Skip to main content
SpringerLink
Log in
Book cover

Diabetes Epidemiology, Genetics, Pathogenesis, Diagnosis, Prevention, and Treatment pp 255–297Cite as

LADA

  • Reference work entry
  • First Online:

Part of the book series: Endocrinology ((ENDOCR))

Abstract

The term latent autoimmune diabetes of the adult (LADA) has been introduced to define the subgroup of adult type 2 diabetes (T2DM) patients who are initially noninsulin requiring but with immune markers of type 1 diabetes (T1DM).

The prevalence of LADA has been estimated in a number of multicenter studies of both European and non-European populations. Around 4–14% of patients classified with T2DM have diabetes associated autoantibodies. Among these autoantibodies, glutamic acid decarboxylase (GAD) has become the main islet autoantibody for LADA screening and the most sensitive autoimmune marker for LADA diagnosis.

It remains to be clarified whether LADA exists as a distinct disease entity or it just represents the end of a wide spectrum of the heterogeneous immune-mediated diabetes. Uncertainties concern almost all aspects of this disease, including the nomenclature, diagnostic criteria, epidemiology, natural history, and pathogenesis with genetic, metabolic, and immunological aspects.

A number of attractive therapeutic interventions may be envisaged for prevention of beta-cell loss in LADA, including hypoglycemic and immunomodulatory agents. Since the autoimmune process in LADA seems to be slower than in T1DM, there is a wider window of opportunities for intervention.

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

References

  • Aaen K, Rygaard J, Josefsen K, Petersen H, Brogren CH, Horn T, Buschard K. Dependence of antigen expression on functional state of beta-cells. Diabetes. 1990;39(6):697–701.

    Article  CAS  PubMed  Google Scholar 

  • Adeleye OO, Ogbera AO, Fasanmade O, Ogunleye OO, Dada AO, Ale AO, Abatan FM. Latent autoimmune diabetes mellitus in adults (LADA) and it’s characteristics in a subset of Nigerians initiallymanaged for type 2 diabetes. Int Arch Med. 2012;5(1):23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Agardh CD, Cilio CM, Lethagen A, Lynch K, Leslie RD, Palmér M, Harris RA, Robertson JA, Lernmark A. Clinical evidence for the safety of GAD65 immunomodulation in adult onset autoimmune diabetes. J Diabetes Complicat. 2005;19(4):238–46.

    Article  Google Scholar 

  • Aggarwal S, Goel A, Jain A. Role of C-peptide in identification of patients suspected of having latent autoimmune diabetes in adults (LADA) in north Indian type 2 diabetes mellitus population. Int J Pharm Biosci. 2010;1:3.

    Google Scholar 

  • Alberti KG, Zimmet PZ. 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. 1998;15(7):539–53.

    Article  CAS  PubMed  Google Scholar 

  • Andersen MK, Lundgren V, Turunen JA, et al. Latent autoimmune diabetes in adults differs genetically from classical T1DM diagnosed after the age of 35 years. Diabetes Care. 2010;33:2062–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andersen MK, Sterner M, Forsén T, Käräjämäki A, Rolandsson O, Forsblom C, Groop PH, Lahti K, Nilsson PM, Groop L, Tuomi T. Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes. Diabetologia. 2014;57(9):1859–68.

    Article  CAS  PubMed  Google Scholar 

  • Argoud GM, Schade DS, Eaton RP. Insulin suppresses its own secretion in vivo. Diabetes. 1987;36(8):959–62.

    Article  CAS  PubMed  Google Scholar 

  • Arikan E, Sabuncu T, Ozer EM, Hatemi H. The clinical characteristics of latent autoimmune diabetes in adults and its relation with chronic complications in metabolically poor controlled Turkish patients with type 2 diabetes mellitus. J Diabetes Complicat. 2005;19:254–8.

    Article  Google Scholar 

  • Atkinson MA, Eisenbarth GS. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet. 2001;358:221–9.

    Article  CAS  PubMed  Google Scholar 

  • 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 Third National Health and Nutrition Examination Survey. Diabetes. 2004;53(5):1293–302.

    Article  CAS  PubMed  Google Scholar 

  • Birk OS, Elias D, Weiss AS, Rosen A, Van-der Zee R, Walker MD, Cohen IR. NOD mouse diabetes: the ubiquitous mouse hsp60 is a beta-cell target antigen of autoimmune T cells. J Autoimmun. 1996;9(2):159–66.

    Article  CAS  PubMed  Google Scholar 

  • Björk E, Kämpe O, Andersson A, Karlsson FA. Expression of the 64 kDa/glutamic acid decarboxylase rat islet cell autoantigen is influenced by the rate of insulin secretion. Diabetologia. 1992;35(5):490–3.

    Article  PubMed  Google Scholar 

  • Bonifacio E, Lampasona V, Genovese S, Ferrari M, Bosi E. Identification of protein tyrosine phosphatase-like (islet cell antigen 512) as the insulindependent diabetes-related 37/40K autoantigen and a target of islet-cell antibodies. J Immunol. 1995;155(11):5419–26.

    CAS  PubMed  Google Scholar 

  • Borg H, Gottsäter A, Fernlund P, Sundkvist G. A 12-year prospective study of the relationship between islet antibodies and beta-cell function at and after the diagnosis in patients with adult-onset diabetes. Diabetes. 2002;51(6):1754–62.

    Article  CAS  PubMed  Google Scholar 

  • Bottazzo GF, Florin-Christensen A, Doniach D. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet. 1974;2(7892):1279–82.

    Article  CAS  PubMed  Google Scholar 

  • Bottazzo GF, Bosi E, Cull CA, Bonifacio E, Locatelli M, Zimmet P, Mackay IR, Holman RR. IA-2 antibody prevalence and risk assessment of early insulin requirement in subjects presenting with type 2 diabetes (UKPDS 71). Diabetologia. 2005;48(4):703–8.

    Article  CAS  PubMed  Google Scholar 

  • Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, Mac-Murray J, Meloni GF, Lucarelli P, Pellecchia M, Eisenbarth GS, Comings D, Mustelin T. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet. 2004;36:337–8.

    Article  CAS  PubMed  Google Scholar 

  • Brooks-Worrell BM, Juneja R, Minokadeh A, Greenbaum CJ, Palmer JP. Cellular immune responses to human islet proteins in antibody-positive type 2 diabetic patients. Diabetes. 1999;48(5):983–8.

    Article  CAS  PubMed  Google Scholar 

  • Brophy S, Yderstraede K, Mauricio D, Hunter S, Hawa M, Pozzilli P, Schernthaner G, Schloot N, Buzzetti R, Davies H, Leslie D, Williams R, Action LADA Group. Time to insulin initiation cannot be used in defining latent autoimmune diabetes in adults. Diabetes Care. 2008;31(3):439–41.

    Article  PubMed  Google Scholar 

  • Buzzetti R, Galgani A, Petrone A, Del Buono ML, Erlich HA, Bugawan TL, Lorini R, Meschi F, Multari G, Pozzilli P, Locatelli M, Bottazzo G, Di Mario U. Genetic prediction of T1DM in a population with low frequency of HLA risk genotypes and low incidence of the disease (the DIABFIN study). Diabetes Metab Res Rev. 2004;20(2):137–43.

    Article  CAS  PubMed  Google Scholar 

  • Buzzetti R, Di Pietro S, Giaccari A, Petrone A, Locatelli M, Suraci C, Capizzi M, Arpi ML, Bazzigaluppi E, Dotta F, Bosi E, Non Insulin Requiring Autoimmune Diabetes Study Group. High titer of autoantibodies to GAD identifies a specific phenotype of adult-onset autoimmune diabetes. Diabetes Care. 2007;30(4):932–8.

    Article  CAS  PubMed  Google Scholar 

  • Buzzetti R, Spoletini M, Zampetti S, Campagna G, Marandola L, Panimolle F, Dotta F, Tiberti C, NIRAD Study Group (NIRAD 8). Tyrosine phosphatase-related islet antigen 2(256–760) autoantibodies, the only marker of islet autoimmunity that increases by increasing the degree of BMI in obese subjects with type 2 diabetes. Diabetes Care. 2015a;38(3):513–20.

    Article  CAS  PubMed  Google Scholar 

  • Buzzetti R, Pozzilli P, Frederich R, Iqbal N, Hirshberg B. Saxagliptin improves glycaemic control and C-peptide secretion in latent autoimmune diabetes in adults (LADA). Diabetes Metab Res Rev. 2016;32(3):298–96.

    Article  PubMed  CAS  Google Scholar 

  • Cabrera-Rode E, Perich P, Diaz-Horta O, Tiberti C, Molina G, Arranz C, Martin JM, Licea M, De Leiva AD, Puig-Domingo M, Di Mario U. Slowly progressing type 1 diabetes: persistence of islet cell autoantibodies is related to glibenclamide treatment. Autoimmunity. 2002;35(7):469–74.

    Article  PubMed  Google Scholar 

  • Campbell-Thompson M, Fu A, Kaddis JS, Wasserfall C, Schatz DA, Pugliese A, Atkinson MA. Insulitis and β-cell mass in the natural history of type 1 diabetes. Diabetes. 2016;65(3):719–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Carlsson S, Midthjell K, Grill V. Influence of family history of diabetes on incidence and prevalence of latent autoimmune diabetes of the adult: results from the Nord-Trøndelag Health Study. Diabetes Care. 2007a;30(12):3040–5.

    Article  PubMed  Google Scholar 

  • Carlsson S, Midthjell K, Tesfamarian MY, Grill V. Age, overweight and physical inactivity increase the risk of latent autoimmune diabetes in adults: results from the Nord-Trøndelag Health Study. Diabetologia. 2007b;50(1):55–8.

    Article  CAS  PubMed  Google Scholar 

  • Carlsson S, Midthjell K, Grill V. LADA (latent autoimmune diabetes in adults) in Norway – occurrence, risk factors, treatment and complications. Nor Epidemiol. 2013;23(1):39–44.

    Google Scholar 

  • Cernea S, Buzzetti R, Pozzilli P. Beta-cell protection and therapy for latent autoimmune diabetes in adults. Diabetes Care. 2009;32(Suppl 2):S246–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cervin C, Lyssenko V, Bakhtadze E, et al. Genetic similarities between latent autoimmune diabetes in adults, type 1 diabetes, and type 2 diabetes. Diabetes. 2008;57(5):1433–7.

    CAS  PubMed  Google Scholar 

  • Chatenoud L, Bluestone J. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol. 2007;7:622–32.

    Article  CAS  PubMed  Google Scholar 

  • Cnop M, Welsh N, Jonas JC, Jörns A, Lenzen S, Eizirik DL. Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes. 2005;54(Suppl 2):S97–107.

    Article  CAS  PubMed  Google Scholar 

  • Davis TM, Wright AD, Mehta ZM, Cull CA, Stratton IM, Bottazzo GF, Bosi E, Mackay IR, Holman RR. Islet autoantibodies in clinically diagnosed type 2 diabetes: prevalence and relationship with metabolic control (UKPDS 70). Diabetologia. 2005;48(4):695–702.

    Article  CAS  PubMed  Google Scholar 

  • Deng C, Xiang Y, Tan T, Ren Z, Cao C, Huang G, Wen L, Zhou Z. Altered peripheral B-lymphoctye subsets in T1DM and latent autoimmune diabetes in adults. Diabetes Care. 2016;39(3):434–40.

    Google Scholar 

  • Desai M, Zeggini E, Horton VA, Owen KR, Hattersley AT, Levy JC, Hitman GA, Walker M, Holman RR, McCarthy MI, Clark A. The variable number of tandem repeats upstream of the insulin gene is a susceptibility locus for latent autoimmune diabetes in adults. Diabetes. 2006;55(6):1890–4.

    Article  CAS  PubMed  Google Scholar 

  • Desai M, Zeggini E, Horton VA, Owen KR, Hattersley AT, Levy JC, Walker M, Gillespie KM, Bingley PJ, Hitman GA, Holman RR, McCarthy MI, Clark A. An association analysis of the HLA gene region in latent autoimmune diabetes in adults. Diabetologia. 2007;50(1):68–73.

    Article  CAS  PubMed  Google Scholar 

  • Donath MY, Schumann DM, Faulenbach M, Ellingsgaard H, Perren A, Ehses JA. Islet inflammation in type 2 diabetes. Diabetes Care. 2008;31(Suppl 2):S161–4.

    Article  CAS  PubMed  Google Scholar 

  • Dong F, Yang G, Pan HW, Huang WH, Jing LP, Liang WK, Zhang N, Zhang BH, Wang M, Liu Y, Zhang LJ, Zhang SH, Li H, Chen C, Nie LH, Jing CX. The association of PTPN22 rs2476601 polymorphism and CTLA-4 rs231775 polymorphism with LADA risks: a systematic review and meta-analysis. Acta Diabetol. 2014;51(5):691–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dowse GK, Zimmet PZ, Spark RA, Mavo B, Rowley MJ, Mackay IR. Lack of antibodies to glutamic acid decarboxylase in young adults of the high diabetes prevalence Wanigela people of Papua New Guinea. Diabetes Res Clin Pract. 1994;24(3):195–8.

    Article  CAS  PubMed  Google Scholar 

  • Dupre J. Glycaemic effects of incretins in T1DM mellitus: a concise review, with emphasis on studies in humans. Regul Pept. 2005;128(2):149–57.

    Article  CAS  PubMed  Google Scholar 

  • Falorni A, Brozzetti A. Diabetes-related antibodies in adult diabetic patients. Best Pract Res Clin Endocrinol Metab. 2005;19(1):119–33.

    Article  CAS  PubMed  Google Scholar 

  • Falorni A, Calcinaro F. Autoantibody profile and epitope mapping in latent autoimmune diabetes in adults. Ann N Y Acad Sci. 2002;958:99–106.

    Article  CAS  PubMed  Google Scholar 

  • Field LL. Genetic linkage and association studies of type 1 diabetes: challenges and rewards. Diabetologia. 2002;45:21–35.

    Article  CAS  PubMed  Google Scholar 

  • Finegood DT, McArthur MD, Kojwang D, Thomas MJ, Topp BG, Leonard T, Buckingham RE. Beta-cell mass dynamics in Zucker diabetic fatty rats: rosiglitazone prevents the rise in net cell death. Diabetes. 2001;50(5):1021–9.

    Article  CAS  PubMed  Google Scholar 

  • Fourlanos S, Dotta F, Greenbaum CJ, Palmer JP, Rolandsson O, Colman PG, Harrison LC. Latent autoimmune diabetes in adults (LADA) should be less latent. Diabetologia. 2005;48(11):2206–12.

    Article  CAS  PubMed  Google Scholar 

  • Fourlanos S, Perry C, Stein MS, Stankovich J, Harrison LC, Colman PG. A clinical screening tool identifies autoimmune diabetes in adults. Diabetes Care. 2006;29(5):970–5.

    Article  PubMed  Google Scholar 

  • Füchtenbusch M, Kredel K, Bonifacio E, Schnell O, Ziegler AG. Exposure to exogenous insulin promotes IgG1 and the T-helper 2-associated IgG4 responses to insulin but not to other islet autoantigens. Diabetes. 2000;49(6):918–25.

    Article  PubMed  Google Scholar 

  • Gale EA. Latent autoimmune diabetes in adults: a guide for the perplexed. Diabetologia. 2005;48(11):2195–9.

    Article  CAS  PubMed  Google Scholar 

  • Gautier JF, Fetita S, Sobngwi E, Salaün-Martin C. Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes. Diabetes Metab. 2005;31(3):233–42.

    Article  CAS  PubMed  Google Scholar 

  • Genovese S, Bazzigaluppi E, Gonçalves D, Ciucci A, Cavallo MG, Purrello F, Anello M, Rotella CM, Bardini G, Vaccaro O, Riccardi G, Travaglini P, Morenghi E, Bosi E, Pozzilli P. Clinical phenotype and β-cell autoimmunity in Italian patients with adult-onset diabetes. Eur J Endocrinol. 2006;154(3):441–7.

    Article  CAS  PubMed  Google Scholar 

  • Ghanaat-Pour H, Sjöholm A. Gene expression regulated by pioglitazone and exenatide in normal and diabetic rat islets exposed to lipotoxicity. Diabetes Metab Res Rev. 2009;25(2):163–84.

    Article  CAS  PubMed  Google Scholar 

  • Guglielmi C, Palermo A, Pozzilli P. Latent autoimmune diabetes in the adults (LADA) in Asia: from pathogenesis and epidemiology to therapy. Diabetes Metab Res Rev. 2012;28(Suppl 2):40–6.

    Article  PubMed  Google Scholar 

  • Hampe CS, Kockum I, Landin-Olsson M, Törn C, Ortqvist E, Persson B, Rolandsson O, Palmer J, Lernmark A. GAD65 antibody epitope patterns of patients with type 1.5 differ from that of T1DM patients. Diabetes Care. 2002;25(8):1481–2.

    Article  PubMed  Google Scholar 

  • Hampe CS, Hall TR, Agren A, Rolandsson O. Longitudinal changes in epitope recognition of autoantibodies against glutamate decarboxylase 65 (GAD65Ab) in prediabetic adults developing diabetes. Clin Exp Immunol. 2007;148(1):72–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hawa MI, Kolb H, Schloot N, Beyan H, Paschou SA, Buzzetti R, Mauricio D, De Leiva A, Yderstraede K, Beck-Neilsen H, Tuomilehto J, Sarti C, Thivolet C, Hadden D, Hunter S, Schernthaner G, Scherbaum WA, Williams R, Brophy S, Pozzilli P, Leslie RD, Action LADA Consortium. Adult-onset autoimmune diabetes in Europe is prevalent with a broad clinical phenotype: Action LADA 7. Diabetes Care. 2013;36(4):908–13.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hawa MI, Buchan AP, Ola T, Wun CC, DeMicco DA, Bao W, Betteridge DJ, Durrington PN, Fuller JH, Neil HA, Colhoun H, Leslie RD, Hitman G. LADA and CARDS: a prospective study of clinical outcome in established adult-onset autoimmune diabetes. Diabetes Care. 2014;37(6):1643–9.

    Article  CAS  PubMed  Google Scholar 

  • Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA, Bluestone JA. Anti-CD3 monoclonal antibody in new-onset T1DM mellitus. N Engl J Med. 2002;346(22):1692–8.

    Article  CAS  PubMed  Google Scholar 

  • Hillman M, Törn C, Thorgeirsson H, Landin-Olsson M. IgG4-subclass of glutamic acid decarboxylase antibody is more frequent in latent autoimmune diabetes in adults than in type 1 diabetes. Diabetologia. 2004;47(11):1984–9.

    Article  CAS  PubMed  Google Scholar 

  • Holloway AC, Petrik JJ, Bruin JE, Gerstein HC. Rosiglitazone prevents diabetes by increasing beta-cell mass in an animal model of type 2 diabetes characterized by reduced beta-cell mass at birth. Diabetes Obes Metab. 2008;10(9):763–71.

    Article  CAS  PubMed  Google Scholar 

  • Horton V, Stratton I, Bottazzo GF, Shattock M, Mackay I, Zimmet P, Manley S, Holman R, Turner R. Genetic heterogeneity of autoimmune diabetes: age of presentation in adults is influenced by HLA DRB1 and DQB1 genotypes (UKPDS 43). Diabetologia. 1999;42:608–16.

    Article  CAS  PubMed  Google Scholar 

  • Hosszufalusi N, Vatay A, Rajczy K, Prohaszka Z, Pozsonyi E, Horvath L, Grosz A, Gero L, Madacsy L, Romics L, Karadi I, Fust G, Panczel P. Similar genetic features and different islet cell autoantibody pattern of latent autoimmune diabetes in adults (LADA) compared with adult-onset T1DM with rapid progression. Diabetes Care. 2003;26(2):452–7.

    Article  PubMed  Google Scholar 

  • Irvine WJ, Gray RS, McCallum CJ, Duncan LJP. Clinical and pathogenic significance of pancreatic-islet-cell antibodies in diabetics treated with oral hypoglycaemic agents. Lancet. 1977;1(8020):1025–7.

    Article  CAS  PubMed  Google Scholar 

  • Isomaa B, Tuomi T, Almgren P, Groop L, Henricsson M, Sarelin M. Chronic complications in patients with slowly progressing autoimmune type 1 diabetes (LADA). Diabetes Care. 1999;22:1347–53.

    Article  CAS  PubMed  Google Scholar 

  • Itariu BK, Stulnig TM. Autoimmune aspects of type 2 diabetes mellitus – a mini-review. Gerontology. 2014;60(3):189–96.

    Article  CAS  PubMed  Google Scholar 

  • Jansen A, Rosmalen JG, Homo-Delarche F, Dardenne M, Drexhage HA. Effect of prophylactic insulin treatment on the number of ER-MP23+ macrophages in the pancreas of NOD mice: is the prevention of diabetes based on beta-cell rest? J Autoimmun. 1996;9(3):341–8.

    Article  CAS  PubMed  Google Scholar 

  • Johansen OE, Boehm BO, Grill V, Torjesen PA, Bhattacharya S, Patel S, Wetzel K, Woerle HJ. C-peptide levels in latent autoimmune diabetes in adults treated with linagliptin versus glimepiride: exploratory results from a 2-year double-blind, randomized, controlled study. Diabetes Care. 2014;37(1):e11–2.

    Article  CAS  PubMed  Google Scholar 

  • Juneja R, Palmer JP. Type 1 1/2 diabetes: myth or reality? Autoimmunity. 1999;29(1):65–83.

    Article  CAS  PubMed  Google Scholar 

  • Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, Gorus F, Goldman M, Walter M, Candon S, Schandene L, Crenier L, De Block C, Seigneurin JM, De Pauw P, Pierard D, Weets I, Rebello P, Bird P, Berrie E, Frewin M, Waldmann H, Bach JF, Pipeleers D, Chatenoud L. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med. 2005;352(25):2598–608.

    Article  CAS  PubMed  Google Scholar 

  • Kisand K, Uibo R. LADA and T1D in Estonian population – two different genetic risk profiles. Gene. 2012;497(2):285–91.

    Article  CAS  PubMed  Google Scholar 

  • Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM, Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403.

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi T, Nakanishi K, Murase T, Kosaka K. Small doses of subcutaneous insulin as a strategy for preventing slowly progressive beta-cell failure in islet cell antibody-positive patients with clinical features of NIDDM. Diabetes. 1996;45(5):622–6.

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi T, Maruyama T, Shimada A, Kasuga A, Kanatsuka A, Takei I, Tanaka S, Yokoyama J. Insulin intervention to preserve beta cells in slowly progressive insulindependent (type 1) diabetes mellitus. Ann N Y Acad Sci. 2002;958:117–30.

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi T, Shimada A, Kanatsuka A, Kasuga A, Takei I, Yokoyama J, Kobayashi T. Multicenter prevention trial of slowly progressive IDDM with small dose of insulin (the Tokyo study). Ann N Y Acad Sci. 2003;1005:362–9.

    Article  PubMed  CAS  Google Scholar 

  • Kolb H. Benign versus destructive insulitis. Diabetes Metab Rev. 1997;13(3):139–46.

    Article  CAS  PubMed  Google Scholar 

  • Krause S, Landherr U, Agardh CD, Hausmann S, Link K, Hansen JM, Lynch KF, Powell M, Furmaniak J, Rees-Smith B, Bonifacio E, Ziegler AG, Lernmark A, Achenbach P. GAD autoantibody affinity in adult patients with latent autoimmune diabetes, the study participants of a GAD65 vaccination trial. Diabetes Care. 2014;37(6):1675–80.

    Article  CAS  PubMed  Google Scholar 

  • Lampasona V, Petrone A, Tiberti C, Capizzi M, Spoletini M, Di Pietro S, Songini M, Bonicchio S, Giorgino F, Bonifacio E, Bosi E, Buzzetti R, Non Insulin Requiring Autoimmune Diabetes (NIRAD) Study Group. Zinc transporter 8 antibodies complement GAD and IA-2 antibodies in the identification and characterization of adult-onset autoimmune diabetes: Non Insulin Requiring Autoimmune Diabetes (NIRAD) 4. Diabetes Care. 2010;33(1):104–8.

    Article  CAS  PubMed  Google Scholar 

  • Landstedt-Hallin L, Arner P, Lins PE, Bolinder J, Olsen H, Groop L. The role of sulphonylurea in combination therapy assessed in a trial of sulphonylurea withdrawal. Scandinavian Insulin-Sulphonylurea Study Group Research Team. Diabet Med. 1999;16(10):827–34.

    Article  CAS  PubMed  Google Scholar 

  • Laugesen E, Østergaard JA, Leslie RD, Danish Diabetes Academy Workshop and Workshop Speakers. Latent autoimmune diabetes of the adult: current knowledge and uncertainty. Diabet Med. 2015;32(7):843–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee SH, Kwon HS, You SJ, Ahn YB, Yoon KH, Cha BY, Lee KW, Son HY. Identifying latent autoimmune diabetes in adults in Korea: the role of C-peptide and metabolic syndrome. Diabetes Res Clin Pract. 2009;83(2):e62–5.

    Article  CAS  PubMed  Google Scholar 

  • Leslie RD, Delli Castelli M. Age-dependent influences on the origins of autoimmune diabetes: evidence and implications. Diabetes. 2004;53(12):3033–40.

    Article  CAS  PubMed  Google Scholar 

  • Li X, Yang L, Zhou Z, et al. Glutamic acid decarboxylase 65 autoantibody levels discriminate two subtypes of latent autoimmune diabetes in adults. Chin Med J. 2003;116(11):1728–32.

    CAS  PubMed  Google Scholar 

  • Li X, Zhou Z, Huang G, Peng J, Yan X, Yang L, Wang JP, Deng ZM. Study on the positive frequency and distribution of glutamic acid decarboxylase antibody in phenotypic type 2 diabetic patients. Chin J Epidemiol. 2005a;26(10):800–3.

    Google Scholar 

  • Li X, Zhou Z, Huang G, Su H, Yan X, Yang L. Metabolic syndrome in adult-onset latent autoimmune diabetes. Metab Syndr Relat Disord. 2005b;3(2):174–80.

    Article  CAS  PubMed  Google Scholar 

  • Lindström J, Louheranta A, Mannelin M, Rastas M, Salminen V, Eriksson J, Uusitupa M, Tuomilehto J, Finnish Diabetes Prevention Study Group. The Finnish Diabetes Prevention Study (DPS): lifestyle intervention and 3-year results on diet and physical activity. Diabetes Care. 2003;26(12):3230–6.

    Article  PubMed  Google Scholar 

  • Lohmann T, Kellner K, Verlohren HJ, Krug J, Steindorf J, Scherbaum WA, Seissler J. Titre and combination of ICA and autoantibodies to glutamic acid decarboxylase discriminate two clinically distinct types of latent autoimmune diabetes in adults (LADA). Diabetologia. 2001;44(8):1005–10.

    Article  CAS  PubMed  Google Scholar 

  • Lohmann T, Nietzschmann U, Kiess W. ‘Lady-like’: is there a latent autoimmune diabetes in the young? Diabetes Care. 2008;23(11):1707–8.

    Article  Google Scholar 

  • Lu J, Hou X, Zhang L, Hu C, Zhou J, Pang C, Pan X, Bao Y, Jia W. Associations between clinical characteristics and chronic complications in latent autoimmune diabetes in adults and type 2 diabetes. Diabetes Metab Res Rev. 2015;31(4):411–20.

    Article  PubMed  Google Scholar 

  • Ludvigsson J, Faresjo M, Hjorth M, Axelsson S, Chéramy M, Pihl M, Vaarala O, Forsander G, Ivarsson S, Johansson C, Lindh A, Nilsson NO, Aman J, Ortqvist E, Zerhouni P, Casas R. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med. 2008;359(18):1909–20.

    Article  CAS  PubMed  Google Scholar 

  • Ludvigsson J, Hjorth M, Cheramy M, Axelsson S, Pihl M, Forsander G, Nilsson NÖ, Samuelsson BO, Wood T, Aman J, Ortqvist E, Casas R. Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial. Diabetologia. 2011;54(3):634–40.

    Article  CAS  PubMed  Google Scholar 

  • Ludvigsson J, Krisky D, Casas R, et al. GAD65 antigen therapy in recently diagnosed T1DM mellitus. N Engl J Med. 2012;366(5):433–42.

    Article  CAS  PubMed  Google Scholar 

  • Lukacs K, Hosszufalusi N, Dinya E, Bakacs M, Madacsy L, Panczel P. The type 2 diabetes-associated variant in TCF7L2 is associated with latent autoimmune diabetes in adult Europeans and the gene effect is modified by obesity: a meta-analysis and an individual study. Diabetologia. 2012;55:689–93.

    Article  CAS  PubMed  Google Scholar 

  • Lundgren VM, Andersen MK, Isomaa B, Tuomi T. Family history of type 1 diabetes affects insulin secretion in patients with ‘type 2’ diabetes. Diabet Med. 2013;30:e163–9.

    Article  CAS  PubMed  Google Scholar 

  • MacCuish AC, Irvine WJ, Barnes EW, Duncan LJP. Antibodies to pancreatic islet cells in insulin-dependent diabetics with coexistent autoimmune disease. Lancet. 1974;2(7896):1529–31.

    Article  CAS  PubMed  Google Scholar 

  • Maddaloni E, Lessan N, Al Tikriti A, Buzzetti R, Pozzilli P, Barakat MT. Latent autoimmune diabetes in adults in the United Arab Emirates: clinical features and factors related to insulin-requirement. PLoS One. 2015;10(8):e0131837.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Maioli M, Pes GM, Delitala G, Puddu L, Falorni A, Tolu F, Lampis R, Orrù V, Secchi G, Cicalò AM, Floris R, Madau GF, Pilosu RM, Whalen M, Cucca F. Number of autoantibodies and HLA genotype, more than high titers of glutamic acid decarboxylase autoantibodies, predict insulin dependence in latent autoimmune diabetes of adults. Eur J Endocrinol. 2010;163(4):541–19.

    Article  CAS  PubMed  Google Scholar 

  • Malaisse WJ, Lebrun P. Mechanisms of sulfonylurea-induced insulin release. Diabetes Care. 1990;13(Suppl 3):9–17.

    Article  PubMed  Google Scholar 

  • Maruyama T, Tanaka S, Shimada A, Funae O, Kasuga A, Kanatsuka A, Takei I, Yamada S, Harii N, Shimura H, Kobayashi T. Insulin intervention in slowly progressive insulin-dependent (type 1) diabetes mellitus. J Clin Endocrinol Metab. 2008;93(6):2115–21.

    Article  CAS  PubMed  Google Scholar 

  • Mohatt J, Gilliam LK, Bekris L, Ebbesson S, Lernmark A. Type 1 diabetes-related autoantibodies are rare in Alaska native populations. Int J Circumpolar Health. 2002;61(1):21–31.

    Article  PubMed  Google Scholar 

  • Monge L, Bruno G, Pinach S, Grassi G, Maghenzani G, Dani F. A clinically orientated approach increases the efficiency of screening for latent autoimmune diabetes in adults (LADA) in a large clinic-based cohort of patients with diabetes onset over 50 years. Diabet Med. 2004;21(5):456–9.

    Article  CAS  PubMed  Google Scholar 

  • Myhill P, Davis WA, Bruce DG, Mackay IR, Zimmet P, Davis TME. Chronic complications and mortality in community-based patients with latent autoimmune diabetes in adults: the Fremantle Diabetes Study. Diabet Med. 2008;25:1245–50.

    Article  CAS  PubMed  Google Scholar 

  • Naik RG, Brooks-Worrell BM, Palmer JP. Latent autoimmune diabetes in adults. J Clin Endocrinol Metab. 2009;94(12):4635–44.

    Article  CAS  PubMed  Google Scholar 

  • Nisticò L, Buzzetti R, Pritchard LE, Van der Auwera B, Giovannini C, Bosi E, Larrad MT, Rios MS, Chow CC, Cockram CS, Jacobs K, Mijovic C, Bain SC, Barnett AH, Vandewalle CL, Schuit F, Gorus FK, Tosi R, Pozzilli P, Todd JA. The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. Hum Mol Genet. 1996;5(7):1075–80.

    Article  PubMed  Google Scholar 

  • Olsson L, Ahlbom A, Grill V, Midthjell K, Carlsson S. Sleep disturbances and low psychological well-being are associated with an increased risk of autoimmune diabetes in adults. Results from the Nord-Trøndelag Health Study. Diabetes Res Clin Pract. 2012;98(2):302–11.

    Article  PubMed  Google Scholar 

  • Park Y, Hong S, Park L, Woo J, Baik S, Nam M, Lee K, Kim Y, KNDP Collaboratory Group. LADA prevalence estimation and insulin dependency during follow-up. Diabetes Metab Res Rev. 2011;27(8):975–9.

    Article  CAS  PubMed  Google Scholar 

  • Petrone A, Suraci C, Capizzi M, Giaccari A, Bosi E, Tiberti C, Cossu E, Pozzilli P, Falorni A, Buzzetti R. The protein tyrosine phosphatase nonreceptor 22 (PTPN22) is associated with high GAD antibody titer in latent autoimmune diabetes in adults: Non Insulin Requiring Autoimmune Diabetes (NIRAD) Study 3. Diabetes Care. 2008;31(3):534–8.

    Article  PubMed  Google Scholar 

  • Pettersen E, Skorpen F, Kvaloy K, Midthjell K, Grill V. Genetic heterogeneity in latent autoimmune diabetes is linked to various degrees of autoimmune activity: results from the Nord-Trondelag Health Study. Diabetes. 2010;59(1):302–10.

    Article  CAS  PubMed  Google Scholar 

  • Pham MN, Hawa MI, Pfleger C, Roden M, Schernthaner G, Pozzilli P, Buzzetti R, Scherbaum WA, Seissler J, Kolb H, Hunter S, Leslie RD, Schloot NC, Action LADA Study Group. Pro- and anti-inflammatory cytokines in latent autoimmune diabetes in adults, type 1 and type 2 diabetes patients: Action LADA 4. Diabetologia. 2011;54(7):1630–8.

    Article  CAS  PubMed  Google Scholar 

  • Pham MN, Hawa MI, Roden M, Schernthaner G, Pozzilli P, Buzzetti R, Scherbaum WA, Seissler J, Hunter S, Leslie RD, Kolb H, Schloot NC, Action LADA Study Group. Increased serum concentrations of adhesion molecules but not of chemokines in patients with type 2 diabetes compared with patients with type 1 diabetes and latent autoimmune diabetes in adult age: Action LADA 5. Diabet Med. 2012;29(4):470–8.

    Article  CAS  PubMed  Google Scholar 

  • Pozzilli P, Di Mario U. Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult): definition, characterization, and potential prevention. Diabetes Care. 2001;24(8):1460–7.

    Article  CAS  PubMed  Google Scholar 

  • Pozzilli P, Guglielmi C. Immunomodulation for the prevention of SPIDDM and LADA. Ann N Y Acad Sci. 2006;1079:90–8.

    Article  CAS  PubMed  Google Scholar 

  • Qi X, Sun J, Wang J, Wang PP, Xu Z, Murphy M, Wang J, Xie Y, Xu W. Prevalence and correlates of latent autoimmune diabetes in adults in Tianjin China: a population based cross-sectional study. Diabetes Care. 2011;34(1):66–70.

    Article  PubMed  Google Scholar 

  • Radtke MA, Midthjell K, Nilsen TI, Grill V. Heterogeneity of patients with latent autoimmune diabetes in adults: linkage to autoimmunity is apparent only in those with perceived need for insulin treatment: results from the Nord-Trondelag Health (HUNT) study. Diabetes Care. 2009;32(2):245–50.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ramos-Lopez E, Lange B, Kahles H, Willenberg HS, Meyer G, Penna-Martinez M, Reisch N, Hahner S, Seissler J, Badenhoop K. Insulin gene polymorphisms in type 1 diabetes, Addison’s disease and the polyglandular autoimmune syndrome type II. BMC Med Genet. 2008;9:65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Raz I, Elias D, Avron A, Tamir M, Metzger M, Cohen IR. Beta cell function in new-onset T1DM and immune-modulation with a heatshock protein peptide (Dia-Pep277): a randomised, doubleblind, phase II trial. Lancet. 2001;358(9295):1749–53.

    Article  CAS  PubMed  Google Scholar 

  • Raz I, Avron A, Tamir M, Metzger M, Symer L, Eldor R, Cohen IR, Elias D. Treatment of new-onset T1DM with peptide DiaPep277 is safe and associated with preserved beta-cell function: extension of a randomized, double-blind, phase II trial. Diabetes Metab Res Rev. 2007;23(4):292–8.

    Article  CAS  PubMed  Google Scholar 

  • Roh MO, Jung CH, Kim BY, Mok JO, Kim CH. The prevalence and characteristics of latent autoimmune diabetes in adults (LADA) and its relation with chronic complications in a clinical department of a university hospital in Korea. Acta Diabetol. 2013;50(2):129–34.

    Article  CAS  PubMed  Google Scholar 

  • Sachan A, Zaidi G, Sahu RP, Agrawal S, Colman PG, Bhatia E. Low prevalence of latent autoimmune diabetes in adults in northern India. Diabet Med. 2015;32(6):810–3.

    Article  CAS  PubMed  Google Scholar 

  • Schloot N, Eisenbarth GS. Isohormonal therapy of endocrine autoimmunity. Immunol Today. 1995;16(6):289–94.

    Article  CAS  PubMed  Google Scholar 

  • Schlosser M, Banga JP, Madec AM, Binder KA, Strebelow M, Rjasanowski I, Wassmuth R, Gilliam LK, Luo D, Hampe CS. Dynamic changes of GAD65 autoantibody epitope specificities in individuals at risk of developing type 1 diabetes. Diabetologia. 2005;48(5):922–30.

    Article  CAS  PubMed  Google Scholar 

  • Schlosser M, Mueller PW, Torn C, Bonifacio E, Bingley PJ. Diabetes Antibody Standardization Program: evaluation of assays for insulin autoantibodies. Diabetologia. 2010;53(12):2611–20.

    Article  CAS  PubMed  Google Scholar 

  • Seissler J, de Sonnaville JJ, Morgenthaler NG, Steinbrenner H, Glawe D, Khoo-Morgenthaler UY, Lan MS, Notkins AL, Heine RJ, Scherbaum WA. Immunological heterogeneity in type 1 diabetes: presence of distinct autoantibody patterns in patients with acute onset and slowly progressive disease. Diabetologia. 1998;41(8):891–7.

    Article  CAS  PubMed  Google Scholar 

  • Shimada A, Imazu Y, Moringa S, Funae O, Kasuga A, Matsuoka K. T-cell insulitis found in anti-GAD65+ diabetes with residual β-cell function: a case report (Letter). Diabetes Care. 1999;22(4):615–7.

    Article  CAS  PubMed  Google Scholar 

  • Signore A, Chianelli M, Ronga G, Pozzilli P, Beverley PC. In vivo labelling of activated T lymphocytes by i.v. injection of 123I-IL2 for detection of insulitis in type 1 diabetes. Prog Clin Biol Res. 1990;355:229–38.

    CAS  PubMed  Google Scholar 

  • Signore A, Capriotti G, Chianelli M, Bonanno E, Galli F, Catalano C, Quintero AM, De Toma G, Manfrini S, Pozzilli P, Action LADA Group. Detection of insulitis by pancreatic scintigraphy with 99mTc-labeled IL-2 and MRI in patients with LADA (Action LADA 10). Diabetes Care. 2015;38(4):652–8.

    CAS  PubMed  Google Scholar 

  • Song WJ, Schreiber WE, Zhong E, Liu FF, Kornfeld BD, Wondisford FE, Hussain MA. Exendin-4 stimulation of cyclin A2 in beta-cell proliferation. Diabetes. 2008;57(9):2371–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sørgjerd EP, Skorpen F, Kvaløy K, Midthjell K, Grill V. Time dynamics of autoantibodies are coupled to phenotypes and add to the heterogeneity of autoimmune diabetes in adults: the HUNT study, Norway. Diabetologia. 2012;55:1310–8.

    Article  PubMed  CAS  Google Scholar 

  • Soriguer-Escofet F, Esteva I, Rojo-Martinez G, Ruiz de Adana S, Catalá M, Merelo MJ, Aguilar M, Tinahones F, García-Almeida JM, Gómez-Zumaquero JM, Cuesta-Muñoz AL, Ortego J, Freire JM. Prevalence of latent autoimmune diabetes of adults (LADA) in Southern Spain. Diabetes Res Clin Pract. 2002;56(3):213–20.

    Article  PubMed  Google Scholar 

  • Spoletini M, Petrone A, Zampetti S, Capizzi M, Zavarella S, Osborn J, Foffi C, Tuccinardi D. Low-risk HLA genotype in T1DM is associated with less destruction of pancreatic B-cells 12 months after diagnosis. Diabet Med. 2007;24(12):1487–90.

    Article  CAS  PubMed  Google Scholar 

  • Sutanegara D, Budhiarta AA. The epidemiology and management of diabetes mellitus in Indonesia. Diabetes Res Clin Pract. 2000;50(Suppl 2):S9–S16.

    Article  PubMed  Google Scholar 

  • Szepietowska B, Głębocka A, Puch U, Górska M, Szelachowska M. Latent autoimmune diabetes in adults in a population-based cohort of Polish patients with newly diagnosed diabetes mellitus. Arch Med Sci. 2012;8(3):491–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takeda H, Kawasaki E, Shimizu I, Konoue E, Fujiyama M, Murao S, et al. Clinical, autoimmune, and genetic characteristics of adultonset diabetic patients with GAD autoantibodies in Japan (Ehime Study). Diabetes Care. 2002;25(6):995–1001.

    Article  PubMed  Google Scholar 

  • Thai AC, Ng WY, Loke KY, Lee WR, Lui KF, Cheah JS. Anti-GAD antibodies in Chinese patients with youth and adultonset IDDM and NID. Diabetologia. 1997;40(12):1425–30.

    Article  CAS  PubMed  Google Scholar 

  • Thunander M, Thorgeirsson H, Torn C, Petersson C, Landin-Olsson M. β-cell function and metabolic control in latent autoimmune diabetes in adults with early insulin versus conventional treatment: a 3-year follow-up. Eur J Endocrinol. 2011;164(2):239–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tiberti C, Giordano C, Locatelli M, Bosi E, Bottazzo GF, Buzzetti R, Cucinotta D, Galluzzo A, Falorni A, Dotta F. Identification of tyrosine phosphatase 2(256–760) construct as a new, sensitive marker for the detection of islet autoimmunity in type 2 diabetic patients: the non-insulin requiring autoimmune diabetes (NIRAD) study 2. Diabetes. 2008;57(5):1276–83.

    Article  CAS  PubMed  Google Scholar 

  • Tree TI, Roep BO, Peakman M. A mini meta-analysis of studies on CD4+CD25+ T cells in human type 1 diabetes: report of the Immunology of Diabetes Society T Cell Workshop. Ann N Y Acad Sci. 2006;1079:9–18.

    Article  PubMed  Google Scholar 

  • Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR. Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes. 1993;42(2):359–62.

    Article  CAS  PubMed  Google Scholar 

  • Tuomi T, Carlsson A, Li H, Isomaa B, Miettinen A, Nilsson A, Nissén M, Ehrnström BO, Forsén B, Snickars B, Lahti K, Forsblom C, Saloranta C, Taskinen MR, Groop LC. Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes. 1999;48(1):150–7.

    Article  CAS  PubMed  Google Scholar 

  • Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, Shattock M, Bottazzo GF, Holman R. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group. Lancet. 1997;350(9087):1288–93.

    Article  CAS  PubMed  Google Scholar 

  • UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854–65.

    Article  Google Scholar 

  • Vang T, Congia M, Macis MD, Musumeci L, Orru V, Zavattari P, Nika K, Tautz L, Tasken K, Cucca F, Mustelin T, Bottini N. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet. 2005;37:1317–9.

    Article  CAS  PubMed  Google Scholar 

  • Vatay A, Rajczy K, Pozsonyi E, Hosszúfalusi N, Prohászka Z, Füst G, Karádi I, Szalai C, Grósz A, Bártfai Z, et al. Differences in the genetic background of latent autoimmune diabetes in adults (LADA) and T1DM mellitus. Immunol Lett. 2002;84:109–15.

    Article  CAS  PubMed  Google Scholar 

  • Wenzlau JM, Moua O, Sarkar SA, Yu L, Rewers M, Eisenbarth GS, Davidson HW, Hutton JC. SIC30A8 is a major target of humoral autoimmunity in T1DM and a predictive marker in prediabetes. Ann N Y Acad Sci. 2008;1150:256–9.

    Article  PubMed  Google Scholar 

  • Wherrett DK, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Greenbaum CJ, Herold KC, Marks JB, Monzavi R, Moran A, Orban T, Palmer JP, Raskin P, Rodriguez H, Schatz D, Wilson DM, Krischer JP, Skyler JS, T1DM TrialNet GAD Study Group. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised doubleblind trial. Lancet. 2011;378(9788):319–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilkin TJ. The accelerator hypothesis: weight gain as the missing link between type I and type II diabetes. Diabetologia. 2001;44(7):914–22.

    Article  CAS  PubMed  Google Scholar 

  • Wilkin T, Greene S, McCrimmon R. Testing the accelerator hypothesis: a new approach to T1DM prevention (adAPT 1). Diabetes Obes Metab. 2016;18(1):3–5.

    Article  CAS  PubMed  Google Scholar 

  • Xiang Y, Zhou P, Li X, Huang G, Liu Z, Xu A, Leslie RD, Zhou Z. Heterogeneity of altered cytokine levels across the clinical spectrum of diabetes in China. Diabetes Care. 2011;34(7):1639–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both β-cell replication and neogenesis, resulting in increased β-cell mass and improved glucose tolerance in diabetic rats. Diabetes. 1999;48:2270–6.

    Article  CAS  PubMed  Google Scholar 

  • Yang Z, Zhou Z, Huang G, Ling H, Yan X, Peng J, Li X. The CD4 regulatory T-cells is decreased in adults with latent autoimmune diabetes. Diabetes Res Clin Pract. 2007;76(1):126–31.

    Article  CAS  PubMed  Google Scholar 

  • Zampetti S, Spoletini M, Petrone A, Capizzi M, Arpi ML, Tiberti C, Di Pietro S, Bosi E, Pozzilli P, Giorgino F, Buzzetti R, NIRAD Study Group. Association of TCF7L2 gene variants with low GAD autoantibody titre in LADA subjects (NIRAD study 5). Diabet Med. 2010;27(6):701–4.

    Article  CAS  PubMed  Google Scholar 

  • Zampetti S, Capizzi M, Spoletini M, Campagna G, Leto G, Cipolloni L, Tiberti C, Bosi E, Falorni A, Buzzetti R, NIRAD Study Group. GADA titer-related risk for organ-specific autoimmunity in LADA subjects subdivided according to gender (NIRAD study 6). J Clin Endocrinol Metab. 2012;97(10):3759–65.

    Article  CAS  PubMed  Google Scholar 

  • Zampetti S, Campagna G, Tiberti C, Songini M, Arpi ML, De Simone G, Cossu E, Cocco L, Osborn J, Bosi E, Giorgino F, Spoletini M, Buzzetti R, NIRAD Study Group. High GADA titer increases the risk of insulin requirement in LADA patients: a 7-year follow-up (NIRAD study 7). Eur J Endocrinol. 2014;171(6):697–704.

    Article  CAS  PubMed  Google Scholar 

  • Zhang N, Huang W, Dong F, Liu Y, Zhang B, Jing L, Wang M, Yang G, Jing C. Insulin gene VNTR polymorphisms -2221MspI and -23HphI are associated with T1DM and latent autoimmune diabetes in adults: a meta-analysis. Acta Diabetol. 2015;52(6):1143–55.

    Article  CAS  PubMed  Google Scholar 

  • Zhao Y, Yang L, Xiang Y, Liu L, Huang G, Long Z, Li X, Leslie RD, Wang X, Zhou Z. Dipeptidyl peptidase 4 inhibitor sitagliptin maintains beta-cell function in patients with recent-onset latent autoimmune diabetes in adults: one year prospective study. J Clin Endocrinol Metab. 2014;99(5):E876–80.

    Article  CAS  PubMed  Google Scholar 

  • Zhou Z, Li X, Huang G, Peng J, Yang L, Yan X, Wang J. Rosiglitazone combined with insulin preserves islet beta cell function in adult-onset latent autoimmune diabetes (LADA). Diabetes Metab Res Rev. 2005;21(2):203–8.

    Article  PubMed  CAS  Google Scholar 

  • Zhou J, Ma XJ, Bao YQ, Pan XP, Lu W, Hu C, Xiang KS, Jia WP. Study on prevalence of latent autoimmune diabetes in adults and its relationship with metabolic syndrome. Zhonghua Yi Xue Za Zhi. 2009;89(18):1250–4.

    CAS  PubMed  Google Scholar 

  • Zhou Z, Xiang Y, Ji L, Jia W, Ning G, Huang G, Yang L, Lin J, Liu Z, Hagopian WA, Leslie RD, on behalf of LADA China Study Group. Frequency, immunogenetics, and clinical characteristics of latent autoimmune diabetes in China (LADA China study): a nationwide, multicenter, clinic-based cross-sectional study. Diabetes. 2013;62(2):543–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zinman B, Kahn SE, Haffner SM, O’Neill MC, Heise MA, Freed MI, ADOPT Study Group. Phenotypic characteristics of GAD antibody-positive recently diagnosed patients with type 2 diabetes in North America and Europe. Diabetes. 2004;53(12):3193–200.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Experimental Medicine, “Sapienza” University of Rome, Rome, Italy

    Simona Zampetti & Raffaella Buzzetti

Authors
  1. Simona Zampetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raffaella Buzzetti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raffaella Buzzetti .

Editor information

Editors and Affiliations

  1. Division of Endocrinology, Diabetes and Metabolism, University and Hospital Trust of Verona, Verona, Italy

    Enzo Bonora

  2. Diabetes Division, Diabetes Research Unit, University of Texas Health Science Center, San Antonio, TX, USA

    Ralph A. DeFronzo

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Zampetti, S., Buzzetti, R. (2018). LADA. In: Bonora, E., DeFronzo, R. (eds) Diabetes Epidemiology, Genetics, Pathogenesis, Diagnosis, Prevention, and Treatment . Endocrinology. Springer, Cham. https://doi.org/10.1007/978-3-319-45015-5_9

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-45015-5_9

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-45014-8

  • Online ISBN: 978-3-319-45015-5

  • eBook Packages: MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation