Dis 1867(6):166114. https://doi.org/10.1016/j.bbadis.2021.166114

    Article  CAS  PubMed  Google Scholar 

  111. Prasad MK, Mohandas S, Kunka Mohanram R (2023) Role of ferroptosis inhibitors in the management of diabetes. BioFactors 49(2):270–296. https://doi.org/10.1002/biof.1920

    Article  CAS  Google Scholar 

  112. Bruni A, Pepper AR, Pawlick RL, Gala-Lopez B, Gamble AF, Kin T et al (2018) Ferroptosis-inducing agents compromise in vitro human islet viability and functibon. Cell Death Dis 9(6):595. https://doi.org/10.1038/s41419-018-0506-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hamad M, Mohammed AK, Hachim MY, Mukhopadhy D, Khalique A, Laham A et al (2021) Heme Oxygenase-1 (HMOX-1) and inhibitor of differentiation proteins (ID1, ID3) are key response mechanisms against iron-overload in pancreatic beta-cells. Mol Cell Endocrinol 538:111462. https://doi.org/10.1016/j.mce.2021.111462

    Article  CAS  PubMed  Google Scholar 

  114. Howlett TA, Rees LH (1987) Endogenous opioid peptides and human reproduction. Oxf Rev Reprod Biol 9:260–293

    CAS  PubMed  Google Scholar 

  115. Linkermann A, Skouta R, Himmerkus N, Mulay SR, Dewitz C, De Zen F et al (2014) Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci U S A 111(47):16836–16841. https://doi.org/10.1073/pnas.1415518111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Mittler R, Darash-Yahana M, Sohn YS, Bai F, Song L, Cabantchik IZ et al (2019) NEET proteins: a new link between iron metabolism, reactive oxygen species, and cancer. Antioxid Redox Signal 30(8):1083–1095. https://doi.org/10.1089/ars.2018.7502

    Article  CAS  PubMed  Google Scholar 

  117. Damame HH, Rooge SB, Patil RS, Arvindekar AU (2020) In vitro model using cytokine cocktail to evaluate apoptosis in Min6 pancreatic beta cells. J Pharmacol Toxicol Methods 106:106914. https://doi.org/10.1016/j.vascn.2020.106914

    Article  CAS  PubMed  Google Scholar 

  118. Lacraz G, Figeac F, Movassat J, Kassis N, Portha B (2010) Diabetic GK/Par rat beta-cells are spontaneously protected against H2O2-triggered apoptosis. A cAMP-dependent adaptive response. Am J Physiol Endocrinol Metab 298(1):17–27. https://doi.org/10.1152/ajpendo.90871.2008

    Article  CAS  Google Scholar 

  119. Pagliuca FW, Millman JR, Gurtler M, Segel M, Van Dervort A, Ryu JH et al (2014) Generation of functional human pancreatic beta cells in vitro. Cell 159(2):428–439. https://doi.org/10.1016/j.cell.2014.09.040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Stancic A, Saksida T, Markelic M, Vucetic M, Grigorov I, Martinovic V et al (2022) Ferroptosis as a novel determinant of beta-cell death in diabetic conditions. Oxid Med Cell Longev 2022:3873420. https://doi.org/10.1155/2022/3873420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Chen WP, Chi TC, Chuang LM, Su MJ (2007) Resveratrol enhances insulin secretion by blocking K(ATP) and K(V) channels of beta cells. Eur J Pharmacol 568(1–3):269–277. https://doi.org/10.1016/j.ejphar.2007.04.062

    Article  CAS  PubMed  Google Scholar 

  122. Zhang J, Dong XJ, Ding MR, You CY, Lin X, Wang Y et al (2020) Resveratrol decreases high glucose-induced apoptosis in renal tubular cells via suppressing endoplasmic reticulum stress. Mol Med Rep 22(5):4367–4375. https://doi.org/10.3892/mmr.2020.11511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Cai EP, Lin JK (2009) Epigallocatechin gallate (EGCG) and rutin suppress the glucotoxicity through activating IRS2 and AMPK signaling in rat pancreatic beta cells. J Agric Food Chem 57(20):9817–9827. https://doi.org/10.1021/jf902618v

    Article  CAS  PubMed  Google Scholar 

  124. Wolfram S, Raederstorff D, Preller M, Wang Y, Teixeira SR, Riegger C et al (2006) Epigallocatechin gallate supplementation alleviates diabetes in rodents. J Nutr 136(10):2512–2518. https://doi.org/10.1093/jn/136.10.2512

    Article  CAS  PubMed  Google Scholar 

  125. Ohno T, Kato N, Ishii C, Shimizu M, Ito Y, Tomono S et al (1993) Genistein augments cyclic adenosine 3’5’-monophosphate(cAMP) accumulation and insulin release in MIN6 cells. Endocr Res 19(4):273–285. https://doi.org/10.1080/07435809309026682

    Article  CAS  PubMed  Google Scholar 

  126. Liu D, Zhen W, Yang Z, Carter JD, Si H, Reynolds KA (2006) Genistein acutely stimulates insulin secretion in pancreatic beta-cells through a cAMP-dependent protein kinase pathway. Diabetes 55(4):1043–1050. https://doi.org/10.2337/diabetes.55.04.06.db05-1089

    Article  CAS  PubMed  Google Scholar 

  127. Elliott J, Scarpello JH, Morgan NG (2002) Differential effects of genistein on apoptosis induced by fluoride and pertussis toxin in human and rat pancreatic islets and RINm5F cells. J Endocrinol 172(1):137–143. https://doi.org/10.1677/joe.0.1720137

    Article  CAS  PubMed  Google Scholar 

  128. Wang Y, Zhu X, Yuan S, Wen S, Liu X, Wang C et al (2019) TLR4/NF-kappaB signaling induces GSDMD-related pyroptosis in tubular cells in diabetic kidney disease. Front Endocrinol 10:603. https://doi.org/10.3389/fendo.2019.00603

    Article  Google Scholar 

  129. Ding Y, Zhang Z, Dai X, Jiang Y, Bao L, Li Y et al (2013) Grape seed proanthocyanidins ameliorate pancreatic beta-cell dysfunction and death in low-dose streptozotocin- and high-carbohydrate/high-fat diet-induced diabetic rats partially by regulating endoplasmic reticulum stress. Nutr Metab 10:51. https://doi.org/10.1186/1743-7075-10-51

    Article  CAS  Google Scholar 

  130. Bashir N, Manoharan V, Miltonprabu S (2016) Grape seed proanthocyanidins protects against cadmium induced oxidative pancreatitis in rats by attenuating oxidative stress, inflammation and apoptosis via Nrf-2/HO-1 signaling. J Nutr Biochem 32:128–141. https://doi.org/10.1016/j.jnutbio.2016.03.001

    Article  CAS  PubMed  Google Scholar 

  131. Sharma AK, Bharti S, Ojha S, Bhatia J, Kumar N, Ray R et al (2011) Up-regulation of PPARgamma, heat shock protein-27 and -72 by naringin attenuates insulin resistance, beta-cell dysfunction, hepatic steatosis and kidney damage in a rat model of type 2 diabetes. Br J Nutr 106(11):1713–1723. https://doi.org/10.1017/S000711451100225X

    Article  CAS  PubMed  Google Scholar 

  132. Zahid A, Li B, Kombe AJK, Jin T, Tao J (2019) Pharmacological inhibitors of the NLRP3 inflammasome. Front Immunol 10:2538. https://doi.org/10.3389/fimmu.2019.02538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Pan Y, Zhang X, Wang Y, Cai L, Ren L, Tang L et al (2013) Targeting JNK by a new curcumin analog to inhibit NF-kB-mediated expression of cell adhesion molecules attenuates renal macrophage infiltration and injury in diabetic mice. PLoS ONE 8(11):e79084. https://doi.org/10.1371/journal.pone.0079084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Aggarwal S, Kelly S, Paramor J, Seeberger K, Rosko M, Polishevska K et al (2021) P.113: The role of necroptosis in beta-cell loss following islet cell transplantation. Transplantation 105(12S1):S42-S. https://doi.org/10.1097/01.tp.0000804536.23741.ad

    Article  Google Scholar 

  135. Li D, Jiang C, Mei G, Zhao Y, Chen L, Liu J et al (2020) Quercetin alleviates ferroptosis of pancreatic beta cells in type 2 diabetes. Nutrients. https://doi.org/10.3390/nu12102954

    Article  PubMed  PubMed Central  Google Scholar 

  136. Kang YJ, Jung UJ, Lee MK, Kim HJ, Jeon SM, Park YB et al (2008) Eupatilin, isolated from Artemisia princeps Pampanini, enhances hepatic glucose metabolism and pancreatic beta-cell function in type 2 diabetic mice. Diabetes Res Clin Pract 82(1):25–32. https://doi.org/10.1016/j.diabres.2008.06.012

    Article  CAS  PubMed  Google Scholar 

  137. Prasath GS, Sundaram CS, Subramanian SP (2013) Fisetin averts oxidative stress in pancreatic tissues of streptozotocin-induced diabetic rats. Endocrine 44(2):359–368. https://doi.org/10.1007/s12020-012-9866-x

    Article  CAS  PubMed  Google Scholar 

  138. Stanley Mainzen Prince P, Kamalakkannan N (2006) Rutin improves glucose homeostasis in streptozotocin diabetic tissues by altering glycolytic and gluconeogenic enzymes. J Biochem Mol Toxicol 20(2):96–102. https://doi.org/10.1002/jbt.20117

    Article  CAS  PubMed  Google Scholar 

  139. Ortsater H, Grankvist N, Wolfram S, Kuehn N, Sjoholm A (2012) Diet supplementation with green tea extract epigallocatechin gallate prevents progression to glucose intolerance in db/db mice. Nutr Metab. https://doi.org/10.1186/1743-7075-9-11

    Article  Google Scholar 

  140. Badr AM, Sharkawy H, Farid AA, El-Deeb S (2020) Curcumin induces regeneration of β cells and suppression of phosphorylated-NF-κB in streptozotocin-induced diabetic mice. J Basic Appl Zool. https://doi.org/10.1186/s41936-020-00156-0

    Article  Google Scholar 

Download references

Funding

The authors gratefully acknowledge the financial support from the Indian Council of Medical Research (ICMR), India (Grant No.: 59/02/2022-TRM/BMS [2021–11487]).

Author information

Authors and Affiliations

  1. Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India

    Murali Krishna Prasad, Sundhar Mohandas & Kunka Mohanram Ramkumar

Authors
  1. Murali Krishna Prasad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sundhar Mohandas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kunka Mohanram Ramkumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, KP, SM, KMR; methodology and analysis, KP and SM; investigation, KP and SM; writing-original draft preparation, KP, and SM; writing-review and editing, RKM and SM; visualization, KP and SM; supervision, RKM. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Kunka Mohanram Ramkumar.

Ethics declarations

Competing interests

The authors declare that they have no competing interests.

Ethical approval

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Prasad, M.K., Mohandas, S. & Ramkumar, K.M. Dysfunctions, molecular mechanisms, and therapeutic strategies of pancreatic β-cells in diabetes. Apoptosis 28, 958–976 (2023). https://doi.org/10.1007/s10495-023-01854-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-023-01854-0

Keywords

Search

Navigation