Life and death of β cells in Type 1 diabetes: A comprehensive review

Journal of Autoimmunity

Volumn 71, Issue , 2016, Pages 51-58

  Wilcox, Nicholas S ^a   Rui, Jinxiu ^a   Hebrok, Matthias ^b   Herold, Kevan C ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Autoimmunity; Biomarkers; Imaging; Immune therapy; Neogenesis; Regeneration; Type 1 diabetes; cell death

Indexed keywords

DNA METHYLTRANSFERASE; BIOLOGICAL MARKER;

APOPTOSIS; B LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL DEATH; CELL DIFFERENTIATION; DISEASE COURSE; GLUCOSE TOLERANCE; HUMAN; IMMUNE RESPONSE; IMMUNOLOGICAL TOLERANCE; IMMUNOTHERAPY; INFLAMMATION; INSULIN DEPENDENT DIABETES MELLITUS; MACROPHAGE; METHYLATION; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; ADVERSE EFFECTS; ANIMAL; AUTOIMMUNITY; CELL SURVIVAL; DIABETES MELLITUS, TYPE 1; GENETIC PREDISPOSITION; GENETICS; IMMUNOLOGY; METABOLISM; NECROSIS; PANCREAS ISLET BETA CELL; PATHOLOGY; PHYSIOLOGICAL STRESS; PROCEDURES;

ANIMALS; AUTOIMMUNITY; BIOMARKERS; CELL DEATH; CELL SURVIVAL; DIABETES MELLITUS, TYPE 1; GENETIC PREDISPOSITION TO DISEASE; HUMANS; IMMUNOTHERAPY; INSULIN-SECRETING CELLS; NECROSIS; STRESS, PHYSIOLOGICAL;

EID: 84961784179     PISSN: 08968411     EISSN: 10959157     Source Type: Journal    
DOI: 10.1016/j.jaut.2016.02.001     Document Type: Review

References (73)

1. Hagopian W., Ferry R.J., Sherry N., Carlin D., Bonvini E., Johnson S., Stein K.E., Koenig S., Daifotis A.G., Herold K.C., Ludvigsson J. Teplizumab preserves C-peptide in recent-onset Type 1 diabetes: two-year results from the randomized, placebo-controlled protege trial. Diabetes 2013, 62:3901-3908.
2. Herold K.C., Gitelman S.E., Ehlers M.R., Gottlieb P.A., Greenbaum C.J., Hagopian W., Boyle K.D., Keyes-Elstein L., Aggarwal S., Phippard D., Sayre P.H., McNamara J., Bluestone J.A. Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset Type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders. Diabetes 2013, 62:3766-3774.
3. Herold K.C., Gitelman S.E., Masharani U., Hagopian W., Bisikirska B., Donaldson D., Rother K., Diamond B., Harlan D.M., Bluestone J.A. A single course of anti-CD3 monoclonal antibody hOKT3(gamma)1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of Type 1 diabetes. Diabetes 2005, 54:1763-1769.
4. Herold K.C., Gitelman S.E., Willi S.M., Gottlieb P.A., Waldron-Lynch F., Devine L., Sherr J., Rosenthal S.M., Adi S., Jalaludin M.Y., Michels A.W., Dziura J., Bluestone J.A. Teplizumab treatment may improve C-peptide responses in participants with Type 1 diabetes after the new-onset period: a randomised controlled trial. Diabetologia 2013, 56:391-400.
5. Herold K.C., Hagopian W., Auger J.A., Poumian-Ruiz E., Taylor L., Donaldson D., Gitelman S.E., Harlan D.M., Xu D., Zivin R.A., Bluestone J.A. Anti-CD3 monoclonal antibody in new-onset Type 1 diabetes mellitus. N. Engl. J. Med. 2002, 346:1692-1698.
6. Keymeulen B., Vandemeulebroucke E., Ziegler A.G., Mathieu C., Kaufman L., Hale G., Gorus F., Goldman M., Walter M., Candon S., Schandene L., Crenier L., De Block C., Seigneurin J.M., De Pauw P., Pierard D., Weets I., Rebello P., Bird P., Berrie E., Frewin M., Waldmann H., Bach J.F., Pipeleers D., Chatenoud L. Insulin needs after CD3-antibody therapy in new-onset Type 1 diabetes. N. Engl. J. Med. 2005, 352:2598-2608.
7. Keymeulen B., Walter M., Mathieu C., Kaufman L., Gorus F., Hilbrands R., Vandemeulebroucke E., Van de Velde U., Crenier L., De Block C., Candon S., Waldmann H., Ziegler A.G., Chatenoud L., Pipeleers D. Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset Type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia 2010, 53:614-623.
8. Orban T., Bundy B., Becker D.J., Dimeglio L.A., Gitelman S.E., Goland R., Gottlieb P.A., Greenbaum C.J., Marks J.B., Monzavi R., Moran A., Raskin P., Rodriguez H., Russell W.E., Schatz D., Wherrett D., Wilson D.M., Krischer J.P., Skyler J.S. Co-stimulation modulation with abatacept in patients with recent-onset Type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet 2011, 378:412-419.
9. Pescovitz M.D., Greenbaum C.J., Bundy B., Becker D.J., Gitelman S.E., Goland R., Gottlieb P.A., Marks J.B., Moran A., Raskin P., Rodriguez H., Schatz D.A., Wherrett D.K., Wilson D.M., Krischer J.P., Skyler J.S. B-lymphocyte depletion with rituximab and beta-cell function: two-year results. Diabetes Care 2014, 37:453-459.
10. Pescovitz M.D., Greenbaum C.J., Krause-Steinrauf H., Becker D.J., Gitelman S.E., Goland R., Gottlieb P.A., Marks J.B., McGee P.F., Moran A.M., Raskin P., Rodriguez H., Schatz D.A., Wherrett D., Wilson D.M., Lachin J.M., Skyler J.S. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N. Engl. J. Med. 2009, 361:2143-2152.
11. Rigby M., DiMeglio L., Rendell M., Felner E., Dostou J., Gitelman S., Patel C., Griffin K., Tsalikian E., Gottlieb P., Greenbaum C., Sherry N., Moore W., Roshanak M., Willi S., Raskin P., Moran A., Russell W., Pinckney A., Keyes-Elstein L., Howell M., Aggarwal S., Lim N., Phippard D., Nepom G., McNamara J., Ehlers M.R. Targeting effector memory T cells with alefacept in new onset Type 1 diabetes: 12 month results from the TIDAL study. Lancet Endocrinol. Metabol. 2013.
12. Rigby M.R., Harris K.M., Pinckney A., DiMeglio L.A., Rendell M.S., Felner E.I., Dostou J.M., Gitelman S.E., Griffin K.J., Tsalikian E., Gottlieb P.A., Greenbaum C.J., Sherry N.A., Moore W.V., Monzavi R., Willi S.M., Raskin P., Keyes-Elstein L., Long S.A., Kanaparthi S., Lim N., Phippard D., Soppe C.L., Fitzgibbon M.L., McNamara J., Nepom G.T., Ehlers M.R. Alefacept provides sustained clinical and immunological effects in new-onset Type 1 diabetes patients. J. Clin. Invest 2015, 125:3285-3296.
13. Keenan H.A., Sun J.K., Levine J., Doria A., Aiello L.P., Eisenbarth G., Bonner-Weir S., King G.L. Residual insulin production and pancreatic ss-cell turnover after 50 years of diabetes: joslin medalist study. Diabetes 2010, 59:2846-2853.
14. Oram R.A., Jones A.G., Besser R.E., Knight B.A., Shields B.M., Brown R.J., Hattersley A.T., McDonald T.J. The majority of patients with long-duration Type 1 diabetes are insulin microsecretors and have functioning beta cells. Diabetologia 2014, 57:187-191.
15. Eizirik D.L., Darville M.I. beta-cell apoptosis and defense mechanisms: lessons from Type 1 diabetes. Diabetes 2001, 50(Suppl. 1):S64-S69.
16. Akirav E.M., Baquero M.T., Opare-Addo L.W., Akirav M., Galvan E., Kushner J.A., Rimm D.L., Herold K.C. Glucose and inflammation control islet vascular density and beta-cell function in NOD mice: control of islet vasculature and vascular endothelial growth factor by glucose. Diabetes 2011, 60:876-883.
17. Jorns A., Arndt T., Meyer zu Vilsendorf A., Klempnauer J., Wedekind D., Hedrich H.J., Marselli L., Marchetti P., Harada N., Nakaya Y., Wang G.S., Scott F.W., Gysemans C., Mathieu C., Lenzen S. Islet infiltration, cytokine expression and beta cell death in the NOD mouse, BB rat, Komeda rat, LEW.1AR1-iddm rat and humans with Type 1 diabetes. Diabetologia 2014, 57:512-521.
18. Zhao Y., Scott N.A., Fynch S., Elkerbout L., Wong W.W., Mason K.D., Strasser A., Huang D.C., Kay T.W., Thomas H.E. Autoreactive T cells induce necrosis and not BCL-2-regulated or death receptor-mediated apoptosis or RIPK3-dependent necroptosis of transplanted islets in a mouse model of Type 1 diabetes. Diabetologia 2015, 58:140-148.
19. Kawasaki E., Abiru N., Eguchi K. Prevention of Type 1 diabetes: from the view point of beta cell damage. Diabetes Res. Clin. Pract. 2004, 66(Suppl. 1):S27-S32.
20. Thomas H.E., Kay T.W. Intracellular pathways of pancreatic beta-cell apoptosis in Type 1 diabetes. Diabetes Metab. Res. Rev. 2011, 27:790-796.
21. Wali J.A., Rondas D., McKenzie M.D., Zhao Y., Elkerbout L., Fynch S., Gurzov E.N., Akira S., Mathieu C., Kay T.W., Overbergh L., Strasser A., Thomas H.E. The proapoptotic BH3-only proteins bim and puma are downstream of endoplasmic reticulum and mitochondrial oxidative stress in pancreatic islets in response to glucotoxicity. Cell Death Dis. 2014, 5:e1124.
22. Vanlangenakker N., Vanden Berghe T., Krysko D.V., Festjens N., Vandenabeele P. Molecular mechanisms and pathophysiology of necrotic cell death. Curr. Mol. Med. 2008, 8:207-220.
23. Dorn G.W. Molecular mechanisms that differentiate apoptosis from programmed necrosis. Toxicol. Pathol. 2013, 41:227-234.
24. Marroqui L., Dos Santos R.S., Floyel T., Grieco F.A., Santin I., Op de Beeck A., Marselli L., Marchetti P., Pociot F., Eizirik D.L. TYK2, a candidate gene for Type 1 diabetes, modulates apoptosis and the innate immune response in human pancreatic beta-Cells. Diabetes 2015, 64:3808-3817.
25. Walter U., Franzke A., Sarukhan A., Zober C., von Boehmer H., Buer J., Lechner O. Monitoring gene expression of TNFR family members by beta-cells during development of autoimmune diabetes. Eur. J. Immunol. 2000, 30:1224-1232.
26. Stephens L.A., Thomas H.E., Ming L., Grell M., Darwiche R., Volodin L., Kay T.W. Tumor necrosis factor-alpha-activated cell death pathways in NIT-1 insulinoma cells and primary pancreatic beta cells. Endocrinology 1999, 140:3219-3227.
27. Cieslak M., Wojtczak A., Cieslak M. Role of pro-inflammatory cytokines of pancreatic islets and prospects of elaboration of new methods for the diabetes treatment. Acta Biochim. Pol. 2015, 62:15-21.
28. Cnop M., Welsh N., Jonas J.C., Jorns A., Lenzen S., Eizirik D.L. Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 2005, 54(Suppl. 2):S97-S107.
29. Irawaty W., Kay T.W., Thomas H.E. Transmembrane TNF and IFNgamma induce caspase-independent death of primary mouse pancreatic beta cells. Autoimmunity 2002, 35:369-375.
30. Kjorholt C., Akerfeldt M.C., Biden T.J., Laybutt D.R. Chronic hyperglycemia, independent of plasma lipid levels, is sufficient for the loss of beta-cell differentiation and secretory function in the db/db mouse model of diabetes. Diabetes 2005, 54:2755-2763.
31. Steil G.M., Trivedi N., Jonas J.C., Hasenkamp W.M., Sharma A., Bonner-Weir S., Weir G.C. Adaptation of beta-cell mass to substrate oversupply: enhanced function with normal gene expression. Am. J. Physiol. Endocrinol. Metab. 2001, 280:E788-E796.
32. Vernier S., Chiu A., Schober J., Weber T., Nguyen P., Luer M., McPherson T., Wanda P.E., Marshall C.A., Rohatgi N., McDaniel M.L., Greenberg A.S., Kwon G. Beta-cell metabolic alterations under chronic nutrient overload in rat and human islets. Islets 2012, 4:379-392.
33. Sherry N.A., Kushner J.A., Glandt M., Kitamura T., Brillantes A.M., Herold K.C. Effects of autoimmunity and immune therapy on beta-cell turnover in Type 1 diabetes. Diabetes 2006, 55:3238-3245.
34. Gaglia J.L., Guimaraes A.R., Harisinghani M., Turvey S.E., Jackson R., Benoist C., Mathis D., Weissleder R. Noninvasive imaging of pancreatic islet inflammation in Type 1A diabetes patients. J. Clin. Invest 2011, 121:442-445.
35. Gaglia J.L., Harisinghani M., Aganj I., Wojtkiewicz G.R., Hedgire S., Benoist C., Mathis D., Weissleder R. Noninvasive mapping of pancreatic inflammation in recent-onset Type-1 diabetes patients. Proc. Natl. Acad. Sci. U. S. A. 2015, 112:2139-2144.
36. Freeby M., Goland R., Ichise M., Maffei A., Leibel R., Harris P. VMAT2 quantitation by PET as a biomarker for beta-cell mass in health and disease. Diabetes Obes. Metab. 2008, 10(Suppl. 4):98-108.
37. Goland R., Freeby M., Parsey R., Saisho Y., Kumar D., Simpson N., Hirsch J., Prince M., Maffei A., Mann J.J., Butler P.C., Van Heertum R., Leibel R.L., Ichise M., Harris P.E. 11C-dihydrotetrabenazine PET of the pancreas in subjects with long-standing Type 1 diabetes and in healthy controls. J. Nucl. Med. 2009, 50:382-389.
38. Maffei A., Liu Z., Witkowski P., Moschella F., Del Pozzo G., Liu E., Herold K., Winchester R.J., Hardy M.A., Harris P.E. Identification of tissue-restricted transcripts in human islets. Endocrinology 2004, 145:4513-4521.
39. Souza F., Simpson N., Raffo A., Saxena C., Maffei A., Hardy M., Kilbourn M., Goland R., Leibel R., Mann J.J., Van Heertum R., Harris P.E. Longitudinal noninvasive PET-based beta cell mass estimates in a spontaneous diabetes rat model. J. Clin. Invest 2006, 116:1506-1513.
40. Reiner T., Thurber G., Gaglia J., Vinegoni C., Liew C.W., Upadhyay R., Kohler R.H., Li L., Kulkarni R.N., Benoist C., Mathis D., Weissleder R. Accurate measurement of pancreatic islet beta-cell mass using a second-generation fluorescent exendin-4 analog. Proc. Natl. Acad. Sci. U. S. A. 2011, 108:12815-12820.
41. Antkowiak P.F., Tersey S.A., Carter J.D., Vandsburger M.H., Nadler J.L., Epstein F.H., Mirmira R.G. Noninvasive assessment of pancreatic beta-cell function in vivo with manganese-enhanced magnetic resonance imaging. Am. J. Physiol. Endocrinol. Metab. 2009, 296:E573-E578.
42. Akirav E.M., Lebastchi J., Galvan E.M., Henegariu O., Akirav M., Ablamunits V., Lizardi P.M., Herold K.C. Detection of beta cell death in diabetes using differentially methylated circulating DNA. Proc. Natl. Acad. Sci. U. S. A. 2011, 108:19018-19023.
43. Husseiny M.I., Kaye A., Zebadua E., Kandeel F., Ferreri K. Tissue-specific methylation of human insulin gene and PCR assay for monitoring beta cell death. PLoS One 2014, 9:e94591.
44. Husseiny M.I., Kuroda A., Kaye A.N., Nair I., Kandeel F., Ferreri K. Development of a quantitative methylation-specific polymerase chain reaction method for monitoring beta cell death in Type 1 diabetes. PLoS One 2012, 7:e47942.
45. Usmani-Brown S., Lebastchi J., Steck A.K., Beam C., Herold K.C., Ledizet M. Analysis of beta-cell death in Type 1 diabetes by droplet digital PCR. Endocrinology 2014, 155:3694-3698.
46. Fisher M.M., Watkins R.A., Blum J., Evans-Molina C., Chalasani N., DiMeglio L.A., Mather K.J., Tersey S.A., Mirmira R.G. Elevations in circulating methylated and unmethylated preproinsulin DNA in new-onset Type 1 diabetes. Diabetes 2015, 64:3867-3872.
47. Herold K.C., Usmani-Brown S., Ghazi T., Lebastchi J., Beam C.A., Bellin M.D., Ledizet M., Sosenko J.M., Krischer J.P., Palmer J.P. beta Cell death and dysfunction during Type 1 diabetes development in at-risk individuals. J. Clin. Invest 2015, 125:1163-1173.
48. Lebastchi J., Deng S., Lebastchi A.H., Beshar I., Gitelman S., Willi S., Gottlieb P., Akirav E.M., Bluestone J.A., Herold K.C. Immune therapy and beta-cell death in Type 1 diabetes. Diabetes 2013, 62:1676-1680.
49. Lo Y.M., Zhang J., Leung T.N., Lau T.K., Chang A.M., Hjelm N.M. Rapid clearance of fetal DNA from maternal plasma. Am. J. Hum. Genet. 1999, 64:218-224.
50. Poy M.N., Hausser J., Trajkovski M., Braun M., Collins S., Rorsman P., Zavolan M., Stoffel M. miR-375 maintains normal pancreatic alpha- and beta-cell mass. Proc. Natl. Acad. Sci. U. S. A. 2009, 106:5813-5818.
51. Jiang L., Brackeva B., Ling Z., Kramer G., Aerts J.M., Schuit F., Keymeulen B., Pipeleers D., Gorus F., Martens G.A. Potential of protein phosphatase inhibitor 1 as biomarker of pancreatic beta-cell injury in vitro and in vivo. Diabetes 2013, 62:2683-2688.
52. Berney T., Mamin A., James Shapiro A.M., Ritz-Laser B., Brulhart M.C., Toso C., Demuylder-Mischler S., Armanet M., Baertschiger R., Wojtusciszyn A., Benhamou P.Y., Bosco D., Morel P., Philippe J. Detection of insulin mRNA in the peripheral blood after human islet transplantion predicts deterioration of metabolic control. Am. J. Transpl. 2006, 6:1704-1711.
53. Ritz-Laser B., Oberholzer J., Toso C., Brulhart M.C., Zakrzewska K., Ris F., Bucher P., Morel P., Philippe J. Molecular detection of circulating beta-cells after islet transplantation. Diabetes 2002, 51:557-561.
54. Marhfour I., Lopez X.M., Lefkaditis D., Salmon I., Allagnat F., Richardson S.J., Morgan N.G., Eizirik D.L. Expression of endoplasmic reticulum stress markers in the islets of patients with Type 1 diabetes. Diabetologia 2012, 55:2417-2420.
55. Puri S., Akiyama H., Hebrok M. VHL-mediated disruption of Sox9 activity compromises beta-cell identity and results in diabetes mellitus. Genes Dev. 2013, 27:2563-2575.
56. Puri S., Cano D.A., Hebrok M. A role for von Hippel-Lindau protein in pancreatic beta-cell function. Diabetes 2009, 58:433-441.
57. Corbett J.A., Sweetland M.A., Wang J.L., Lancaster J.R., McDaniel M.L. Nitric oxide mediates cytokine-induced inhibition of insulin secretion by human islets of Langerhans. Proc. Natl. Acad. Sci. U. S. A. 1993, 90:1731-1735.
58. Moran A., Bundy B., Becker D.J., Dimeglio L.A., Gitelman S.E., Goland R., Greenbaum C.J., Herold K.C., Marks J.B., Raskin P., Sanda S., Schatz D., Wherrett D.K., Wilson D.M., Krischer J.P., Skyler J.S., Pickersgill L., de Koning E., Ziegler A.G., Boehm B., Badenhoop K., Schloot N., Bak J.F., Pozzilli P., Mauricio D., Donath M.Y., Castano L., Wagner A., Lervang H.H., Perrild H., Mandrup-Poulsen T. Interleukin-1 antagonism in Type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet 2013, 381:1905-1915.
59. Meier J.J., Bhushan A., Butler A.E., Rizza R.A., Butler P.C. Sustained beta cell apoptosis in patients with long-standing Type 1 diabetes: indirect evidence for islet regeneration?. Diabetologia 2005, 48:2221-2228.
60. Pinkse G.G., Tysma O.H., Bergen C.A., Kester M.G., Ossendorp F., van Veelen P.A., Keymeulen B., Pipeleers D., Drijfhout J.W., Roep B.O. Autoreactive CD8 T cells associated with beta cell destruction in Type 1 diabetes. Proc. Natl. Acad. Sci. U. S. A. 2005, 102:18425-18430.
61. Herold K.C., Pescovitz M.D., McGee P., Krause-Steinrauf H., Spain L.M., Bourcier K., Asare A., Liu Z., Lachin J.M., Dosch H.M. Increased T cell proliferative responses to islet antigens identify clinical responders to anti-CD20 monoclonal antibody (Rituximab) therapy in Type 1 diabetes. J. Immunol. 2011, 187:1998-2005.
62. Couri C.E., Oliveira M.C., Stracieri A.B., Moraes D.A., Pieroni F., Barros G.M., Madeira M.I., Malmegrim K.C., Foss-Freitas M.C., Simoes B.P., Martinez E.Z., Foss M.C., Burt R.K., Voltarelli J.C. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed Type 1 diabetes mellitus. JAMA 2009, 301:1573-1579.
63. Bluestone J.A., Buckner J.H., Fitch M., Gitelman S.E., Gupta S., Hellerstein M.K., Herold K.C., Lares A., Lee M.R., Li K., Liu W., Long S.A., Masiello L.M., Nguyen V., Putnam A.L., Rieck M., Sayre P.H., Tang Q. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci. Transl. Med. 2015, 7:315ra189.
64. Marek-Trzonkowska N., Mysliwiec M., Dobyszuk A., Grabowska M., Techmanska I., Juscinska J., Wujtewicz M.A., Witkowski P., Mlynarski W., Balcerska A., Mysliwska J., Trzonkowski P. Administration of CD4+CD25highCD127-regulatory T cells preserves beta-cell function in Type 1 diabetes in children. Diabetes Care 2012, 35:1817-1820.
65. Tooley J.E., Vudattu N., Choi J., Cotsapas C., Devine L., Raddassi K., Ehlers M.R., McNamara J.G., Harris K.M., Kanaparthi S., Phippard D., Herold K.C. Changes in T-cell subsets identify responders to FcR non-binding anti-CD3 mAb (teplizumab) in patients with Type 1 diabetes. Eur. J. Immunol 2016, 46:230-241.
66. Jaberi-Douraki M., Schnell S., Pietropaolo M., Khadra A. Unraveling the contribution of pancreatic beta-cell suicide in autoimmune Type 1 diabetes. J. Theor. Biol. 2015, 375:77-87.
67. Talchai C., Xuan S., Lin H.V., Sussel L., Accili D. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell 2012, 150:1223-1234.
68. Guo S., Dai C., Guo M., Taylor B., Harmon J.S., Sander M., Robertson R.P., Powers A.C., Stein R. Inactivation of specific beta cell transcription factors in Type 2 diabetes. J. Clin. Invest 2013, 123:3305-3316.
69. Sosenko J.M., Palmer J.P., Greenbaum C.J., Mahon J., Cowie C., Krischer J.P., Chase H.P., White N.H., Buckingham B., Herold K.C., Cuthbertson D., Skyler J.S. Patterns of metabolic progression to Type 1 diabetes in the diabetes prevention trial-Type 1. Diabetes Care 2006, 29:643-649.
70. Sosenko J.M., Skyler J.S., Herold K.C., Palmer J.P. The metabolic progression to Type 1 diabetes as indicated by serial oral glucose tolerance testing in the diabetes prevention trial-Type 1. Diabetes 2012, 61:1331-1337.
71. Walker M., Mari A., Jayapaul M.K., Bennett S.M., Ferrannini E. Impaired beta cell glucose sensitivity and whole-body insulin sensitivity as predictors of hyperglycaemia in non-diabetic subjects. Diabetologia 2005, 48:2470-2476.
72. Lehmann-Werman R., Neiman D., Zemmour H., Moss J., Magenheim J., Vaknin-Dembinsky A., Rubertsson S., NellGard B., Blennow K., Zetterberg H., Spalding K., Haller M.J., Wasserfall C.H., Schatz D.A., Greenbaum C.J., Dorrell C., Grompe M., Zick A., Hubert A., Maoz M., Fendrich V., Bartsch D.K., Golan T., Ben Sasson S.A., Zamir G., Razin A., Cedar H., Shapiro A.M., Glaser B., Shemer R., Dor Y. Identification of tissue-specific cell death using methylation patterns of circulating DNA. Proc. Natl. Acad. Sci. (USA) (2016, on line March 14, 2016.
73. Rui J., Deng S., Lebastchi J., Clark P.L., Usmani-Brown S., Herold K.C. Methylation of insulin DNA in response to proinflammatory cytokines during the progression of autoimmune diabetes in NOD mice. Diabetologia 2016 Feb 24, Epub.