Skip to main content
SpringerLink
Log in

Mechanisms of Pancreatic β-Cell Apoptosis in Diabetes and Its Therapies

  • Living reference work entry
  • First Online:
Islets of Langerhans, 2. ed.

  • 199 Accesses

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.

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

Access this chapter

Log in via an institution

Institutional subscriptions

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 beta-cell apoptosis. J Biol Chem 283(4):2407–2417

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Barratt BJ et al (2004) Remapping the insulin gene/IDDM2 locus in type 1 diabetes. Diabetes 53(7):1884–1889

    Article  PubMed  CAS  Google Scholar 

  • Beith JL, Alejandro EU, Johnson JD (2008) Insulin stimulates primary beta-cell proliferation via Raf-1 kinase. Endocrinology 149(5):2251–2260

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Bell GI, Polonsky KS (2001) Diabetes mellitus and genetically programmed defects in beta-cell function. Nature 414(6865):788–791

    Article  PubMed  CAS  Google Scholar 

  • Bennett ST, Todd JA (1996) Human type 1 diabetes and the insulin gene: principles of mapping polygenes. Annu Rev Genet 30:343–370

    Article  PubMed  CAS  Google Scholar 

  • Boslem E et al (2011) A lipidomic screen of palmitate-treated MIN6 beta-cells links sphingolipid metabolites with endoplasmic reticulum (ER) stress and impaired protein trafficking. Biochem J 435(1):267–276

    Article  PubMed  CAS  Google Scholar 

  • Boslem E, Meikle PJ, Biden TJ (2012) Roles of ceramide and sphingolipids in pancreatic beta-cell function and dysfunction. Islets 4(3):177–187

    Article  PubMed Central  PubMed  Google Scholar 

  • Boslem E et al (2013) Alteration of endoplasmic reticulum lipid rafts contributes to lipotoxicity in pancreatic beta-cells. J Biol Chem 288(37):26569–26582

    Article  PubMed  CAS  Google Scholar 

  • Butler AE et al (2003a) Increased beta-cell apoptosis prevents adaptive increase in beta-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

    Article  PubMed  CAS  Google Scholar 

  • Butler AE et al (2003b) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52(1):102–110

    Article  PubMed  CAS  Google Scholar 

  • 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 beta-cells. Diabetes 54(2):452–461

    Article  PubMed  CAS  Google Scholar 

  • Chen J et al (2008) Thioredoxin-interacting protein: a critical link between glucose toxicity and beta-cell apoptosis. Diabetes 57(4):938–944

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Chu KY et al (2010) ATP-citrate lyase reduction mediates palmitate-induced apoptosis in pancreatic beta cells. J Biol Chem 285(42):32606–32615

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Chu KY et al (2011) Differential regulation and localization of carboxypeptidase D and carboxypeptidase E in human and mouse beta-cells. Islets 3(4):155–165

    Article  PubMed  Google Scholar 

  • Chu KY et al (2012) Ubiquitin C-terminal hydrolase L1 is required for pancreatic beta cell survival and function in lipotoxic conditions. Diabetologia 55(1):128–140

    Article  PubMed  CAS  Google Scholar 

  • Clee SM et al (2006) Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus. Nat Genet 38(6):688–693

    Article  PubMed  CAS  Google Scholar 

  • Cnop M et al (2005) Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54(Suppl 2):S97–S107

    Article  PubMed  CAS  Google Scholar 

  • Colli ML et al (2010) MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic beta-cell responses to the viral by-product double-stranded RNA. Hum Mol Genet 19(1):135–146

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Danial NN et al (2008) Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat Med 14(2):144–153

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • David KK et al (2009) Parthanatos, a messenger of death. Front Biosci 14:1116–1128

    Article  CAS  Google Scholar 

  • Donath MY, Halban PA (2004) Decreased beta-cell mass in diabetes: significance, mechanisms and therapeutic implications. Diabetologia 47(3):581–589

    Article  PubMed  CAS  Google Scholar 

  • Dror V et al (2007) Notch signalling suppresses apoptosis in adult human and mouse pancreatic islet cells. Diabetologia 50(12):2504–2515

    Article  PubMed  CAS  Google Scholar 

  • Dror V et al (2008a) Glucose and Endoplasmic Reticulum Calcium Channels Regulate HIF-1{beta} via Presenilin in Pancreatic {beta}-Cells. J Biol Chem 283(15):9909–9916

    Article  PubMed  CAS  Google Scholar 

  • Dror V et al (2008b) Glucose and endoplasmic reticulum calcium channels regulate HIF-1beta via presenilin in pancreatic beta-cells. J Biol Chem 283(15):9909–9916

    Article  PubMed  CAS  Google Scholar 

  • Ebato C 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

    Article  PubMed  Google Scholar 

  • Efanova IB et al (1998) Glucose and tolbutamide induce apoptosis in pancreatic beta-cells. A process dependent on intracellular Ca2+ concentration. J Biol Chem 273(50):33501–33507

    Article  PubMed  CAS  Google Scholar 

  • Eguchi Y, Shimizu S, Tsujimoto Y (1997) Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res 57(10):1835–1840

    PubMed  CAS  Google Scholar 

  • Ehses JA et al (2007) Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56(9):2356–2370

    Article  PubMed  CAS  Google Scholar 

  • Eizirik DL, Grieco FA (2012) On the immense variety and complexity of circumstances conditioning pancreatic beta-cell apoptosis in type 1 diabetes. Diabetes 61(7):1661–1663

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Eizirik DL, Cardozo AK, Cnop M (2008) The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 29(1):42–61

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • El-Assaad W et al (2003) Saturated fatty acids synergize with elevated glucose to cause pancreatic beta-cell death. Endocrinology 144(9):4154–4163

    Article  PubMed  CAS  Google Scholar 

  • Estella E et al (2006) Granzyme B-mediated death of pancreatic beta-cells requires the proapoptotic BH3-only molecule bid. Diabetes 55(8):2212–2219

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Fink SL, Cookson BT (2005) Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect Immun 73(4):1907–1916

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Fleming A et al (2011) Chemical modulators of autophagy as biological probes and potential therapeutics. Nat Chem Biol 7(1):9–17

    Article  PubMed  CAS  Google Scholar 

  • Frisch SM, Francis H (1994) Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 124(4):619–626

    Article  PubMed  CAS  Google Scholar 

  • Fujimoto K et al (2010) Loss of Nix in Pdx1-deficient mice prevents apoptotic and necrotic beta cell death and diabetes. J Clin Invest 120(11):4031–4039

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Garcia-Ocana A et al (2001) Using beta-cell growth factors to enhance human pancreatic Islet transplantation. J Clin Endocrinol Metab 86(3):984–988

    PubMed  CAS  Google Scholar 

  • Golstein P, Kroemer G (2007) Cell death by necrosis: towards a molecular definition. Trends Biochem Sci 32(1):37–43

    Article  PubMed  CAS  Google Scholar 

  • Guillen C et al (2008) Biphasic effect of insulin on beta cell apoptosis depending on glucose deprivation. FEBS Lett 582(28):3855–3860

    Article  PubMed  CAS  Google Scholar 

  • Gunton JE et al (2005) Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Cell 122(3):337–349

    Article  PubMed  CAS  Google Scholar 

  • Gwiazda KS et al (2009) Effects of palmitate on er and cytosolic CA2+ homeostasis in {beta}-cells. Am J Physiol Endocrinol Metab 296(4):E690–E701

    Article  PubMed  CAS  Google Scholar 

  • Haataja L et al (2008) Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis. Endocr Rev 29(3):303–316

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Harding HP, Ron D (2002) Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes 51(Suppl 3):S455–S461

    Article  PubMed  CAS  Google Scholar 

  • Hennige AM et al (2003) Upregulation of insulin receptor substrate-2 in pancreatic beta cells prevents diabetes. J Clin Invest 112(10):1521–1532

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Jeffrey KD et al (2008) Carboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis. Proc Natl Acad Sci U S A 105(24):8452–8457

    Article  PubMed Central  PubMed  Google Scholar 

  • Johnson JD (2007) Pancreatic beta-cell apoptosis in maturity onset diabetes of the young. Can J Diabetes 31(1):001–008

    Google Scholar 

  • Johnson JD, Alejandro EU (2008) Control of pancreatic beta-cell fate by insulin signaling: the sweet spot hypothesis. Cell Cycle 7(10):1343–1347

    Article  PubMed  CAS  Google Scholar 

  • Johnson JD et al (2003) Increased islet apoptosis in Pdx1+/− mice. J Clin Invest 111(8):1147–1160

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Johnson JD et al (2004) RyR2 and calpain-10 delineate a novel apoptosis pathway in pancreatic islets. J Biol Chem 279(23):24794–24802

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Johnson JD et al (2006b) Suppressed insulin signaling and increased apoptosis in CD38-null islets. Diabetes 55(10):2737–2746

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  Google Scholar 

  • Jung HS et al (2008) Loss of autophagy diminishes pancreatic beta cell mass and function with resultant hyperglycemia. Cell Metab 8(4):318–324

    Article  PubMed  CAS  Google Scholar 

  • Kaneto H et al (2005) Oxidative stress and pancreatic beta-cell dysfunction. Am J Ther 12(6):529–533

    Article  PubMed  Google Scholar 

  • Kang R et al (2011) The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 18(4):571–580

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Kroemer G, Marino G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40(2):280–293

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Kulkarni RN et al (1999a) Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 96(3):329–339

    Article  PubMed  CAS  Google Scholar 

  • Kulkarni RN et al (1999b) Altered function of insulin receptor substrate-1-deficient mouse islets and cultured beta-cell lines. J Clin Invest 104(12):R69–R75

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Laybutt DR et al (2007) Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 50(4):752–763

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Leonardi O, Mints G, Hussain MA (2003) Beta-cell apoptosis in the pathogenesis of human type 2 diabetes mellitus. Eur J Endocrinol 149(2):99–102

    Article  PubMed  CAS  Google Scholar 

  • Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132(1):27–42

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Levine B, Yuan J (2005) Autophagy in cell death: an innocent convict? J Clin Invest 115(10):2679–2688

    Article  PubMed Central  PubMed  Google Scholar 

  • Li Y et al (2005) beta-Cell Pdx1 expression is essential for the glucoregulatory, proliferative, and cytoprotective actions of glucagon-like peptide-1. Diabetes 54(2):482–491

    Article  PubMed  CAS  Google Scholar 

  • Liadis N et al (2005) Caspase-3-dependent beta-cell apoptosis in the initiation of autoimmune diabetes mellitus. Mol Cell Biol 25(9):3620–3629

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Liadis N et al (2007) Distinct in vivo roles of caspase-8 in beta-cells in physiological and diabetes models. Diabetes 56(9):2302–2311

    Article  PubMed  CAS  Google Scholar 

  • Lim GE, Piske M, Johnson JD (2013) 14-3-3 proteins are essential signalling hubs for beta cell survival. Diabetologia 56(4):825–837

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Luciani DS et al (2013) Bcl-2 and Bcl-xL suppress glucose signaling in pancreatic beta-cells. Diabetes 62(1):170–182

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Lupi R et al (2002) Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes 51(5):1437–1442

    Article  PubMed  CAS  Google Scholar 

  • Lyssenko V, Groop L (2009) Genome-wide association study for type 2 diabetes: clinical applications. Curr Opin Lipidol 20(2):87–91

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Maedler K, Donath MY (2004) Beta-cells in type 2 diabetes: a loss of function and mass. Horm Res 62(Suppl 3):67–73

    Article  PubMed  CAS  Google Scholar 

  • Maedler K et al (2004) Glucose- and interleukin-1beta-induced beta-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

    Article  PubMed  CAS  Google Scholar 

  • Maedler K et al (2005) Sulfonylurea induced beta-cell apoptosis in cultured human islets. J Clin Endocrinol Metab 90(1):501–506

    Article  PubMed  CAS  Google Scholar 

  • Marshall C et al (2005) Evidence that an isoform of calpain-10 is a regulator of exocytosis in pancreatic beta-cells. Mol Endocrinol 19(1):213–224

    Article  PubMed  CAS  Google Scholar 

  • Martinez SC et al (2008) Inhibition of Foxo1 protects pancreatic islet beta-cells against fatty acid and endoplasmic reticulum stress-induced apoptosis. Diabetes 57(4):846–859

    Article  PubMed  CAS  Google Scholar 

  • Mathis D, Vence L, Benoist C (2001) Beta-cell death during progression to diabetes. Nature 414(6865):792–798

    Article  PubMed  CAS  Google Scholar 

  • McKenzie MD et al (2008) Proapoptotic BH3-only protein Bid is essential for death receptor-induced apoptosis of pancreatic beta-cells. Diabetes 57(5):1284–1292

    Article  PubMed  CAS  Google Scholar 

  • Mehran AE et al (2012) Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metab 16(6):723–737

    Article  PubMed  CAS  Google Scholar 

  • Meier JJ et al (2008) Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans. Diabetes 57(6):1584–1594

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Miao G et al (2006) Dynamic production of hypoxia-inducible factor-1alpha in early transplanted islets. Am J Transplant 6(11):2636–2643

    Article  PubMed  CAS  Google Scholar 

  • Moore F et al (2009) PTPN2, a candidate gene for type 1 diabetes, modulates interferon-gamma-induced pancreatic beta-cell apoptosis. Diabetes 58(6):1283–1291

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Nogueira TC et al (2013) GLIS3, a susceptibility gene for type 1 and type 2 diabetes, modulates pancreatic beta cell apoptosis via regulation of a splice variant of the BH3-only protein Bim. PLoS Genet 9(5):e1003532

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Okada T et al (2007) Insulin receptors in beta-cells are critical for islet compensatory growth response to insulin resistance. Proc Natl Acad Sci U S A 104(21):8977–8982

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Otani K et al. (2004) Reduced beta-cell mass and altered glucose sensing impair insulin-secretory function in betaIRKO mice. Am J Physiol Endocrinol Metab 286(1):E41–9

    Article  PubMed  CAS  Google Scholar 

  • Oyadomari S, Araki E, Mori M (2002) Endoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells. Apoptosis 7(4):335–345

    Article  PubMed  CAS  Google Scholar 

  • Ozcan U et al (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306(5695):457–461

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Pearson GL et al (2014) Lysosomal acid lipase and lipophagy are constitutive negative regulators of glucose-stimulated insulin secretion from pancreatic beta cells. Diabetologia 57(1):129–139

    Article  PubMed  CAS  Google Scholar 

  • Potter KJ et al (2009) Amyloid inhibitors enhance survival of cultured human islets. Biochim Biophys Acta 1790(6):566–574

    Article  PubMed  CAS  Google Scholar 

  • Prentki M, Nolan CJ (2006) Islet beta cell failure in type 2 diabetes. J Clin Invest 116(7):1802–1812

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Preston AM et al (2009) Reduced endoplasmic reticulum (ER)-to-Golgi protein trafficking contributes to ER stress in lipotoxic mouse beta cells by promoting protein overload. Diabetologia 52(11):2369–2373

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Rhodes CJ (2005) Type 2 diabetes-a matter of beta-cell life and death? Science 307(5708):380–384

    Article  PubMed  CAS  Google Scholar 

  • Riggs AC et al (2005) Mice conditionally lacking the Wolfram gene in pancreatic islet beta cells exhibit diabetes as a result of enhanced endoplasmic reticulum stress and apoptosis. Diabetologia 48(11):2313–2321

    Article  PubMed  CAS  Google Scholar 

  • Robertson RP et al (2004) Beta-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes. Diabetes 53(Suppl 1):S119–S124

    Article  PubMed  CAS  Google Scholar 

  • Santin I et al (2011) PTPN2, a candidate gene for type 1 diabetes, modulates pancreatic beta-cell apoptosis via regulation of the BH3-only protein Bim. Diabetes 60(12):3279–3288

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Shu L et al (2008) Transcription factor 7-like 2 regulates beta-cell survival and function in human pancreatic islets. Diabetes 57(3):645–653

    Article  PubMed  CAS  Google Scholar 

  • Song B et al (2008) Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. J Clin Invest 118(10):3378–3389

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Steer SA et al (2006) Interleukin-1 stimulates beta-cell necrosis and release of the immunological adjuvant HMGB1. PLoS Med 3(2):e17

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Szabat M et al (2012) Maintenance of beta-cell maturity and plasticity in the adult pancreas: developmental biology concepts in adult physiology. Diabetes 61(6):1365–1371

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Thomas HE et al (2009) Beta cell apoptosis in diabetes. Apoptosis 14(12):1389–1404

    Article  PubMed  Google Scholar 

  • Trudeau JD et al (2000) Neonatal beta-cell apoptosis: a trigger for autoimmune diabetes? Diabetes 49(1):1–7

    Article  PubMed  CAS  Google Scholar 

  • Ueki K et al (2006) Total insulin and IGF-I resistance in pancreatic beta cells causes overt diabetes. Nat Genet 38(5):583–588

    Article  PubMed  CAS  Google Scholar 

  • Vandenabeele P et al (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11(10):700–714

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Wobser H et al (2002a) Dominant-negative suppression of HNF-1 alpha 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

    Article  PubMed  CAS  Google Scholar 

  • Wobser H et al (2002b) Dominant-negative suppression of HNF-1 alpha 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

    Article  PubMed  CAS  Google Scholar 

  • Yamada K et al (1999) Essential role of caspase-3 in apoptosis of mouse beta-cells transfected with human Fas. Diabetes 48(3):478–483

    Article  PubMed  CAS  Google Scholar 

  • Yang YH, Johnson JD (2013) Multi-parameter, single-cell, kinetic analysis reveals multiple modes of cell death in primary pancreatic beta-cells. J Cell Sci 126(Pt 18):4286–95

    Article  PubMed  CAS  Google Scholar 

  • Yang YH et al (2011) Paracrine signalling loops in adult human and mouse pancreatic islets: netrins modulate beta cell apoptosis signalling via dependence receptors. Diabetologia 54(4):828–842

    Article  PubMed  CAS  Google Scholar 

  • Yang YH et al (2013) Intraislet SLIT-ROBO signaling is required for beta-cell survival and potentiates insulin secretion. Proc Natl Acad Sci U S A 110(41):16480–16485

    Article  PubMed Central  PubMed  Google Scholar 

  • Zehetner J et al (2008) PVHL is a regulator of glucose metabolism and insulin secretion in pancreatic beta cells. Genes Dev 22(22):3135–3146

    Article  PubMed Central  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Diabetes Research Group, Department of Cellular and Physiological Sciences, University of British Columbia, 5358 Life Sciences Building, V6T 1Z3, Vancouver, BC, Canada

    Prof. James D. Johnson

  2. Diabetes Research Group, Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, V6T 1Z3, Vancouver, BC, Canada

    Yu Hsuan Carol Yang

  3. Diabetes Research Program, Child & Family Research Institute, University of British Columbia, A4-146, 950W. 28th Avenue, V5Z 4H4, Vancouver, BC, Canada

    Dr. Dan S. Luciani

Authors
  1. Prof. James D. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu Hsuan Carol Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dr. Dan S. Luciani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James D. Johnson .

Editor information

Editors and Affiliations

  1. Södersjukhuset, Karolinska Institutet Dept. Clinical Research & Education, Stockholm, Sweden

    Md. Shahidul Islam

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media Dordrecht

About this entry

Cite this entry

Johnson, J.D., Yang, Y.C., Luciani, D.S. (2014). Mechanisms of Pancreatic β-Cell Apoptosis in Diabetes and Its Therapies. In: Islam, M. (eds) Islets of Langerhans, 2. ed.. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6884-0_14-2

Download citation

  • DOI: https://doi.org/10.1007/978-94-007-6884-0_14-2

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Dordrecht

  • Online ISBN: 978-94-007-6884-0

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation