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Dysfunction and Death of Pancreatic Beta-Cells in Type 2 Diabetes

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Abstract

β-cells represent the functional unit of pancreatic islets, and they are responsible for glucose homeostasis regulation. β-cells possess the ability to modify insulin secretion according to the organism-specific needs. Thus, during physiological changes such as pregnancy or obesity, glycemia is increased concomitantly with the ability of β-cells to secrete insulin. However, when demand for insulin chronically increases, a steady stimulation of β-cells eventually may lead to death. In spite of the conducted efforts in order to elucidate the glucotoxicity mechanisms acting on β-cells, they remain largely unknown. Hyperglycemia promotes several metabolic alterations such as glucolipotoxicity, mitochondrial alterations, oxidative stress, endoplasmic reticulum stress, amyloid polypeptide accumulation, and proinflammatory cytokine accumulation. The latter are commonly engaged during apoptosis triggering in β-cells. In recent years, p53 has been also proposed as a major trigger of apoptosis in β-cells during hyperglycemia conditions. Because insulin-producing cells are cultured using high glucose levels, the presence of p53 in mitochondria induces apoptosis. The insight on the mechanisms triggering cell death in pancreatic β-cells will support the proposal of alternatives for prevention and/or cell protection also contributing to the treatment of diabetic patients.

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Abbreviations

AGE:

Advanced glycation end products

AIF:

Apoptosis inducing factor

Apaf-1:

Apoptotic protease-activating factor 1

ATF6:

Activating transcription factor 6

ATM:

ATM serine/threonine kinase protein

Bak:

Bcl-2 homologous antagonist killer

Bax:

Bcl-2-associated X protein

Bcl-2:

B-cell lymphoma 2

Bcl-xl:

B-cell lymphoma-extra large

BH (1–4):

Bcl-2 homology domains

Bok:

Bcl-2 related ovarian killer

Caspasa:

Cysteine-aspartic proteases, cysteine aspartases

CHOP:

C/EBP homologous protein

ChREBP:

Carbohydrate response element-binding protein

Drp1:

Dynamin-related protein 1

ΔΨm:

Mitochondrial membrane potential

eif2α:

Eukaryotic translation initiation factor 2α

ER:

Reticulum stress

ERE:

Endoplasmic reticulum stress

EZH2:

Enhancer of Zeste Homologue 2

FADD:

FAS-associating death domain-containing protein

Fas:

Death receptor

FFA:

Free fatty acids

Fis1:

Mitochondrial fission 1 protein

FOX A1/2:

Forkhead box

G3P:

Glyceraldehyde 3-phosphate

GADD34:

Downstream growth arrest and DNA damage-inducible protein

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GATA4/6:

GATA-binding protein

GLUT:

Glucose transporter

GSIS:

Glucose-stimulated insulin secretion

H3K27me3:

Histone H3 trimethyl K27

HNF1β:

Hepatocyte nuclear factor

IAPP:

Islet amyloid polypeptide

IFNγ:

Interferon gamma

IGF1:

Insulin-like growth factor 1

IL-1β:

Interleukin 1 beta

iNOS:

Nitric oxide synthases inducible

Ins :

Insulin gene

INS1:

Insulin secreting beta-cell-derived line

IRE1α:

Inositol-requiring enzyme

IRS-2:

Insulin receptor substrate

Isl:

Islet

MafA:

Musculo aponeurotic fibrosarcoma protein A

Mdm2:

Murine double minute 2

Mff:

Mitochondrial fission factor

Mfn:

Mitofusin

Mouse db/db:

Model of obesity, diabetes, and dyslipidemia with a mutation in leptin receptor

mTOR:

Mammalian target of rapamycin

NAD+:

Nicotinamide adenine dinucleotide

NADH:

Nicotinamide adenine dinucleotide reduced

NADPH oxi:

Nicotinamide adenine dinucleotide phosphate-oxidase

NeuroD1:

Neurogenic differentiation 1

NF-κB:

Nuclear factor kappa B

Nkx:

Homeobox protein

NLRP3:

NACHT, LRR, and PYD domain-containing protein 3

NLRs:

Nucleotide oligomerization domain (NOD)-like receptors

NO:

Nitric oxide

NOD :

Nucleotide oligomerization domain

Notch:

Transcription factor

•OH:

Hydroxyl radical

8-OHdG:

8-hydroxy-2′-deoxyguanosine

O−2:

Superoxide anion

O-GlcNAc:

O-linked β-N-acetylglucosamine

Opa1:

Protein of mitocondrial internal membrane

P/CAF:

P300/CBP-associated factor

p16:

Cyclin-dependent kinase inhibitor 2A, multiple tumor suppressor 1

p21:

Cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1

p27:

Cyclin-dependent kinase inhibitor 1B

p300/CBP:

E1A binding protein p300/CREB-binding protein

p38 MAPK:

P38 mitogen-activated protein kinases

p53:

Tumor protein p53

PARP:

Poly ADP ribose polymerase

Pax4:

Transcription factors paired box gene 4

Pdx1:

Pancreatic and duodenal homeobox 1

PERK:

Protein kinase-like ER kinase

PI3k:

Phosphatidylinositol-3-kinases

PKC:

Protein kinase C

PP-1:

Protein phosphatase 1

Ptf1α:

Pancreas transcription factor 1α

RAMP1:

Receptor activity-modifying protein 1

Rfx 6:

Regulatory factor x

RING-finger:

Really interesting new gene

RINm5F:

Rat insulinoma cells

ROS:

Reactive oxygen species

Sox9 SRY:

Sex-determining region Y-box 9

SPT:

Serine C-palmitoyltransferase

T2D:

Type 2 diabetes

TLRs:

Toll-like receptors

TNFRI:

Tumor necrosis factor receptor type I

TNFα:

Tumor necrosis factor alpha

TXNIP:

Thioredoxin-interacting protein

UCP2:

Uncoupling protein 2

UDP-GlcNAc:

Uridine diphosphate N-acetylglucosamine

UPR:

Unfolded protein response

References

  1. Assmann A, Hinault C, Kulkarni RN. Growth factor control of pancreatic islet regeneration and function. Pediatr Diabetes. 2009;10:14–32.

    Article  CAS  PubMed  Google Scholar 

  2. Hudish LI, Reusch JE, Sussel L. β Cell dysfunction during progression of metabolic syndrome to type 2 diabetes. J Clin Invest. 2019;129:4001–8.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ortega-Camarillo C, Guzmán-Grenfell AM, García-Macedo R, et al. Hyperglycemia induces apoptosis and p53 mobilization to mitochondria in RINm5F cells. Mol Cell Biochem. 2006;281:163–70.

    Article  CAS  PubMed  Google Scholar 

  4. Hinault C, Kawamori D, Liew CW, et al. D40 isoform of p53 controls b-cell proliferation and glucose homeostasis in mice. Diabetes. 2011;60:1210–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Jurczyk A, Bortell R, Alonso LC. Human β-cell regeneration: progress, hurdles, and controversy. Curr Opin Endocrinol Diabetes Obes. 2014;21:102–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yagihashi S, Inaba W, Mizukami H. Dynamic pathology of islet endocrine cells in type 2 diabetes: β-cell growth, death, regeneration and their clinical implications. J Clin Invest. 2016;7:155–65.

    CAS  Google Scholar 

  7. Oliver-Krasinski JM, Stoffers DA. On the origin of the β cell. Genes Dev. 2008;22:1998–2021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gittes GK, Rutter WJ. Onset of cell-specific gene expression in the developing mouse pancreas. Proc Natl Acad Sci U S A. 1992;89:1128–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Meier JJ, Butler AE, Saisho Y, et al. β-cell replication is the primary mechanism subserving the postnatal expansion of β-cell mass in humans. Diabetes. 2008;57:1584–94.

    Article  CAS  PubMed  Google Scholar 

  10. Mizukami H, Takahashi K, Inaba W, et al. Age-associated changes of islet endocrine cells and the effects of body mass index in Japanese. J Diabetes Investig. 2014;5:38–47.

    Article  CAS  PubMed  Google Scholar 

  11. Alejandro EU, Gregg B, Blandino-Rosano M, Cras-Méneur C, Bernal-Mizrachi E. Natural history of β-cell adaptation and failure in type 2 diabetes. Mol Aspects Med. 2015;42:19–41.

    Article  CAS  PubMed  Google Scholar 

  12. Butler AE, Janson J, Bonner-Weir S. β-Cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102–10.

    Article  CAS  PubMed  Google Scholar 

  13. Khadra A, Schnell S. Development, growth and maintenance of β-cell mass: models are also part of the story. Mol Aspects Med. 2015;42:78–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ward W, Bolgiano D, McKnight B, Halter J, Porte DJ. Diminished β cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Invest. 1984;74:1318–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Meier JJ. Beta cell mass in diabetes: a realistic therapeutic target? Diabetologia. 2008;51:703–13.

    Article  CAS  PubMed  Google Scholar 

  16. Unger RH. Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology. 2003;144:5159–65.

    Article  CAS  PubMed  Google Scholar 

  17. Kjørholt C, Åkerfeldt MC, Biden TJ, Laybutt DR. Chronic hyperglycemia, independent of plasma lipid levels, is sufficient for the loss of β-cell differentiation and secretory function in the db/db mouse model of diabetes. Diabetes. 2005;54:2755–63.

    Article  PubMed  Google Scholar 

  18. Thornberry AN, Lazebnik Y. Caspases: enemies within. Science. 1998;281:1312–6.

    Article  CAS  PubMed  Google Scholar 

  19. Schwartzman RA, Cidlowski JA. Apoptosis: the biochemistry and molecular biology of programmed cell death. Endocr Rev. 1993;14:133–51.

    CAS  PubMed  Google Scholar 

  20. Höppener JW, Ahrén B, Lips CJ. Islet amyloid and type 2 diabetes mellitus. N Engl J Med. 2000;343:411–9.

    Article  Google Scholar 

  21. Tomita T. Apoptosis in pancreatic β-islet cells in type 2 diabetes. Bosn J Basic Med Sci. 2016;16:162–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kilpatrick ED, Robertson RP. Differentiation between glucose-induced desensitization of insulin secretion and β-cell exhaustion in the HIT-T15 cell line. Diabetes. 1998;47:606–11.

    Article  CAS  PubMed  Google Scholar 

  23. Robertoson RP. β-cell deterioration during diabetes: what’s in the gun? Trends Endocrinol Metab. 2009;20:388–93.

    Article  Google Scholar 

  24. Kajimoto Y, Watada H, Matsuoka T-a, et al. Suppression of transcription factor PDX-1/IPF1/STF-1/IDX-1 causes no decrease in insulin mRNA in MIN6 cells. J Clin Invest. 1997;100:1840–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Federici M, Hribal M, Perego L, et al. High glucose causes apoptosis in cultured human pancreatic islets of Langerhans. A potential role for regulation of specific Bcl family genes toward an apoptotic cell death program. Diabetes. 2001;50:1290–300.

    Article  CAS  PubMed  Google Scholar 

  26. Donath MY, Gross DJ, Cerasi E, Kaiser N. Hyperglycemia-induced -cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes. Diabetes. 1999;48:738–44.

    Article  CAS  PubMed  Google Scholar 

  27. Kim W-H, Lee JW, Suh YH, et al. Exposure to chronic high glucose induces b-cell apoptosis through decreased interaction of glucokinase with mitochondria. Diabetes. 2005;54:2602–11.

    Article  CAS  PubMed  Google Scholar 

  28. Piro S, Anello M, Pietro CD, et al. Chronic exposure to free fatty acids or high glucose induces apoptosis in rat pancreatic islets: possible role of oxidative stress. Metabolism. 2002;51:1340–7.

    Article  CAS  PubMed  Google Scholar 

  29. Chan CB, Saleh MC, Koshkin V, Wheeler MB. Uncoupling protein 2 and islet function. Diabetes. 2004;53:S136–42.

    Article  CAS  PubMed  Google Scholar 

  30. Joseph JW, Koshkin V, Saleh MC, et al. Free fatty acid-induced -cell defects are dependent on uncoupling protein 2 expression. J Biol Chem. 2004;279:51049–56.

    Article  CAS  PubMed  Google Scholar 

  31. Laybutt DR, Preston AM, Åkerfeldt MC, et al. Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia. 2007;50:752–63.

    Article  CAS  PubMed  Google Scholar 

  32. Ogihara T, Mirmira RG. An islet in distress: β cell failure in type 2 diabetes. J Diabetes Investig. 2010;1:123–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Kelpe CL, Moore PC, Parazzoli SD, et al. Palmitate inhibition of insulin gene expression is mediated at the transcriptional level via ceramide synthesis. J Biol Chem. 2003;278:30015–21.

    Article  CAS  PubMed  Google Scholar 

  34. Stein DT, Esser V, Stevenson BE, et al. Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat. J Clin Invest. 1996;97:2728–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Véret J, Coant N, Berdyshev EV, et al. Ceramide synthase 4 and de novo production of ceramides with specific N-acyl chain lengths are involved in glucolipotoxicity-induced apoptosis of INS-1 β-cells. Biochem J. 2011;438:177–89.

    Article  PubMed  Google Scholar 

  36. Galadari S, Rahman A, Pallichankandy S, Galadari A, Thayyullathil F. Role of ceramide in diabetes mellitus: evidence and mechanisms. Lipids Health Dis. 2013;12:98–114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Unger RH, Zhou Y-T. Lipotoxicity of β-cells in obesity and in other causes of fatty acid spillover. Diabetes. 2001;50:S118–21.

    Article  CAS  PubMed  Google Scholar 

  38. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813–20.

    Article  CAS  PubMed  Google Scholar 

  39. Oliveira HR, Verlengia R, Carvalho CRO, et al. Pancreatic β-cells express phagocyte-like NAD(P)H oxidase. Diabetes. 2003;52:1457–63.

    Article  CAS  PubMed  Google Scholar 

  40. Yan L-J. Pathogenesis of chronic hyperglycemia: from reductive stress to oxidative stress. J Diabetes Res. 2014;2014:137919.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Grankvist K, Marklund SL, Täljedal I-B. CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse. Biochem J. 1981;199:393–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Brownlee M. The pathology of diabetic complications: a unifying mechanism. Diabetes. 2005;54:1615–25.

    Article  CAS  PubMed  Google Scholar 

  43. Nishikawa T, Edelstein D, Du JX, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;404:787–90.

    Article  CAS  PubMed  Google Scholar 

  44. Maechler P, Wollheim CB. Mitochondrial function in normal and diabetic b-cells. Nature. 2001;414:807–12.

    Article  CAS  PubMed  Google Scholar 

  45. Orrenius S, Zhivotovsky B. Cardiolipin oxidation sets cytochrome c free. Nat Chem Biol. 2005;1:188–9.

    Article  CAS  PubMed  Google Scholar 

  46. Ma ZA, Zhao Z, Turk J. Mitochondrial dysfunction and β-cell failure in type 2 diabetes mellitus. Exp Diabetes Res. 2012;2012:1–11.

    Article  Google Scholar 

  47. Kaufman BA, Li C, Soleimanpour SA. Mitochondrial regulation of β-cell function: maintaining the momentum for insulin release. Mol Aspects Med. 2015;2015:91–104.

    Article  Google Scholar 

  48. Yoon Y, Krueger EW, Oswald BJ, McNiven MA. The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol Cell Biol. 2003;23:5409–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Maassen JA, Romijn JA, Heine RJ. Fatty acid-induced mitochondrial uncoupling in adipocytes as a key protective factor against insulin resistance and beta cell dysfunction: a new concept in the pathogenesis of obesity-associated type 2 diabetes mellitus. Diabetologia. 2007;50:2036–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hasnain SZ, Prins JB, McGuckin MA. Oxidative and endoplasmic reticulum stress in b-cell dysfunction in diabetes. J Mol Endocrinol. 2016;56:R33–54.

    Article  CAS  PubMed  Google Scholar 

  51. Karunakaran U, Kim H-J, Kim J-Y, Lee I-K. Guards and culprits in the endoplasmic reticulum: glucolipotoxicity and β-cell failure in type II diabetes. Exp Diabetes Res. 2012;2012:9.

    Article  Google Scholar 

  52. Sharma RB, Alonso LC. Lipotoxicity in the pancreatic beta cell: not just survival and function, but proliferation as well? Curr Diab Rep. 2014;14:492–508.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Cui W, Ma J, Wang X, et al. Free fatty acid induces endoplasmic reticulum stress and apoptosis of β-cells by Ca2+/Calpain-2 pathways. PLoS One. 2013;8:e59921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Meigs JB, Wilson PWF, Fox CS, et al. Body mass index, metabolic syndrome, and risk of type 2 diabetes or cardiovascular disease. J Clin Endocrinol Metab. 2006;91:2906–12.

    Article  CAS  PubMed  Google Scholar 

  55. Meier JJ, Bonadonna RC. Role of reduced B-cell function in the pathogenesis of type 2 diabetes. Diabetes Care. 2013;36:S13–9.

    Article  Google Scholar 

  56. Cantley J, Ashcroft FM. Q&A: insulin secretion and type 2 diabetes: why do β-cells fail? BMC Biol. 2015;13:33–40.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Saisho Y, Butler AE, Manesso E, et al. β-cell mass and turnover in humans: effects of obesity and aging. Diabetes Care. 2013;36:111–7.

    Article  PubMed  Google Scholar 

  58. Hull RL, Kodama K, Utzschneider KM, et al. Dietary-fat induced obesity in mice results in beta cell hyperplasia but not increased insulin release: evidence for specificity of impaired beta cell adaptation. Diabetologia. 2005;48:1350–8.

    Article  CAS  PubMed  Google Scholar 

  59. Cheng Z, Almeida FA. Mitochondrial alteration in type 2 diabetes and obesity. Cell Cycle. 2014;13:890–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Itariu BK, Stulnig TM. Autoimmune aspects of type 2 diabetes mellitus – a mini-review. Gerontology. 2014;60:189–96.

    Article  CAS  PubMed  Google Scholar 

  61. Araki E, Oyadomari S, Mori M. Impact of endoplasmic reticulum stress pathway on pancreatic b-cells and diabetes mellitus. Exp Biol Med. 2003;228:1213–7.

    Article  CAS  Google Scholar 

  62. Chen J, Saxena G, Mungrue IN, Lusis AJ, Shalev A. Thioredoxin-Interacting protein: a critical link between glucose toxicity and beta cell apoptosis. Diabetes. 2008;57:938–44.

    Article  CAS  PubMed  Google Scholar 

  63. Teff KL, Elliott SS, Tschöp M, et al. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab. 2004;89:2963–72.

    Article  CAS  PubMed  Google Scholar 

  64. Lowell B, Shulman I. Mitochondrial dysfunction and type 2 diabetes. Science. 2005;307:384–7.

    Article  CAS  PubMed  Google Scholar 

  65. Ritzel RA, Meier JJ, Lin C-Y, Veldhuis JD, Butler PC. Human islet amyloid polypeptide oligomers disrupt cell coupling, induce apoptosis, and impair insulin secretion in isolated human islets. Diabetes. 2007;56:65–71.

    Article  CAS  PubMed  Google Scholar 

  66. Arnelo U, Permert J, Larsson J, et al. Chronic low dose islet amyloid polypeptide infusion reduces food intake, but does not influence glucose metabolism, in unrestrained conscious rats: studies using a novel aortic catheterization technique. Endocrinology. 1997;138:4081–5.

    Article  CAS  PubMed  Google Scholar 

  67. Hull RL, Westermark GT, Westermark P, Kahn SE. Islet Amyloid: a critical entity in the pathogenesis of type 2 diabetes. J Clin Endocrinol Metab. 2004;89:629–3643.

    Article  Google Scholar 

  68. Mihara M, Erster S, Zaika A, et al. p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 2003;11:577–90.

    Article  CAS  PubMed  Google Scholar 

  69. Ortega-Camarillo C, Flores-López LA, Ávalos-Rodríguez A. The role of p53 in pancreatic b-cell apoptosis. Immunoendocrinology. 2015;2:E1075.

    Google Scholar 

  70. Balmanno K, Cook SJ. Tumour cell survival signalling by the ERK1/2 pathway. Cell Death Differ. 2009;16:368–77.

    Article  CAS  PubMed  Google Scholar 

  71. Elkholi R, Chipuk JE. How do I kill thee? Let me count the ways: p53 regulates PARP-1 dependent necrosis. Bioessays. 2014;36:46–51.

    Article  CAS  PubMed  Google Scholar 

  72. Lavin MF, Gueven N. The complexity of p53 stabilization and activation. Cell Death Differ. 2006;13:941–50.

    Article  CAS  PubMed  Google Scholar 

  73. Flores-López LA, Díaz-Flores M, García-Macedo R, et al. High glucose induces mitochondrial p53 phosphorylation by p38 MAPK in pancreatic RINm5F cells. Mol Biol Rep. 2013;40:4947–58.

    Article  PubMed  Google Scholar 

  74. Yang WH, Kim JE, Nam HW, et al. Modification of p53 with O-linked N-acetylglucosamine regulates p53 activity and stability. Nat Cell Biol. 2006;8:1074–83.

    Article  CAS  PubMed  Google Scholar 

  75. Flores-López LA, Cruz-López M, García-Macedo R, et al. Phosphorylation, ON-acetylglucosaminylation and poly-ADP-ribosylation of p53 in RINm5F cells cultured in high glucose. Free Radic Biol Med. 2012;53:S95.

    Article  Google Scholar 

  76. Ogawara Y, Kishishita S, Obata T, et al. Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Biol Chem. 2002;277:21843–50.

    Article  CAS  PubMed  Google Scholar 

  77. Barzalobre-Gerónimo R, Flores-López LA, Baiza-Gutman LA, et al. Hyperglycemia promotes p53-Mdm2 interaction but reduces p53 ubiquitination in RINm5f cells. Mol Cell Biochem. 2015;405:257–64.

    Article  PubMed  Google Scholar 

  78. Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM. Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J Biol Chem. 2000;275:8945–51.

    Article  CAS  PubMed  Google Scholar 

  79. Zhong I, Georgia S, Tschen S-i, et al. Essential role of Skp2-mediated p27 degradation in growth and adaptive expansion of pancreatic b cells. J Clin Invest. 2007;117:2869–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Vetere A, Choudhary A, Burns SM, Warner BK. Targeting the pancreatic b-cell to treat diabetes. Nat Rev Drug Discov. 2014;13:278–89.

    Article  CAS  PubMed  Google Scholar 

  81. Wang Z, York NW, Nichols CG, Remedi MS. Pancreatic β-cell dedifferentiation in diabetes and re-differentiation following insulin therapy. Cell Metab. 2014;19:872–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lorenzo PI, Fuente-Martín E, Brun T, et al. PAX4 defines an expandable β-cell subpopulation in the adult pancreatic islet. Sci Rep. 2015;5:15672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Shirakawa J, Fernandez M, Takatani T, et al. Insulin signaling regulates the FoxM1/PLK1/CENP-A pathway to promote adaptive pancreatic β cell proliferation. Cell Metab. 2017;25:868–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Bock T, Pakkenberg B, Buschard K. Increased islet volume but unchanged islet number in ob/ob mice. Diabetes. 2003;52:1716–22.

    Article  CAS  PubMed  Google Scholar 

  85. Fransson L, Franzén S, Rosengren V, et al. β-cell adaptation in a mouse model of glucocorticoid-induced metabolic syndrome. J Endocrinol. 2013;219:231–41.

    Article  CAS  PubMed  Google Scholar 

  86. Maiztegui B, Borelli MI, Raschia MA, Zotto HHD, Gagliardino JJ. Islet adaptive changes to fructose-induced insulin resistance: β-cell mass, glucokinase, glucose metabolism, and insulin secretion. J Endocrinol. 2009;200:139–49.

    Article  CAS  PubMed  Google Scholar 

  87. Rizkalla SW. Health implications of fructose consumption: a review of recent data. Nutr Metab (Lond). 2010;7:82.

    Article  PubMed  Google Scholar 

  88. Prentki M, Nolan CJ. Islet B cell failure in type 2 diabetes. J Clin Invest. 2006;116:1802–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Jones A, Danielson KM, Benton MC, et al. miRNA Signatures of insulin resistance in obesity. Obesity. 2017;25:1734–44.

    Article  CAS  PubMed  Google Scholar 

  90. Guay C, Regazzi R. MicroRNAs and the functional cell mass: for better or worse. Diabetes Metab. 2015;41:369–77.

    Article  CAS  PubMed  Google Scholar 

  91. Kalis M, Bolmeson C, Esguerra JLS, et al. Beta-cell specific deletion of Dicer1 leads to defective insulin secretion and diabetes mellitus. PLoS One. 2011;6:e29166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Fischer-Posovszky P, Roos J, Kotnik P, et al. Functional significance and predictive value of MicroRNAs in pediatric obesity: tiny molecules with huge impact? Horm Res Paediatr. 2016;86:3–10.

    Article  CAS  PubMed  Google Scholar 

  93. Peng Y, Yu S, Li H, et al. MicroRNAs: emerging roles in adipogenesis and obesity. Cell Signal. 2015;26:1886–96.

    Google Scholar 

  94. Grieco E, Brusco N, Licata G, et al. Landscape of microRNAs in cell: between phenotype maintenance and protection. Int J Mol Sci. 2021;22:803–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Esguerra JLS, Bolmeson C, Cilio CM, Eliasson L. Differential glucose-regulation of MicroRNAs in pancreatic islets of non-obese type 2 diabetes model Goto-Kakizaki Rat. PLoS One. 2011;6:e18613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Gaddam RR, Kim Y-R, Li Q, et al. Genetic deletion of miR-204 improves glycemic control despite obesity in db/db mice. Biochem Biophys Res Commun. 2020;532:167–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lovis P, Roggli E, Laybutt DR, et al. Alterations in microRNA expression contribute to fatty acid–induced pancreatic β-cell dysfunction. Diabetes. 2008;57:2728–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Green DR, Kroemer G. Cytoplasmic functions of the tumour suppressor p53. Nature. 2009;458:1127–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Zhang X-D, Qin Z-H, Wang J. The role of p53 in cell metabolism. Acta Pharmacol Sin. 2010;31:1208–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Vienberg S, Geiger J, Madsen S, Dalgaard LT. MicroRNAs in metabolism. Acta Physiol. 2017;219:346–61.

    Article  CAS  Google Scholar 

  101. Belongie K, Ferrannini E, Johnson K, et al. Identification of novel biomarkers to monitor β-cell function and enable early detection of type 2 diabetes risk. PLoS One. 2017;12:e0182932.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Zhu Y, You W, Wang H, et al. MicroRNA-24/MODY gene regulatory pathway mediates pancreatic β-cell dysfunction. Diabetes. 2013;62:3194–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Nesca V, Guay C, Jacovetti C, et al. Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes. Diabetologia. 2013;56:2203–12.

    Article  CAS  PubMed  Google Scholar 

  104. Shaer A, Azarpira N, Karimi MH. Differentiation of human induced pluripotent stem cells into insulin-like cell clusters with miR-186 and miR-375 by using chemical transfection. Appl Biochem Biotechnol. 2014;174:242–58.

    Article  CAS  PubMed  Google Scholar 

  105. Regazzi R. MicroRNAs as therapeutic targets for the treatment of diabetes mellitus and its complications. Expert Opin Ther Targets. 2018;22:153–60.

    Article  CAS  PubMed  Google Scholar 

  106. Accili D. Can COVID-19 cause diabetes? Nat Metab. 2021;3:123–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Shang J, Wan Y, Luo C, et al. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci U S A. 2020;117:11727–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ibrahim S, Monaco GS, Sims EK. Not so sweet and simple: impacts of SARS-CoV-2 on the β cell. Islets. 2021;13:66–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Geravandi S, Mahmoudi-aznaveh A, Azizi Z, Maedler K, Ardestani A. SARS-CoV-2 and pancreas: a potential pathological interaction? Trends Endocrinol Metab. 2021;32:842–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Hayden MR. An immediate and long-term complication of COVID-19 may be type 2 diabetes mellitus: the central role of β-cell dysfunction, apoptosis and exploration of possible mechanisms. Cell. 2020;9:2475–98.

    Article  CAS  Google Scholar 

  111. Wu C-T, Lidsk PV, Xiao Y, et al. SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment. Cell Metab. 2021;33:1565–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Steenblock C, Richter S, Berger I, et al. Viral infiltration of pancreatic islets in patients with COVID-19. Nat Commun. 2021;12:3534.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Coate KC, Cha J, Shrestha S, et al. SARS-CoV-2 cell entry factors ACE2 and TMPRSS2 are expressed in the microvasculature and ducts of human pancreas but are not enriched in β cells. Cell Metab. 2020;32:1028–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Further Reading

  • Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54(6):1615–25. The author presents a unified mechanism that links overproduction of superoxide by the mitochondrial electron-transport chain to high glucose-mediated damage and diabetes complications. This paper provides the basis for understanding of the origin of ROS and oxidative stress in diabetes.

    Article  CAS  PubMed  Google Scholar 

  • Grieco E, Brusco N, Licata G, Fignani D, Formichi C, Nigi L, Sebastiani G, Dotta F. Landscape of microRNAs in cell: between phenotype maintenance and protection. Int J Mol Sci. 2021;22:803–21. https://doi.org/10.3390/ijms22020803. This review is about the most important miRNAs regulating the maintenance and the robustness of β cell identity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hasnain SZ, et al. Oxidative and endoplasmic reticulum stress in b-cell dysfunction in diabetes. J Mol Endocrinol. 2016;56:R33–54. https://doi.org/10.1530/JME-15-0232. Here, the importance of deleterious effects of oxidative stress and endoplasmic reticulum stress-induced unfolded protein response is evaluated on β-cell insulin synthesis and secretion as well as on inflammatory signaling and apoptosis. Additionally, the authors describe recent findings on how inflammatory cytokines contribute to β-cell dysfunction and protect interleukin 22.

    Article  CAS  PubMed  Google Scholar 

  • Hayden MR. An immediate and long-term complication of COVID-19 may be type 2 diabetes mellitus: the central role of β-cell dysfunction, apoptosis and exploration of possible mechanisms. Cell. 2020;9:2475–98. https://doi.org/10.3390/cells9112475. The author review COVID-19 participation on development of type 2 diabetes.

    Article  CAS  Google Scholar 

  • Hudish LI, Reusch JE, Sussel L. β Cell dysfunction during progression of metabolic syndrome to type 2 diabetes. J Clin Investig. 2019;129:4001–8. https://doi.org/10.1172/JCI129188. These authors focus on the current understanding from rodent and human studies of the progression of β cell responses during the development of MetS.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kaufman B, et al. Mitochondrial regulation of β-cell function: maintaining the momentum for insulin release. Mol Aspects Med. 2015;42:91–104. https://doi.org/10.1016/j.mam.2015.01.004. Pancreatic β-cell function and insulin release is mitochondria dependent. In this work, the authors review mitochondrial metabolism and control of mitochondrial mass as they relate to pancreatic β-cell function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ortega-Camarillo C, et al. The role of p53 in pancreatic β-cell apoptosis. Immunoendocrinology. 2015;2:e1075. https://doi.org/10.14800/ie.1075. © 2015. This paper examines p53 mobilization to a mitochondrion and its phosphorylation, as well as the activation of the intrinsic route of β-cell apoptosis by hyperglycemia. They also describe how hyperglycemia affects the p53 degradation pathways.

    Article  Google Scholar 

  • Sharma RB, Alonso LC. Lipotoxicity in the pancreatic beta cell: not just survival and function, but proliferation as well? Curr Diab Rep. 2014;14(6):492. https://doi.org/10.1007/s11892-014-0492-2. This paper reviews free fatty acids’ (FFAs) positive and negative effects on beta cell survival and insulin secretion. It also examines strong new findings that lipids may also impair compensatory beta cell proliferation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Strycharz J, et al. Is p53 involved in tissue-specific insulin resistance formation? Oxid Med Cell Longev. 2017;2017:9270549, 23p. https://doi.org/10.1155/2017/9270549. The protein p53 is connected with metabolic defects underlying cellular aging, obesity, inflammation and β-cells apoptosis. Additionally, the authors discuss p53 regulation of multiple biochemical processes such as glycolysis, oxidative phosphorylation, lipolysis, lipogenesis, 𝛽-oxidation, gluconeogenesis, and glycogen synthesis.

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  1. Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Torreón, Coahuila, Mexico

    Clara Ortega Camarillo

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    Joel Rodriguez-Saldana

Glossary

Adipokines

Cytokines (cell signaling proteins) secreted by adipose tissue.

Amylin

A 37-amino acid peptide hormone, discovered in 1987, which is co-located and co-secreted with insulin by the pancreatic beta-cells in response to nutrient stimuli.

Antioxidant

Molecule that inhibits the oxidation of other molecules.

Apoptosis (a-po-toe-sis)

Was first used by Kerr, Wyllie, and Currie in 1972 to describe a morphologically distinct form of cell death and energy-dependent biochemical mechanisms.

Apoptosome

Molecular complex of two major components—the adapter protein apoptotic protease activating factor 1 (Apaf1) and the pro caspase-9. These are assembled during apoptosis upon Apaf1 interaction with cytochrome c. Apoptosome assembly triggers effector caspase activation.

Cardiolipin

Phospholipid important of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid composition.

Caspase (cysteine-aspartic proteases, cysteine aspartases, or cysteine-dependent aspartate-directed proteases)

Family of protease enzymes playing essential roles in apoptosis and inflammation.

Ceramides

Family of waxy lipid molecules. A ceramide is composed of sphingosine and a fatty acid.

Cytochrome c

Heme protein serving as electron carrier in respiration. Cytochrome c is also an intermediate of apoptosis.

Cytokines

Cell signaling small proteins. Involved in autocrine signalling, paracrine signalling, and endocrine signalling as immunomodulating agents

Dedifferentiation process

Processes by which cell that were specialized for a specific function lose their specialization.

Fission

Division of mitochondria into new mitochondria.

Flavoprotein

Proteins that contain a nucleic acid derivative of riboflavin: the flavin adenine dinucleotide (FAD) or flavin mononucleotide (FMN).

Fusion

Process mediated by several large GTPases whose combined effects lead to the dynamic mitochondrial networks seen in many cell types.

Glucolipotoxicity

Combined, deleterious effects of elevated glucose, and fatty acid levels on pancreatic beta-cell function and survival.

Hyperlipidemia

Elevation of fats or lipids in the blood.

Hyperplasia

Enlargement of an organ or tissue caused by an increase in the cell proliferation rate.

Inflammasome

A multiprotein cytoplasmic complex which activates one or more caspases, leading to the processing and secretion of pro-inflammatory cytokines—e.g., IL-1 beta, IL-18, and IL-33. Assembly of inflammasomes depends on the NOD-like receptor family members, such as the NALP proteins kinase: enzyme-catalyzing phosphorylation of an acceptor molecule by ATP.

Misfolded proteins

Are proteins structurally abnormal, and thereby disrupt the function of cells, tissues, and organs. Proteins that fail to fold into their normal configuration; in this misfolded state, the proteins can become noxious in some way and can lose their normal function.

Mitofusins

Proteins that participate in mitochondrial fusion.

Necrosis

Morphological changes in cell death caused by enzymatic degradation.

Neogenesis

Generation of new cells.

Oxidative stress

Pathological changes in living organisms in response to excessive levels of intracellular free radicals.

Proenzyme

Precursor of an enzyme, requiring some change (hydrolysis of an inhibiting fragment that masks an active grouping) to render it active form.

Proteasome

An intracellular complex enzymatic that degrades misfolded or damaged proteins (proteolysis), after damaged proteins are tagged by ubiquitin.

Resistance to insulin

Pathological condition in which cells fail to respond normally to the hormone insulin.

RING finger domain

Really interesting new gene-finger is a proteins domain that plays a key role in the ubiquitination process.

Stem cells

Undifferentiated biological cells that can differentiate into specialized cells and can divide.

Sumoylation

Small ubiquitin-like modifier (or SUMO) proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. Post-translational modification involved in various cellular processes.

Triacylglycerol

Ester of glycerol with three molecules of fatty acid.

Ubiquitin

Small (8.5 kDa) regulatory protein that has been found in almost all tissues (ubiquitously) of eukaryotic organisms and regulated proteolysis.

Ubiquitin ligase

Protein that recruits, recognizes a protein substrate, and catalyzes the transfer of ubiquitin from the E2 enzyme to the protein substrate.

Uncoupling proteins

Proteins that uncouples phosphorylation of ADP from electron transport.

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Camarillo, C.O. (2023). Dysfunction and Death of Pancreatic Beta-Cells in Type 2 Diabetes. In: Rodriguez-Saldana, J. (eds) The Diabetes Textbook. Springer, Cham. https://doi.org/10.1007/978-3-031-25519-9_13

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  • DOI: https://doi.org/10.1007/978-3-031-25519-9_13

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  • Publisher Name: Springer, Cham

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