Advertisement

Dysfunction and Death of Pancreatic Beta Cells in Type 2 Diabetes

  • Clara Ortega-Camarillo
Chapter

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 cytokines accumulation. The latter is 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 induce 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 treatment of diabetic patients.

Keywords

Beta-cell dysfunction Apoptosis Oxidative stress Mitochondria p53 Glucolipotoxicity 

Abbreviations

°OH

Hydroxyl radical

8-OHdG

8-hydroxy-2′-deoxyguanosine

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 1–4 domains

Bok

Bcl-2 related ovarian killer

Caspase

Cysteine-aspartic proteases, cysteine aspartases

CHOP

C/EBP homologous protein

ChREBP

Carbohydrate response element binding protein

Drp1

Dynamin-related protein 1

eif2α

Eukaryotic translation initiation factor 2α

ER

Endoplasmic reticulum

ERS

Endoplasmic reticulum stress

EZH2

Enhancer of zeste homologue 2

FADD

Fas-associated death domain

Fas

Death receptor

FFA

Free fatty acids

Fis1

Mitochondrial fission 1 protein

FOXA1/2

Forkhead box A1/2

G3P

Glyceraldehyde 3-phosphate

GADD34

Downstream growth arrest and DNA damage-inducible protein

GAPDH

Glyceraldehyde 3-phosphate dehydrogenase

GATA4/6

GATA-binding protein 4/6

GLUT

Glucose transporter

GSIS

Glucose-stimulated insulin secretion

H3K27me3

Histone H3 tri methyl K27

HNF1β

Hepatocyte nuclear factor 1β

IAPP

Islet amyloid polypeptide

IFNγ

Interferon gamma

IGF1

Insulin-like growth factor 1

IL-1β

Interleukin 1 beta

iNOS

Inducible nitric oxide synthases

Ins

Insulin gene

INS1

Insulin-secreting beta cell-derived line

IRE1α

Inositol-requiring enzyme 1α

IRS-2

Insulin receptor substrate-2

Isl

Islet

MafA

Musculoaponeurotic 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 domains-containing protein 3

NLRs

Nucleotide oligomerization domain (NOD)-like receptors

NO

Nitric oxide

NOD

Nucleotide oligomerization domain

Notch

Transcription factor

O.-2

Superoxide anion

O-GlcNAc

O-linked β-N-acetylglucosamine

Opa1

Opa1 mitochondrial dynamin like GTPase

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-kinase

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 6

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

ΔΨm

Mitochondrial membrane potential

Notes

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 procaspase-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 signaling, paracrine signaling, and endocrine signaling 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 proinflammatory 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 protein 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. Posttranslational 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 uncouple phosphorylation of ADP from electron transport.

References

  1. 1.
    Ortega-Camarillo C, Guzmán-Grenfell AM, García-Macedo R, Rosales-Torres AM, Ávalos-Rodríguez A, Duran-Reyes G, et al. Hyperglycemia induces apoptosis and p53 mobilization to mitochondria in RINm5F cells. Mol Cell Biochem. 2006;281:163–70.PubMedCrossRefGoogle Scholar
  2. 2.
    Hinault C, Kawamori D, Liew CW, Maier B, Hu J, Keller SR, et al. D40 isoform of p53 controls β-cell proliferation and glucose homeostasis in mice. Diabetes. 2011;60:1210–22.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Jurczyk A, Bortell R, Alonso LC. Human β-cell regeneration: progress, hurdles, and controversy. Curr Opin Endocrinol Diabetes Obes. 2014;21(2):102–8.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    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.Google Scholar
  5. 5.
    Oliver-Krasinski JM, Stoffers DA. On the origin of the β cell. Genes Dev. 2008;22(15):1998–2021.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Meier JJ, Butler AE, Saisho Y, Monchamp T, Galasso R, Bhushan A, et al. β-Cell replication is the primary mechanism subserving the postnatal expansion of β-cell mass in humans. Diabetes. 2008;57(6):1584–94.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Mizukami H, Takahashi K, Inaba W, Osonoi S, Kamata K, Tsuboi K, et al. Age-associated changes of islet endocrine cells and the effects of body mass index in Japanese. J Diabetes Investig. 2014;5(1):38–47.PubMedCrossRefGoogle Scholar
  9. 9.
    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 Asp Med. 2015;42:19–41.  https://doi.org/10.1016/j.mam.2014.12.002.CrossRefGoogle Scholar
  10. 10.
    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.PubMedCrossRefGoogle Scholar
  11. 11.
    Khadra A, Schnell S. Development, growth and maintenance of β-cell mass: models are also part of the story. Mol Asp Med. 2015;42:78–90.CrossRefGoogle Scholar
  12. 12.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Meier JJ. Beta cell mass in diabetes: a realistic therapeutic target? Diabetologia. 2008;51:703–13.PubMedCrossRefGoogle Scholar
  14. 14.
    Unger RH. Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology. 2003;144(12):5159–65.PubMedCrossRefGoogle Scholar
  15. 15.
    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(9):2755–63.PubMedCrossRefGoogle Scholar
  16. 16.
    Thornberry AN, Lazebnik Y. Caspases: enemies within. Science. 1998;281:1312–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Schwartzman RA, Cidlowski JA. Apoptosis: the biochemistry and molecular biology of programmed cell death. Endocr Rev. 1993;14(2):133–51.PubMedGoogle Scholar
  18. 18.
    Höppener JW, Ahrén B, Lips CJ. Islet amyloid and type 2 diabetes mellitus. N Engl J Med. 2000;343(9):411–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Tomita T. Apoptosis in pancreatic β-islet cells in type 2 diabetes. Bosn J Basic Med Sci. 2016;16(3):162–79.  https://doi.org/10.17305/bjbms.2016.919.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    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(4):606–11.PubMedCrossRefGoogle Scholar
  21. 21.
    Robertoson RP. β-cell deterioration during diabetes: what’s in the gun? Trends Endocrinol Metab. 2009;20(8):388–93.CrossRefGoogle Scholar
  22. 22.
    Kajimoto Y, Watada H, Matsuoka T-a, Kaneto H, Fujitani Y, Miyazaki J-i, 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(7):1840–6.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Federici M, Hribal M, Perego L, Ranalli M, Caradonna Z, Perego C, 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.PubMedCrossRefGoogle Scholar
  24. 24.
    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.PubMedCrossRefGoogle Scholar
  25. 25.
    Kim W-H, Lee JW, Suh YH, Hong SH, Choi JS, Lim JH, et al. Exposure to chronic high glucose induces β-cell apoptosis through decreased interaction of glucokinase with mitochondria. Diabetes. 2005;54:2602–11.PubMedCrossRefGoogle Scholar
  26. 26.
    Piro S, Anello M, Pietro CD, Lizzio MN, Patanè G, Rabuazzo AM, 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(10):1340–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Chan CB, Saleh MC, Koshkin V, Wheeler MB. Uncoupling protein 2 and islet function. Diabetes. 2004;53:S136–S42.PubMedCrossRefGoogle Scholar
  28. 28.
    Joseph JW, Koshkin V, Saleh MC, Sivitz WI, Zhang C-Y, Lowell BB, et al. Free fatty acid-induced -cell defects are dependent on uncoupling protein 2 expression. J Biol Chem. 2004;279(49):51049–56.PubMedCrossRefGoogle Scholar
  29. 29.
    Laybutt DR, Preston AM, Åkerfeldt MC, Kench JG, Busch AK, Biankin AV, et al. Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia. 2007;50(4):752–63.PubMedCrossRefGoogle Scholar
  30. 30.
    Ogihara T, Mirmira RG. An islet in distress: β cell failure in type 2 diabetes. J Diabetes Investig. 2010;1(4):123–33.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Kelpe CL, Moore PC, Parazzoli SD, Wicksteed B, Rhodes CJ, Poitout V. Palmitate inhibition of insulin gene expression is mediated at the transcriptional level via ceramide synthesis. J Biol Chem. 2003;278:30015–21.PubMedCrossRefGoogle Scholar
  32. 32.
    Stein DT, Esser V, Stevenson BE, Lane KE, Whiteside JH, Daniels MB, et al. Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat. J Clin Invest. 1996;97(12):2728–35.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Véret J, Coant N, Berdyshev EV, Skobeleva A, Therville N, Bailbé D, 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.PubMedCrossRefGoogle Scholar
  34. 34.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Unger RH, Zhou Y-T. Lipotoxicity of b-cells in obesity and in other causes of fatty acid spillover. Diabetes. 2001;50(1):S118–S21.PubMedCrossRefGoogle Scholar
  36. 36.
    Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813–20.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Oliveira HR, Verlengia R, Carvalho CRO, Britto LRG, Curi R, Carpinelli AR. Pancreatic β-cells express phagocyte-like NAD(P)H oxidase. Diabetes. 2003;52(6):1457–63.PubMedCrossRefGoogle Scholar
  38. 38.
    Yan L-J. Pathogenesis of chronic hyperglycemia: From reductive stress to oxidative stress. Journal of Diabetes Research. 2014;2014:137919.PubMedPubMedCentralGoogle Scholar
  39. 39.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Brownlee M. The pathology of diabetic complications: a unifying mechanism. Diabetes. 2005;54:1615–25.PubMedCrossRefGoogle Scholar
  41. 41.
    Nishikawa T, Edelstein D, Du JX, Yamagishi S, Matsumura T, Kaneda Y, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;404:787–90.PubMedCrossRefGoogle Scholar
  42. 42.
    Maechler P, Wollheim CB. Mitochondrial function in normal and diabetic β-cells. Nature. 2001;414:807–12.PubMedCrossRefGoogle Scholar
  43. 43.
    Orrenius S, Zhivotovsky B. Cardiolipin oxidation sets cytochrome c free. Nat Chem Biol. 2005;1(4):188–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Ma ZA, Zhao Z, Turk J. Mitochondrial dysfunction and β-cell failure in type 2 diabetes mellitus. Exp Diabetes Res. 2012;2012(703538):1–11.CrossRefGoogle Scholar
  45. 45.
    Kaufman BA, Li C, Soleimanpour SA. Mitochondrial regulation of β-cell function: maintaining the momentum for insulin release. Mol Asp Med. 2015;2015(42):91–104.CrossRefGoogle Scholar
  46. 46.
    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(15):5409–20.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Hasnain SZ, Prins JB, McGuckin MA. Oxidative and endoplasmic reticulum stress in b-cell dysfunction in diabetes. J Mol Endocrinol. 2016;56:R33–54.PubMedCrossRefGoogle Scholar
  49. 49.
    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(Article ID 639762):9 pages  https://doi.org/10.1155/2012/639762.
  50. 50.
    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):492–508.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Cui W, Ma J, Wang X, Yang W, Zhang J, Ji Q. Free fatty acid induces endoplasmic reticulum stress and apoptosis of β-cells by Ca2+/Calpain-2 pathways. PLoS One. 2013;8(3):e59921.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Meigs JB, Wilson PWF, Fox CS, Vasan RS, Nathan DM, Sullivan LM, et al. Body mass index, metabolic syndrome, and risk of type 2 diabetes or cardiovascular disease. J Clin Endocrinol Metab. 2006;91(8):2906–12.PubMedCrossRefGoogle Scholar
  53. 53.
    Meier JJ, Bonadonna RC. Role of reduced Β-cell function in the pathogenesis of type 2 diabetes. Diabetes Care. 2013;36(2):S13–S9.Google Scholar
  54. 54.
    Cantley J, Ashcroft FM. Q&A: insulin secretion and type 2 diabetes: why do β-cells fail? BMC Biol. 2015;13:33–40.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Saisho Y, Butler AE, Manesso E, Elashoff D, Rizza RA, Butler PC. β-cell mass and turnover in humans: effects of obesity and aging. Diabetes Care. 2013;36:111–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Hull RL, Kodama K, Utzschneider KM, Carr DB, Prigeon RL, Kahn SE. 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(7):1350–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Cheng Z, Almeida FA. Mitochondrial alteration in type 2 diabetes and obesity. Cell Cycle. 2014;13(6):890–7.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Itariu BK, Stulnig TM. Autoimmune aspects of type 2 diabetes mellitus – a mini-review. Gerontology. 2014;60:189–96.PubMedCrossRefGoogle Scholar
  59. 59.
    Araki E, Oyadomari S, Mori M. Impact of endoplasmic reticulum stress pathway on pancreatic β-cells and diabetes mellitus. Exp Biol Med. 2003;228:1213–7.CrossRefGoogle Scholar
  60. 60.
    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(4):938–44.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Teff KL, Elliott SS, Tschöp M, Kieffer TJ, Rader D, Heiman 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(6):2963–72.PubMedCrossRefGoogle Scholar
  62. 62.
    Lowell B, Shulman I. Mitochondrial dysfunction and type 2 diabetes. Science. 2005;307:384–7.PubMedCrossRefGoogle Scholar
  63. 63.
    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.PubMedCrossRefGoogle Scholar
  64. 64.
    Arnelo U, Permert J, Larsson J, Reidelberger RD, Arnelo C, Adrian TE. 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.PubMedCrossRefGoogle Scholar
  65. 65.
    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.CrossRefGoogle Scholar
  66. 66.
    Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, et al. p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 2003;11(3):577–90.PubMedCrossRefGoogle Scholar
  67. 67.
    Ortega-Camarillo C, Flores-López LA, Ávalos-Rodríguez A. The role of p53 in pancreatic β-cell apoptosis. Immunoendocrinology. 2015;2:E1075.  https://doi.org/10.14800/Ie.1075.CrossRefGoogle Scholar
  68. 68.
    Balmanno K, Cook SJ. Tumour cell survival signalling by the ERK1/2 pathway. Cell Death Differ. 2009;16:368–77.PubMedCrossRefGoogle Scholar
  69. 69.
    Elkholi R, Chipuk JE. How do I kill thee? Let me count the ways: p53 regulates PARP-1 dependent necrosis. BioEssays. 2014;36(1):46–51.PubMedCrossRefGoogle Scholar
  70. 70.
    Lavin MF, Gueven N. The complexity of p53 stabilization and activation. Cell Death Differ. 2006;13:941–50.PubMedCrossRefGoogle Scholar
  71. 71.
    Flores-López LA, Díaz-Flores M, García-Macedo R, Ávalos-Rodríguez A, Vergara-Onofre M, Cruz M, et al. High glucose induces mitochondrial p53 phosphorylation by p38 MAPK in pancreatic RINm5F cells. Mol Biol Rep. 2013;40(8):4947–58.PubMedCrossRefGoogle Scholar
  72. 72.
    Yang WH, Kim JE, Nam HW, Ju JW, Kim HS, Kim YS, et al. Modification of p53 with O-linked N-acetylglucosamine regulates p53 activity and stability. Nat Cell Biol. 2006;8:1074–83.PubMedCrossRefGoogle Scholar
  73. 73.
    Flores-López LA, Cruz-López M, García-Macedo R, Gómez-Olivares JL, Díaz-Flores M, Konigsberg-Fainstein M, et al. Phosphorylation, ON-acetylglucosaminylation and poly-ADP-ribosylation of p53 in RINm5F cells cultured in high glucose. Free Radical Biol Med. 2012;53:S95.CrossRefGoogle Scholar
  74. 74.
    Ogawara Y, Kishishita S, Obata T, Isazawa Y, Suzuki T, Tanaka K, et al. Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Biol Chem. 2002;277(24):21843–50.PubMedCrossRefGoogle Scholar
  75. 75.
    Barzalobre-Gerónimo R, Flores-López LA, Baiza-Gutman LA, Cruz M, García-Macedo R, Ávalos-Rodríguez A, et al. Hyperglycemia promotes p53-Mdm2 interaction but reduces p53 ubiquitination in RINm5f cells. Mol Cell Biochem. 2015;405:257–64.  https://doi.org/10.1007/S11010-015-2416-0.PubMedCrossRefGoogle Scholar
  76. 76.
    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.PubMedCrossRefGoogle Scholar
  77. 77.
    Zhong L, Georgia S, Tschen S-i, Nakayama K, Nakayama K, Bhushan A. Essential role of Skp2-mediated p27 degradation in growth and adaptive expansion of pancreatic β cells. J Clin Invest. 2007;117(10):2869–76.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Vetere A, Choudhary A, Burns SM, Warner BK. Targeting the pancreatic β-cell to treat diabetes. Nat Rev Drug Discov. 2014;13:278–89.PubMedCrossRefGoogle Scholar
  79. 79.
    Wang Z, York NW, Nichols CG, Remedi MS. Pancreatic β-cell dedifferentiation in diabetes and re-differentiation following insulin therapy. Cell Metab. 2014;19(5):872–82.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Lorenzo PI, Fuente-Martín E, Brun T, Cobo-Vuilleumier N, Jimenez-Moreno CM, Gomez IGH, et al. PAX4 defines an expandable β-cell subpopulation in the adult pancreatic islet. Sci Rep. 2015;5:15672.PubMedPubMedCentralCrossRefGoogle Scholar

Suggested/Further Reading

  1. 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.Google Scholar
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. Strycharz J, et al. Is p53 involved in tissue-specific insulin resistance formation? Oxid Med Cell Longev 2017; Article ID 9270549, 23 p.  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.

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Clara Ortega-Camarillo
    • 1
  1. 1.Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro SocialMexico CityMexico

Personalised recommendations