Abstract
Diabetes occurs when β-cells no longer function properly or have been mostly destroyed. Pancreatic β-cell loss by apoptosis and other modes of death contributes to both autoimmune type 1 diabetes and type 2 diabetes. Programmed pancreatic β-cell death can be induced by multiple stresses in both major types of diabetes. There are also several rare forms of diabetes, including Wolcott-Rallison syndrome, Wolfram syndrome, as well as some forms of maturity onset diabetes of the young that are caused by mutations in genes that may play important roles in β-cell survival. The use of islet transplantation as a treatment for diabetes is also limited by excessive β-cell death. Mechanistic insights into the control of multiple modes of β-cell death are therefore important for the prevention and treatment of diabetes. Indeed, a substantial quantity of research has been dedicated to this area over the past decade. In this chapter, we will review the factors that influence the propensity of β-cells to die and the mechanisms of programmed cell death involved in the initiation and progression of diabetes.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- GLP-1:
-
Glucagon-like peptide 1
- MODY:
-
Maturity onset diabetes of the young
- NOD:
-
Nonobese diabetic
- UPR:
-
Unfolded protein response
- VNTR:
-
Variable number of tandem repeats
References
Alejandro EU, Johnson JD (2008) Inhibition of raf-1 alters multiple downstream pathways to induce pancreatic β-cell apoptosis. J Biol Chem 283(4):2407–2417
Barratt BJ et al (2004) Remapping the insulin gene/IDDM2 locus in type 1 diabetes. Diabetes 53(7):1884–1889
Beith JL, Alejandro EU, Johnson JD (2008) Insulin stimulates primary β-cell proliferation via Raf-1 kinase. Endocrinology 149(5):2251–2260
Bell GI, Polonsky KS (2001) Diabetes mellitus and genetically programmed defects in β-cell function. Nature 414(6865):788–791
Bennett ST, Todd JA (1996) Human type 1 diabetes and the insulin gene: principles of mapping polygenes. Annu Rev Genet 30:343–370
Boslem E et al (2011) A lipidomic screen of palmitate-treated MIN6 β-cells links sphingolipid metabolites with endoplasmic reticulum (ER) stress and impaired protein trafficking. Biochem J 435(1):267–276
Boslem E, Meikle PJ, Biden TJ (2012) Roles of ceramide and sphingolipids in pancreatic β-cell function and dysfunction. Islets 4(3):177–187
Boslem E et al (2013) Alteration of endoplasmic reticulum lipid rafts contributes to lipotoxicity in pancreatic β-cells. J Biol Chem 288(37):26569–26582
Butler AE et al (2003a) Increased β-cell apoptosis prevents adaptive increase in β-cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid. Diabetes 52(9):2304–2314
Butler AE et al (2003b) β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 52(1):102–110
Cardozo AK et al (2005) Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic β-cells. Diabetes 54(2):452–461
Chen J et al (2008) Thioredoxin-interacting protein: a critical link between glucose toxicity and β-cell apoptosis. Diabetes 57(4):938–944
Chu KY et al (2010) ATP-citrate lyase reduction mediates palmitate-induced apoptosis in pancreatic β cells. J Biol Chem 285(42):32606–32615
Chu KY et al (2011) Differential regulation and localization of carboxypeptidase D and carboxypeptidase E in human and mouse β-cells. Islets 3(4):155–165
Chu KY et al (2012) Ubiquitin C-terminal hydrolase L1 is required for pancreatic β cell survival and function in lipotoxic conditions. Diabetologia 55(1):128–140
Clee SM et al (2006) Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus. Nat Genet 38(6):688–693
Cnop M et al (2005) Mechanisms of pancreatic β-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54(Suppl 2):S97–S107
Colli ML et al (2010) MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic β-cell responses to the viral by-product double-stranded RNA. Hum Mol Genet 19(1):135–146
Danial NN et al (2008) Dual role of proapoptotic BAD in insulin secretion and β cell survival. Nat Med 14(2):144–153
David KK et al (2009) Parthanatos, a messenger of death. Front Biosci 14:1116–1128
Donath MY, Halban PA (2004) Decreased β-cell mass in diabetes: significance, mechanisms and therapeutic implications. Diabetologia 47(3):581–589
Dror V et al (2007) Notch signalling suppresses apoptosis in adult human and mouse pancreatic islet cells. Diabetologia 50(12):2504–2515
Dror V et al (2008a) Glucose and Endoplasmic Reticulum Calcium Channels Regulate HIF-1β via Presenilin in Pancreatic β-Cells. J Biol Chem 283(15):9909–9916
Dror V et al (2008b) Glucose and endoplasmic reticulum calcium channels regulate HIF-1β via presenilin in pancreatic β-cells. J Biol Chem 283(15):9909–9916
Ebato C et al (2008) Autophagy is important in islet homeostasis and compensatory increase of β cell mass in response to high-fat diet. Cell Metab 8(4):325–332
Efanova IB et al (1998) Glucose and tolbutamide induce apoptosis in pancreatic β-cells. A process dependent on intracellular Ca2+ concentration. J Biol Chem 273(50):33501–33507
Eguchi Y, Shimizu S, Tsujimoto Y (1997) Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res 57(10):1835–1840
Ehses JA et al (2007) Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56(9):2356–2370
Eizirik DL, Grieco FA (2012) On the immense variety and complexity of circumstances conditioning pancreatic β-cell apoptosis in type 1 diabetes. Diabetes 61(7):1661–1663
Eizirik DL, Cardozo AK, Cnop M (2008) The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 29(1):42–61
Eizirik DL et al (2012) The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines. PLoS Genet 8(3):e1002552
Eizirik DL, Miani M, Cardozo AK (2013) Signalling danger: endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation. Diabetologia 56(2):234–241
El-Assaad W et al (2003) Saturated fatty acids synergize with elevated glucose to cause pancreatic β-cell death. Endocrinology 144(9):4154–4163
Estella E et al (2006) Granzyme B-mediated death of pancreatic β-cells requires the proapoptotic BH3-only molecule bid. Diabetes 55(8):2212–2219
Federici M et al (2001) 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 50(6):1290–1301
Fink SL, Cookson BT (2005) Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect Immun 73(4):1907–1916
Fleming A et al (2011) Chemical modulators of autophagy as biological probes and potential therapeutics. Nat Chem Biol 7(1):9–17
Frisch SM, Francis H (1994) Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 124(4):619–626
Fujimoto K et al (2010) Loss of Nix in Pdx1-deficient mice prevents apoptotic and necrotic β cell death and diabetes. J Clin Invest 120(11):4031–4039
Galluzzi L et al (2009) Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes. Cell Death Differ 16(8):1093–1107
Galluzzi L et al (2012) Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 19(1):107–120
Garcia-Ocana A et al (2001) Using β-cell growth factors to enhance human pancreatic Islet transplantation. J Clin Endocrinol Metab 86(3):984–988
Golstein P, Kroemer G (2007) Cell death by necrosis: towards a molecular definition. Trends Biochem Sci 32(1):37–43
Guillen C et al (2008) Biphasic effect of insulin on β cell apoptosis depending on glucose deprivation. FEBS Lett 582(28):3855–3860
Gunton JE et al (2005) Loss of ARNT/HIF1β mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Cell 122(3):337–349
Gwiazda KS et al (2009) Effects of palmitate on ER and cytosolic Ca2+ homeostasis in β-cells. Am J Physiol Endocrinol Metab 296(4):E690–E701
Haataja L et al (2008) Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis. Endocr Rev 29(3):303–316
Harding HP, Ron D (2002) Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes 51(Suppl 3):S455–S461
Hennige AM et al (2003) Upregulation of insulin receptor substrate-2 in pancreatic β cells prevents diabetes. J Clin Invest 112(10):1521–1532
Horikawa Y et al (2000) Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26(2):163–175
Jeffrey KD et al (2008) Carboxypeptidase E mediates palmitate-induced β-cell ER stress and apoptosis. Proc Natl Acad Sci U S A 105(24):8452–8457
Johnson JD (2007) Pancreatic β-cell apoptosis in maturity onset diabetes of the young. Can J Diabetes 31(1):001–008
Johnson JD, Alejandro EU (2008) Control of pancreatic β-cell fate by insulin signaling: the sweet spot hypothesis. Cell Cycle 7(10):1343–1347
Johnson JD et al (2003) Increased islet apoptosis in Pdx1+/− mice. J Clin Invest 111(8):1147–1160
Johnson JD et al (2004) RyR2 and calpain-10 delineate a novel apoptosis pathway in pancreatic islets. J Biol Chem 279(23):24794–24802
Johnson JD et al (2006a) Insulin protects islets from apoptosis via Pdx1 and specific changes in the human islet proteome. Proc Natl Acad Sci U S A 103(51):19575–19580
Johnson JD et al (2006b) Suppressed insulin signaling and increased apoptosis in CD38-null islets. Diabetes 55(10):2737–2746
Johnson JD, et al. (2009) Different effects of FK506, rapamycin, and mycophenolate mofetil on glucose-stimulated insulin release and apoptosis in human islets. Cell Transpl 18(8):833–845
Jung HS et al (2008) Loss of autophagy diminishes pancreatic β cell mass and function with resultant hyperglycemia. Cell Metab 8(4):318–324
Kaneto H et al (2005) Oxidative stress and pancreatic β-cell dysfunction. Am J Ther 12(6):529–533
Kang R et al (2011) The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 18(4):571–580
Kim JS, He L, Lemasters JJ (2003) Mitochondrial permeability transition: a common pathway to necrosis and apoptosis. Biochem Biophys Res Commun 304(3):463–470
Kroemer G et al (2009) Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 16(1):3–11
Kroemer G, Marino G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40(2):280–293
Kulkarni RN et al (1999a) Tissue-specific knockout of the insulin receptor in pancreatic β cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 96(3):329–339
Kulkarni RN et al (1999b) Altered function of insulin receptor substrate-1-deficient mouse islets and cultured β-cell lines. J Clin Invest 104(12):R69–R75
Laybutt DR et al (2007) Endoplasmic reticulum stress contributes to β cell apoptosis in type 2 diabetes. Diabetologia 50(4):752–763
Lee B et al (1999) Glucose regulates expression of inositol 1,4,5-trisphosphate receptor isoforms in isolated rat pancreatic islets. Endocrinology 140(5):2173–2182
Leist M et al (1997) Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 185(8):1481–1486
Leonardi O, Mints G, Hussain MA (2003) β-cell apoptosis in the pathogenesis of human type 2 diabetes mellitus. Eur J Endocrinol 149(2):99–102
Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132(1):27–42
Levine B, Yuan J (2005) Autophagy in cell death: an innocent convict? J Clin Invest 115(10):2679–2688
Li Y et al (2005) β-Cell Pdx1 expression is essential for the glucoregulatory, proliferative, and cytoprotective actions of glucagon-like peptide-1. Diabetes 54(2):482–491
Liadis N et al (2005) Caspase-3-dependent β-cell apoptosis in the initiation of autoimmune diabetes mellitus. Mol Cell Biol 25(9):3620–3629
Liadis N et al (2007) Distinct in vivo roles of caspase-8 in β-cells in physiological and diabetes models. Diabetes 56(9):2302–2311
Lim GE, Piske M, Johnson JD (2013) 14-3-3 proteins are essential signalling hubs for β cell survival. Diabetologia 56(4):825–837
Lin CY et al (2005) Activation of peroxisome proliferator-activated receptor-gamma by rosiglitazone protects human islet cells against human islet amyloid polypeptide toxicity by a phosphatidylinositol 3′-kinase-dependent pathway. J Clin Endocrinol Metab 90(12):6678–6686
Lovell JF et al (2008) Membrane binding by tBid initiates an ordered series of events culminating in membrane permeabilization by Bax. Cell 135(6):1074–1084
Lu H et al (2008) The identification of potential factors associated with the development of type 2 diabetes: a quantitative proteomics approach. Mol Cell Proteomics 7(8):1434–1451
Luciani DS et al (2013) Bcl-2 and Bcl-xL suppress glucose signaling in pancreatic β-cells. Diabetes 62(1):170–182
Luo X, Kraus WL (2012) On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1. Genes Dev 26(5):417–432
Lupi R et al (2002) Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that β-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes 51(5):1437–1442
Lyssenko V, Groop L (2009) Genome-wide association study for type 2 diabetes: clinical applications. Curr Opin Lipidol 20(2):87–91
Lyssenko V et al (2008) Clinical risk factors, DNA variants, and the development of type 2 diabetes. N Engl J Med 359(21):2220–2232
Maedler K, Donath MY (2004) β-cells in type 2 diabetes: a loss of function and mass. Horm Res 62(Suppl 3):67–73
Maedler K et al (2004) Glucose- and interleukin-1β-induced β-cell apoptosis requires Ca2+ influx and extracellular signal-regulated kinase (ERK) 1/2 activation and is prevented by a sulfonylurea receptor 1/inwardly rectifying K+ channel 6.2 (SUR/Kir6.2) selective potassium channel opener in human islets. Diabetes 53(7):1706–1713
Maedler K et al (2005) Sulfonylurea induced β-cell apoptosis in cultured human islets. J Clin Endocrinol Metab 90(1):501–506
Marshall C et al (2005) Evidence that an isoform of calpain-10 is a regulator of exocytosis in pancreatic β-cells. Mol Endocrinol 19(1):213–224
Martinez SC et al (2008) Inhibition of Foxo1 protects pancreatic islet β-cells against fatty acid and endoplasmic reticulum stress-induced apoptosis. Diabetes 57(4):846–859
Mathis D, Vence L, Benoist C (2001) β-cell death during progression to diabetes. Nature 414(6865):792–798
McKenzie MD et al (2008) Proapoptotic BH3-only protein Bid is essential for death receptor-induced apoptosis of pancreatic β-cells. Diabetes 57(5):1284–1292
Mehran AE et al (2012) Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metab 16(6):723–737
Meier JJ et al (2008) β-cell replication is the primary mechanism subserving the postnatal expansion of β-cell mass in humans. Diabetes 57(6):1584–1594
Miao G et al (2006) Dynamic production of hypoxia-inducible factor-1α in early transplanted islets. Am J Transplant 6(11):2636–2643
Moore F et al (2009) PTPN2, a candidate gene for type 1 diabetes, modulates interferon-gamma-induced pancreatic β-cell apoptosis. Diabetes 58(6):1283–1291
Nogueira TC et al (2013) GLIS3, a susceptibility gene for type 1 and type 2 diabetes, modulates pancreatic β cell apoptosis via regulation of a splice variant of the BH3-only protein Bim. PLoS Genet 9(5):e1003532
Ohsugi M et al (2005) Reduced expression of the insulin receptor in mouse insulinoma (MIN6) cells reveals multiple roles of insulin signaling in gene expression, proliferation, insulin content, and secretion. J Biol Chem 280(6):4992–5003
Okada T et al (2007) Insulin receptors in β-cells are critical for islet compensatory growth response to insulin resistance. Proc Natl Acad Sci U S A 104(21):8977–8982
Otani K et al. (2004) Reduced β-cell mass and altered glucose sensing impair insulin-secretory function in βIRKO mice. Am J Physiol Endocrinol Metab 286(1):E41–9
Oyadomari S, Araki E, Mori M (2002) Endoplasmic reticulum stress-mediated apoptosis in pancreatic β-cells. Apoptosis 7(4):335–345
Ozcan U et al (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306(5695):457–461
Ozcan U et al (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313(5790):1137–1140
Pearson GL et al (2014) Lysosomal acid lipase and lipophagy are constitutive negative regulators of glucose-stimulated insulin secretion from pancreatic β cells. Diabetologia 57(1):129–139
Potter KJ et al (2009) Amyloid inhibitors enhance survival of cultured human islets. Biochim Biophys Acta 1790(6):566–574
Prentki M, Nolan CJ (2006) Islet β cell failure in type 2 diabetes. J Clin Invest 116(7):1802–1812
Preston AM et al (2009) Reduced endoplasmic reticulum (ER)-to-Golgi protein trafficking contributes to ER stress in lipotoxic mouse β cells by promoting protein overload. Diabetologia 52(11):2369–2373
Pugliese A et al (1997) The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 15(3):293–297
Rhodes CJ (2005) Type 2 diabetes-a matter of β-cell life and death? Science 307(5708):380–384
Riggs AC et al (2005) Mice conditionally lacking the Wolfram gene in pancreatic islet β cells exhibit diabetes as a result of enhanced endoplasmic reticulum stress and apoptosis. Diabetologia 48(11):2313–2321
Robertson RP et al (2004) β-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes. Diabetes 53(Suppl 1):S119–S124
Santin I et al (2011) PTPN2, a candidate gene for type 1 diabetes, modulates pancreatic β-cell apoptosis via regulation of the BH3-only protein Bim. Diabetes 60(12):3279–3288
Shu L et al (2008) Transcription factor 7-like 2 regulates β-cell survival and function in human pancreatic islets. Diabetes 57(3):645–653
Song B et al (2008) Chop deletion reduces oxidative stress, improves β cell function, and promotes cell survival in multiple mouse models of diabetes. J Clin Invest 118(10):3378–3389
Steer SA et al (2006) Interleukin-1 stimulates β-cell necrosis and release of the immunological adjuvant HMGB1. PLoS Med 3(2):e17
Stoy J et al (2007) Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci U S A 104(38):15040–15044
Szabat M et al (2012) Maintenance of β-cell maturity and plasticity in the adult pancreas: developmental biology concepts in adult physiology. Diabetes 61(6):1365–1371
Thomas HE et al (2009) β cell apoptosis in diabetes. Apoptosis 14(12):1389–1404
Trudeau JD et al (2000) Neonatal β-cell apoptosis: a trigger for autoimmune diabetes? Diabetes 49(1):1–7
Ueki K et al (2006) Total insulin and IGF-I resistance in pancreatic β cells causes overt diabetes. Nat Genet 38(5):583–588
Vandenabeele P et al (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11(10):700–714
Wang M et al (2013) Is dynamic autocrine insulin signaling possible? A mathematical model predicts picomolar concentrations of extracellular monomeric insulin within human pancreatic islets. PLoS ONE 8(6):e64860
Wobser H et al (2002) Dominant-negative suppression of HNF-1 α results in mitochondrial dysfunction, INS-1 cell apoptosis, and increased sensitivity to ceramide-, but not to high glucose-induced cell death. J Biol Chem 277(8):6413–6421
Yamada K et al (1999) Essential role of caspase-3 in apoptosis of mouse β-cells transfected with human Fas. Diabetes 48(3):478–483
Yang YH, Johnson JD (2013) Multi-parameter, single-cell, kinetic analysis reveals multiple modes of cell death in primary pancreatic β-cells. J Cell Sci 126(Pt 18):4286–95
Yang YH et al (2011) Paracrine signalling loops in adult human and mouse pancreatic islets: netrins modulate β cell apoptosis signalling via dependence receptors. Diabetologia 54(4):828–842
Yang YH et al (2013) Intraislet SLIT-ROBO signaling is required for β-cell survival and potentiates insulin secretion. Proc Natl Acad Sci U S A 110(41):16480–16485
Zehetner J et al (2008) PVHL is a regulator of glucose metabolism and insulin secretion in pancreatic β cells. Genes Dev 22(22):3135–3146
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer Science+Business Media Dordrecht
About this entry
Cite this entry
Johnson, J.D., Yang, Y.H.C., Luciani, D.S. (2015). Mechanisms of Pancreatic β-Cell Apoptosis in Diabetes and Its Therapies. In: Islam, M. (eds) Islets of Langerhans. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6686-0_14
Download citation
DOI: https://doi.org/10.1007/978-94-007-6686-0_14
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-6685-3
Online ISBN: 978-94-007-6686-0
eBook Packages: Biomedical and Life SciencesReference Module Biomedical and Life Sciences