{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T15:18:31Z","timestamp":1773155911607,"version":"3.50.1"},"reference-count":79,"publisher":"American Diabetes Association","issue":"5","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2007,5,1]]},"abstract":"<jats:p>Diabetes is an emblematic example of a heterogeneous disease. Systemic inflammation has emerged as a prominent factor in the type 2 diabetes pathoetiology, but it remains ill-defined in type 1 diabetes. There is a wide spectrum of associations between inflammatory responses and diabetic syndromes. At one end of this spectrum, there is type 1 diabetes for which there is convincing evidence that chronic inflammation of pancreatic islets is a central aspect of disease pathogenesis. At the opposite end, is type 2 diabetes that is clearly associated with systemic inflammation, which could be either the cause or simply mark the underlying pathology. Accumulating evidence has substantiated that a subgroup of adult patients clinically diagnosed with type 2 diabetes exhibit autoantibody responses to islet autoantigens. The presence of these immunologic abnormalities is associated with a severe insulin secretory defect and the absence of signs of systemic inflammation as documented by plasma C-reactive protein and fibrinogen levels that are comparable with those of control populations. Islet autoantibody evaluation should be part of the diagnostic assessment for clinically diagnosed type 2 diabetes not only because it might predict the rate of progression to insulin requirement in adult populations but also to identify a pathogenically distinct disease phenotype characterized by the absence of systemic inflammation and its related disorders. A more appropriate characterization of this subgroup of clinically diagnosed type 2 diabetes, diabetes of autoimmune pathogenesis, will promote future research into the etiology, natural history, and treatment.<\/jats:p>","DOI":"10.2337\/db06-0880","type":"journal-article","created":{"date-parts":[[2007,4,30]],"date-time":"2007-04-30T16:48:34Z","timestamp":1177951714000},"page":"1189-1197","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":66,"title":["The Heterogeneity of Diabetes"],"prefix":"10.2337","volume":"56","author":[{"given":"Massimo","family":"Pietropaolo","sequence":"first","affiliation":[{"name":"Laboratory of Immunogenetics, The Brehm Center for Type 1 Diabetes and Analysis, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma","family":"Barinas-Mitchell","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lewis H.","family":"Kuller","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1167","reference":[{"key":"2022031210484754600_R1","doi-asserted-by":"crossref","unstructured":"Todd JA, Bell JI, McDevitt HO: HLA-DQ\u03b2 gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature\u2008329:599\u2013604,1987","DOI":"10.1038\/329599a0"},{"key":"2022031210484754600_R2","doi-asserted-by":"crossref","unstructured":"Morel PA, Dorman JS, Todd JA, McDevitt HO, Trucco M: Aspartic acid at position 57 of the HLA-DQ beta chain protects against type I diabetes: a family study. Proc Natl Acad Sci U S A\u200885:8111\u20138115,1988","DOI":"10.1073\/pnas.85.21.8111"},{"key":"2022031210484754600_R3","doi-asserted-by":"crossref","unstructured":"Haffner SM: Epidemiology of type 2 diabetes: risk factors. Diabetes Care\u200821 (Suppl. 3):3C\u20136C,1998","DOI":"10.2337\/diacare.21.3.C3"},{"key":"2022031210484754600_R4","doi-asserted-by":"crossref","unstructured":"Kuller LH, Tracy RP, Shaten J, Meilahn EN, for the Multiple Risk Factor Intervention Trial Research Group: Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Am J Epidemiol\u2008144:537\u2013547,1996","DOI":"10.1093\/oxfordjournals.aje.a008963"},{"key":"2022031210484754600_R5","doi-asserted-by":"crossref","unstructured":"Tracy RP, Lemaitre RN, Diane P, Evans RW, Cushman M, Meilahn EN, Kuller LH: Relationship of C-reactive proteins to risk of cardiovascular disease in the elderly: results from the cardiovascular health study and the rural health promotion project. Arterioscler Thromb Vasc Biol\u200817:1121\u20131127,1997","DOI":"10.1161\/01.ATV.17.6.1121"},{"key":"2022031210484754600_R6","doi-asserted-by":"crossref","unstructured":"Willerson JT, Ridker PM: Inflammation as a cardiovascular risk factor. Circulation\u2008109 (Suppl. II):II-2\u2014II-10,2004","DOI":"10.1161\/01.CIR.0000129535.04194.38"},{"key":"2022031210484754600_R7","doi-asserted-by":"crossref","unstructured":"Dandona P, Aljada A, Bandyopadhyay A: Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol\u200825:4\u20137,2004","DOI":"10.1016\/j.it.2003.10.013"},{"key":"2022031210484754600_R8","doi-asserted-by":"crossref","unstructured":"Wellen KE, Hotamisligil GS: Inflammation, stress, and diabetes. J Clin Invest\u2008115:1111\u20131119,2005","DOI":"10.1172\/JCI25102"},{"key":"2022031210484754600_R9","doi-asserted-by":"crossref","unstructured":"Singer M, De S V, Vitale D, Jeffcoate W: Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation. Lancet\u2008364:545\u2013548,2004","DOI":"10.1016\/S0140-6736(04)16815-3"},{"key":"2022031210484754600_R10","doi-asserted-by":"crossref","unstructured":"Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, Atkinson C, Malarkey WB, Glaser R: Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc Natl Acad Sci U S A\u2008100:9090\u20139095,2003","DOI":"10.1073\/pnas.1531903100"},{"key":"2022031210484754600_R11","doi-asserted-by":"crossref","unstructured":"Suschek CV, Schnorr O, Kolb-Bachofen V: The role of iNOS in chronic inflammatory processes in vivo: is it damage-promoting, protective, or active at all?Curr Mol Med\u20084:763\u2013775,2004","DOI":"10.2174\/1566524043359908"},{"key":"2022031210484754600_R12","doi-asserted-by":"crossref","unstructured":"Pickup JC: Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care\u200827:813\u2013823,2004","DOI":"10.2337\/diacare.27.3.813"},{"key":"2022031210484754600_R13","doi-asserted-by":"crossref","unstructured":"Bottazzo GF, Dean BM, McNally JM, Mackay EH, Swift PGF, Gamble DR: In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. N Engl J Med\u2008313:353\u2013360,1985","DOI":"10.1056\/NEJM198508083130604"},{"key":"2022031210484754600_R14","doi-asserted-by":"crossref","unstructured":"Conrad B, Weidmann E, Trucco G, Rudert WA, Ricordi C, Rodriquez-Rilo H, Behboo R, Finegold D, Trucco M: Evidence for superantigen involvment in insulin-dependent diabetes mellitus etiology. Nature\u2008371:351\u2013355,1994","DOI":"10.1038\/371351a0"},{"key":"2022031210484754600_R15","doi-asserted-by":"crossref","unstructured":"Wong FS, Karttunen J, Dumont C, Wen L, Visintin I, Pilip IM, Shastri N, Pamer EG, Janeway CA Jr: Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library. Nat Med\u20085:1026\u20131031,1999","DOI":"10.1038\/12465"},{"key":"2022031210484754600_R16","doi-asserted-by":"crossref","unstructured":"Lieberman SM, Evans AM, Han B, Takaki T, Vinnitskaya Y, Caldwell JA, Serreze DV, Shabanowitz J, Hunt DF, Nathenson SG, Santamaria P, DiLorenzo TP: Identification of the beta cell antigen targeted by a prevalent population of pathogenic CD8+ T cells in autoimmune diabetes. Proc Natl Acad Sci U S A\u2008100:8384\u20138388,2003","DOI":"10.1073\/pnas.0932778100"},{"key":"2022031210484754600_R17","doi-asserted-by":"crossref","unstructured":"Pinkse GG, Tysma OH, Bergen CA, Kester MG, Ossendorp F, van Veelen PA, Keymeulen B, Pipeleers D, Drijfhout JW, Roep BO: Autoreactive CD8 T cells associated with beta cell destruction in type 1 diabetes. Proc Natl Acad Sci U S A\u2008102:18425\u201318430,2005","DOI":"10.1073\/pnas.0508621102"},{"key":"2022031210484754600_R18","doi-asserted-by":"crossref","unstructured":"Arif S, Tree TI, Astill TP, Tremble JM, Bishop AJ, Dayan CM, Roep BO, Peakman M: Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J Clin Invest\u2008113:451\u2013463,2004","DOI":"10.1172\/JCI19585"},{"key":"2022031210484754600_R19","doi-asserted-by":"crossref","unstructured":"Razavi R, Chan Y, Afifiyan FN, Liu XJ, Wan X, Yantha J, Tsui H, Tang L, Tsai S, Santamaria P, Driver JP, Serreze D, Salter MW, Dosch HM: TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes. Cell\u2008127:1123\u20131135,2006","DOI":"10.1016\/j.cell.2006.10.038"},{"key":"2022031210484754600_R20","doi-asserted-by":"crossref","unstructured":"Imagawa A, Hanafusa T, Miyagawa J-I, Matzuzawa Y, for the Osaka IDDM Study Group: A novel subtype of type 1 diabetes mellitus characterized by rapid onset and absence if diabetes-related antibodies. N Engl J Med\u2008342:301\u2013307,2000","DOI":"10.1056\/NEJM200002033420501"},{"key":"2022031210484754600_R21","doi-asserted-by":"crossref","unstructured":"Semakula C, Vandewalle CL, Van Schravendijk CF, Sodoyez JC, Schuit FC, Foriers A, Falorni A, Craen M, Decraene P, Pipeleers DG, Gorus FK: Abnormal circulating pancreatic enzyme activities in more than twenty-five percent of recent-onset insulin-dependent diabetic patients: association of hyperlipasemia with high-titer islet cell antibodies. Belgian Diabetes Registry. Pancreas\u200812:321\u2013333,1996","DOI":"10.1097\/00006676-199605000-00001"},{"key":"2022031210484754600_R22","doi-asserted-by":"crossref","unstructured":"Kahara T, Takamura T, Ando H, Sakurai M, Ota T, Misaki T, Oba S, Iguchi M, Komori K, Kobayashi K: Fulminating onset type 1 diabetes with positivity for anti-GAD antibody and elevated pancreatic exocrine enzyme concentrations. Intern Med\u200842:517\u2013520,2003","DOI":"10.2169\/internalmedicine.42.517"},{"key":"2022031210484754600_R23","doi-asserted-by":"crossref","unstructured":"Kimura T, Ito A, Hancock WW, Maki T: Islet mass plays a critical role in initiation, but not progression, of the diabetogenic process in NOD mice. J Autoimmun\u200812:243\u2013249,1999","DOI":"10.1006\/jaut.1999.0283"},{"key":"2022031210484754600_R24","doi-asserted-by":"crossref","unstructured":"Gianani R, Putnam A, Still T, Yu L, Miao D, Gill RG, Beilke J, Supon P, Valentine A, Iveson A, Dunn S, Eisenbarth GS, Hutton J, Gottlieb P, Wiseman A: Initial results of screening of nondiabetic organ donors for expression of islet autoantibodies. J Clin Endocrinol Metab\u200891:1855\u20131861,2006","DOI":"10.1210\/jc.2005-1171"},{"key":"2022031210484754600_R25","doi-asserted-by":"crossref","unstructured":"Atkinson MA, Eisenbarth GS: Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet\u2008358:221\u2013229,2001","DOI":"10.1016\/S0140-6736(01)05415-0"},{"key":"2022031210484754600_R26","doi-asserted-by":"crossref","unstructured":"Verge CF, Gianani R, Kawasaki E, Yu L, Pietropaolo M, Jackson RA, Chase PH, Eisenbarth GS: Prediction of type I diabetes mellitus in first degree relatives using a combination of insulin, glutamic acid decarboxylase and ICA512bdc\/IA-2 autoantibodies. Diabetes\u200845:926\u2013933,1996","DOI":"10.2337\/diab.45.7.926"},{"key":"2022031210484754600_R27","doi-asserted-by":"crossref","unstructured":"Pietropaolo M, Yu S, Libman IM, Pietropaolo SL, Riley K, LaPorte RE, Drash AL, Mazumdar S, Trucco M, Becker DJ: Cytoplasmic islet cell antibodies remain valuable in defining risk of progression to type 1 diabetes in subjects with other islet autoantibodies. Pediatr Diabetes\u20086:184\u2013192,2005","DOI":"10.1111\/j.1399-543X.2005.00127.x"},{"key":"2022031210484754600_R28","doi-asserted-by":"crossref","unstructured":"Wan EC, Gordon TP, Jackson MW: Autoantibody-mediated bladder dysfunction in type 1 diabetes. Scand J Immunol\u200865:70\u201375,2007","DOI":"10.1111\/j.1365-3083.2006.01877.x"},{"key":"2022031210484754600_R29","doi-asserted-by":"crossref","unstructured":"Bach JF, Bendelac A, Brenner MB, Cantor H, De Libero G, Kronenberg M, Lanier LL, Raulet DH, Shlomchik MJ, von Herrath MG: The role of innate immunity in autoimmunity. J Exp Med\u2008200:1527\u20131531,2004","DOI":"10.1084\/jem.20042110"},{"key":"2022031210484754600_R30","doi-asserted-by":"crossref","unstructured":"Lang KS, Recher M, Junt T, Navarini AA, Harris NL, Freigang S, Odermatt B, Conrad C, Ittner LM, Bauer S, Luther SA, Uematsu S, Akira S, Hengartner H, Zinkernagel RM: Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease. Nat Med\u200811:138\u2013145,2005","DOI":"10.1038\/nm1176"},{"key":"2022031210484754600_R31","doi-asserted-by":"crossref","unstructured":"Poligone B, Weaver P, Sen P, Baldwin AS, Tisch R: Elevated NF-\u03baB activation in nonobese diabetic mouse dendritic cells results in enhanced APC function. J Immunol\u2008168:196,2002","DOI":"10.4049\/jimmunol.168.1.188"},{"key":"2022031210484754600_R32","doi-asserted-by":"crossref","unstructured":"Litherland SA, Xie XT, Hutson AD, Wasserfall C, Whittaker DS, She JX, Hofig A, Dennis MA, Fuller K, Cook R, Schatz D, Moldawer LL, Clare-Salzler MJ: Aberrant prostaglandin synthase 2 expression defines an antigen-presenting cell defect for insulin-dependent diabetes mellitus. J Clin Invest\u2008104:515\u2013523,1999","DOI":"10.1172\/JCI4852"},{"key":"2022031210484754600_R33","doi-asserted-by":"crossref","unstructured":"Clare-Salzler M, Brooks J, Chai A, Van Herle K, Anderson C: Prevention of diabetes in nonobese diabetic mice by dendritic cell transfer. J Clin Invest741\u2013748,1992","DOI":"10.1172\/JCI115946"},{"key":"2022031210484754600_R34","doi-asserted-by":"crossref","unstructured":"Morel PA, Feili-Hariri M: How do dendritic cells prevent autoimmunity?Trends Immunol\u200822:546\u2013547,2001","DOI":"10.1016\/S1471-4906(01)02026-9"},{"key":"2022031210484754600_R35","doi-asserted-by":"crossref","unstructured":"Bluestone JA, Tang Q: How do CD4+CD25+ regulatory T cells control autoimmunity?Curr Opin Immunol\u200817:638\u2013642,2005","DOI":"10.1016\/j.coi.2005.09.002"},{"key":"2022031210484754600_R36","doi-asserted-by":"crossref","unstructured":"Masteller EL, Tang Q, Bluestone JA: Antigen-specific regulatory T cells \u2013ex vivo expansion and therapeutic potential. Semin Immunol\u200818:103\u2013110,2006","DOI":"10.1016\/j.smim.2006.01.004"},{"key":"2022031210484754600_R37","doi-asserted-by":"crossref","unstructured":"Rodacki M, Svoren B, Butty V, Besse W, Laffel L, Benoist C, Mathis D: Altered natural killer cells in type 1 diabetic patients. Diabetes\u200856:177\u2013185,2007","DOI":"10.2337\/db06-0493"},{"key":"2022031210484754600_R38","doi-asserted-by":"crossref","unstructured":"Ogasawara K, Hamerman JA, Ehrlich LR, Bour-Jordan H, Santamaria P, Bluestone JA, Lanier LL: NKG2D blockade prevents autoimmune diabetes in NOD mice. Immunity\u200820:757\u2013767,2004","DOI":"10.1016\/j.immuni.2004.05.008"},{"key":"2022031210484754600_R39","doi-asserted-by":"crossref","unstructured":"Serizawa I, Koezuka Y, Amao H, Saito TR, Takahashi KW: Functional natural killer T cells in experimental mouse strains, including NK1.1-strains. Exp Anim\u200849:171\u2013180,2000","DOI":"10.1538\/expanim.49.171"},{"key":"2022031210484754600_R40","doi-asserted-by":"crossref","unstructured":"Shi FD, Flodstro\u0308m M, Balasa B, Kim SH, Van Gunst K, Strominger JL, Wilson SB, Sarvetnick N: Germ line deletion of the CD1 locus exacerbates diabetes in the NOD mouse. Proc Natl Acad Sci U S A\u200898:6777\u20136782,2001","DOI":"10.1073\/pnas.121169698"},{"key":"2022031210484754600_R41","doi-asserted-by":"crossref","unstructured":"Sharif S, Arreaza GA, Zucker P, Mi QS, Delovitch TL: Regulation of autoimmune disease by natural killer T cells. J Mol Med\u200880:290\u2013300,2002","DOI":"10.1007\/s00109-002-0332-8"},{"key":"2022031210484754600_R42","doi-asserted-by":"crossref","unstructured":"Wilson SB, Kent SC, Patton KT, Orban T, Jackson RA, Exley M, Porcelli S, Schatz DA, Atkinson MA, Balk SP, Strominger JL, Hafler DA: Extreme Th1 bias of invariant V\u03b124J\u03b1Q T cells in type 1 diabetes. Nature\u2008391:177\u2013181,1998","DOI":"10.1038\/34419"},{"key":"2022031210484754600_R43","doi-asserted-by":"crossref","unstructured":"Pickup JC, Crook MA: Is type II diabetes mellitus a disease of the innate immune system?Diabetologia\u200841:1241\u20131248,1998","DOI":"10.1007\/s001250051058"},{"key":"2022031210484754600_R44","doi-asserted-by":"crossref","unstructured":"Wogensen L, Helqvist S, Pociot F, Johannesen J, Reimers J, Mandrup-Poulsen T, Nerup J: Intra-peritoneal administration of interleukin-1 beta induces impaired insulin release from the perfused rat pancreas. Autoimmunity\u20087:1\u201312,1990","DOI":"10.3109\/08916939009041045"},{"key":"2022031210484754600_R45","doi-asserted-by":"crossref","unstructured":"Peraldi P, Spiegelman B: TNF-alpha and insulin resistance: summary and future prospects. Mol Cell Biochem\u2008182:169\u2013175,1998","DOI":"10.1007\/978-1-4615-5647-3_18"},{"key":"2022031210484754600_R46","doi-asserted-by":"crossref","unstructured":"Kwon G, Xu G, Marshall CA, McDaniel ML: Tumor necrosis factor \u03b1-induced pancreatic \u03b2-cell insulin resistance is mediated by nitric oxide and prevented by 15-deoxy-\u039412,14-prostaglandin J2 and aminoguanidine. J Biol Chem\u2008274:18702\u201318708,1999","DOI":"10.1074\/jbc.274.26.18702"},{"key":"2022031210484754600_R47","doi-asserted-by":"crossref","unstructured":"Pakala SV, Chivetta M, Kelly CB, Katz JD: In autoimmune diabetes the transition from benign to pernicious insulitis requires an islet cell response to tumor necrosis factor alpha. J Exp Med\u2008189:1053\u20131062,1999","DOI":"10.1084\/jem.189.7.1053"},{"key":"2022031210484754600_R48","doi-asserted-by":"crossref","unstructured":"Donath MY, Storling J, Maedler K, Mandrup-Poulsen T: Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes. J Mol Med\u200881:455\u2013470,2003","DOI":"10.1007\/s00109-003-0450-y"},{"key":"2022031210484754600_R49","doi-asserted-by":"crossref","unstructured":"Cardozo AK, Ortis F, Storling J, Feng YM, Rasschaert J, Tonnesen M, Van Eylen F, Mandrup-Poulsen T, Herchuelz A, Eizirik DL: 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\u200854:452\u2013461,2005","DOI":"10.2337\/diabetes.54.2.452"},{"key":"2022031210484754600_R50","doi-asserted-by":"crossref","unstructured":"St\u00f8rling J, Binzer J, Andersson AK, Zullig RA, Tonnesen M, Lehmann R, Spinas GA, Sandler S, Billestrup N, Mandrup-Poulsen T: Nitric oxide contributes to cytokine-induced apoptosis in pancreatic beta cells via potentiation of JNK activity and inhibition of Akt. Diabetologia\u200848:2039\u20132050,2005","DOI":"10.1007\/s00125-005-1912-2"},{"key":"2022031210484754600_R51","doi-asserted-by":"crossref","unstructured":"Vessby J, Basu S, Mohsen R, Berne C, Vessby B: Oxidative stress and antioxidant status in type 1 diabetes mellitus. J Intern Med\u2008251:69\u201376,2002","DOI":"10.1046\/j.1365-2796.2002.00927.x"},{"key":"2022031210484754600_R52","doi-asserted-by":"crossref","unstructured":"Varvarovska J, Racek J, Stozicky F, Soucek J, Trefil L, Pomahacova R: Parameters of oxidative stress in children with type 1 diabetes mellitus and their relatives. J Diabetes Complications\u200817:7\u201310,2003","DOI":"10.1016\/S1056-8727(01)00228-8"},{"key":"2022031210484754600_R53","doi-asserted-by":"crossref","unstructured":"Chase HP, Cooper S, Osberg I, Stene LC, Barriga K, Norris J, Eisenbarth GS, Rewers M: Elevated C-reactive protein levels in the development of type 1 diabetes. Diabetes\u200853:2569\u20132573,2004","DOI":"10.2337\/diabetes.53.10.2569"},{"key":"2022031210484754600_R54","doi-asserted-by":"crossref","unstructured":"Bonifacio E, Mollenhauer U, Buuck D, Ziegler AG: C-reactive protein concentration is not related to islet autoimmunity status in offspring of parents with type 1 diabetes. Clin Immunol\u2008115:173\u2013177,2005","DOI":"10.1016\/j.clim.2005.01.004"},{"key":"2022031210484754600_R55","doi-asserted-by":"crossref","unstructured":"Fried LP, Borhani NO, Enright P, Furberg CD, Gardin JM, Kronmal RA, Kuller LH, Manolio TA, Mittelmark MB: The cardiovascular health study: design and rationale. Ann Epidemiol\u20081:263\u2013276,1991","DOI":"10.1016\/1047-2797(91)90005-W"},{"key":"2022031210484754600_R56","doi-asserted-by":"crossref","unstructured":"Fourlanos S, Narendran P, Byrnes GB, Colman PG, Harrison LC: Insulin resistance is a risk factor for progression to type 1 diabetes. Diabetologia\u200847:1661\u20131667,2004","DOI":"10.1007\/s00125-004-1507-3"},{"key":"2022031210484754600_R57","doi-asserted-by":"crossref","unstructured":"Sherry NA, Tsai EB, Herold KC: Natural history of beta-cell function in type 1 diabetes. Diabetes\u200854 (Suppl. 2):S32\u2013S39,2005","DOI":"10.2337\/diabetes.54.suppl_2.S32"},{"key":"2022031210484754600_R58","doi-asserted-by":"crossref","unstructured":"Betts P, Mulligan J, Ward P, Smith B, Wilkin T: Increasing body weight predicts the earlier onset of insulin-dependant diabetes in childhood: testing the \u2018accelerator hypothesis\u2019 (2). Diabet Med\u200822:144\u2013151,2005","DOI":"10.1111\/j.1464-5491.2004.01368.x"},{"key":"2022031210484754600_R59","doi-asserted-by":"crossref","unstructured":"Weir GC, Bonner-Weir S: Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes\u200853 (Suppl. 3):S16\u2013S21,2004","DOI":"10.2337\/diabetes.53.suppl_3.S16"},{"key":"2022031210484754600_R60","doi-asserted-by":"crossref","unstructured":"Prentki M, Nolan CJ: Islet beta cell failure in type 2 diabetes. J Clin Invest\u2008116:1802\u20131812,2006","DOI":"10.1172\/JCI29103"},{"key":"2022031210484754600_R61","doi-asserted-by":"crossref","unstructured":"Butler AE, Janson J, Soeller WC, Butler PC: 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\u200852:2304\u20132314,2003","DOI":"10.2337\/diabetes.52.9.2304"},{"key":"2022031210484754600_R62","doi-asserted-by":"crossref","unstructured":"Asghar Z, Yau D, Chan F, LeRoith D, Chan CB, Wheeler MB: Insulin resistance causes increased beta-cell mass but defective glucose-stimulated insulin secretion in a murine model of type 2 diabetes. Diabetologia\u200849:90\u201399,2006","DOI":"10.1007\/s00125-005-0045-y"},{"key":"2022031210484754600_R63","doi-asserted-by":"crossref","unstructured":"Bruning JC, Winnay J, Bonner-Weir S, Taylor SI, Accili D, Kahn CR: Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell\u200888:561\u2013572,1997","DOI":"10.1016\/S0092-8674(00)81896-6"},{"key":"2022031210484754600_R64","doi-asserted-by":"crossref","unstructured":"Terauchi Y, Takamoto I, Kubota N, Matsui J, Suzuki R, Komeda K, Hara A, Toyoda Y, Miwa I, Aizawa S, Tsutsumi S, Tsubamoto Y, Hashimoto S, Eto K, Nakamura A, Noda M, Tobe K, Aburatani H, Nagai R, Kadowaki T: Glucokinase and IRS-2 are required for compensatory beta cell hyperplasia in response to high-fat diet-induced insulin resistance. J Clin Invest\u2008117:246\u2013257,2007","DOI":"10.1172\/JCI17645"},{"key":"2022031210484754600_R65","doi-asserted-by":"crossref","unstructured":"Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles WJ, Mackay IR: Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes in adults with a non-insulin-dependent onset of diabetes. Diabetes\u200842:359\u2013362,1993","DOI":"10.2337\/diabetes.42.2.359"},{"key":"2022031210484754600_R66","doi-asserted-by":"crossref","unstructured":"Leslie RD, Williams R, Pozzilli P: Clinical review: type 1 diabetes and latent autoimmune diabetes in adults: one end of the rainbow. J Clin Endocrinol Metab\u200891:1654\u20131659,2006","DOI":"10.1210\/jc.2005-1623"},{"key":"2022031210484754600_R67","doi-asserted-by":"crossref","unstructured":"Zimmet PZ, Tuomi T, Mackay IR, Rowley MJ, Knowles W, Cohen M, Lang A: Latent autoimmune diabetes mellitus in adults (LADA): the role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency. Diabet Med\u200811:299\u2013303,1994","DOI":"10.1111\/j.1464-5491.1994.tb00275.x"},{"key":"2022031210484754600_R68","doi-asserted-by":"crossref","unstructured":"Gilliam LK, Palmer JP: How useful is autoantibody screening in adult-onset diabetes?Nat Clin Pract Endocrinol Metab\u20082:490\u2013491,2006","DOI":"10.1038\/ncpendmet0268"},{"key":"2022031210484754600_R69","doi-asserted-by":"crossref","unstructured":"Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, Shattock M, Bottazzo GF, Holman R, for UK Prospective Diabetes Study (UKPDS) Group: UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. Lancet\u2008350:1288\u20131293,1997","DOI":"10.1016\/S0140-6736(97)03062-6"},{"key":"2022031210484754600_R70","doi-asserted-by":"crossref","unstructured":"Alberti KGMM, Zimmet PZ, for the WHO Consultation: Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabet Med\u200815:539\u2013553,1998","DOI":"10.1002\/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S"},{"key":"2022031210484754600_R71","doi-asserted-by":"crossref","unstructured":"Shimada A, Imazu Y, Morinaga S, Funae O, Kasuga A, Atsumi Y, Matsuoka K: T-cell insulitis found in anti-GAD65+ diabetes with residual \u03b2-cell function. Diabetes Care\u200822:615\u2013617,1999","DOI":"10.2337\/diacare.22.4.615"},{"key":"2022031210484754600_R72","doi-asserted-by":"crossref","unstructured":"Barinas-Mitchell E, Kuller LH, Pietropaolo S, Zhang YJ, Henderson T, Pietropaolo M: The prevalence of GAD65 autoantibodies by glucose tolerance status in elderly patients from the Cardiovascular Health Study. J Clin Endocrinol Metab\u200891:2871\u20132877,2006","DOI":"10.1210\/jc.2005-2667"},{"key":"2022031210484754600_R73","unstructured":"Ebstein W: Zur Therapie des Diabetes Mellitus, insbesondere u\u0308ber die Anwendung des Salicylsauren Natron bei demselben. Berliner Klin Wochenschr\u200824:337\u2013340,1876"},{"key":"2022031210484754600_R74","doi-asserted-by":"crossref","unstructured":"Kopp E, Ghosh S: Inhibition of NF-\u03ba B by sodium salycilate and aspirin. Science\u2008265:956\u2013959,1994","DOI":"10.1126\/science.8052854"},{"key":"2022031210484754600_R75","doi-asserted-by":"crossref","unstructured":"Hundal RS, Petersen KF, Mayerson AB, Randhawa PS, Inzucchi S, Shoelson SE, Shulman GI: Mechanisms by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest\u2008109:1321\u20131326,2002","DOI":"10.1172\/JCI0214955"},{"key":"2022031210484754600_R76","doi-asserted-by":"crossref","unstructured":"Barzilay JI, Abraham L, Heckbert SR, Cushman M, Kuller LH, Resnick HE, Tracy RP: The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. Diabetes\u200850:2384\u20132389,2001","DOI":"10.2337\/diabetes.50.10.2384"},{"key":"2022031210484754600_R77","doi-asserted-by":"crossref","unstructured":"Retnakaran R, Hanley AJ, Raif N, Connelly PW, Sermer M, Zinman B: C-reactive protein and gestational diabetes: the central role of maternal obesity. J Clin Endocrinol Metab\u200888:3507\u20133512,2003","DOI":"10.1210\/jc.2003-030186"},{"key":"2022031210484754600_R78","doi-asserted-by":"crossref","unstructured":"Barinas-Mitchell E, Pietropaolo S, Zhang YJ, Henderson T, Trucco M, Kuller LH, Pietropaolo M: Islet cell autoimmunity in a triethnic adult population of the National Health and Nutrition Examination Survey (NHANES) III. Diabetes\u200853:1293\u20131302,2004","DOI":"10.2337\/diabetes.53.5.1293"},{"key":"2022031210484754600_R79","doi-asserted-by":"crossref","unstructured":"Zinman B, Kahn SE, Haffner SM, O'Neill MC, Heise MA, Freed MI: Phenotypic characteristics of GAD antibody-positive recently diagnosed patients with type 2 diabetes in North America and Europe. Diabetes\u200853:3193\u20133200,2004","DOI":"10.2337\/diabetes.53.12.3193"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/56\/5\/1189\/388184\/zdb00507001189.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/56\/5\/1189\/388184\/zdb00507001189.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:08:51Z","timestamp":1667405331000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/56\/5\/1189\/15186\/The-Heterogeneity-of-DiabetesUnraveling-a-Dispute"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,5,1]]},"references-count":79,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2007,5,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db06-0880","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,5,1]]}}}