Slowly Progressive Type 1 Diabetes Mellitus: Current Knowledge And Future Perspectives

Figures & data

Figure 1 Characteristic features of the pancreas in patients with SPIDDM. (A) Pancreatic intraductal papillous neoplasia (PanIN) lesion frequently observed in the patients with SPIDDM. Azan staining. PanIN lesion of pancreatic ducts (arrowheads) is associated with an atrophied, fibrous pancreatic lobe (stained blue), a dilated pancreatic duct (asterisk) and extensive mononuclear cell infiltration. (B) Insulitis in a patient with SPIDDM. CD45 (leukocyte common antigen) ⁺ mononuclear cells (MNCs) are infiltrated around (arrowheads) and into the islet cells (arrows). Most of the CD45⁺ cells are CD8⁺ T cells and CD68⁺ macrophages. Aida K, Fukui T, Jimbo E, et al. Distinct inflammatory changes of the pancreas of slowly progressive insulin-dependent (Type 1) Diabetes. Pancreas. 2018;47(9):1101–1109.²¹

Figure 2 (A) Longitudinal changes of patients who progressed from the non-insulin-requiring stage to an insulin-dependent stage (IDS) in five study groups. IDS is defined as the state when integrated values of serum C-peptide levels at 0, 30, 60, 90, and 120 min during a 100-g oral glucose tolerance test (sigma C-peptide) reach <5 ng/mL. (B) Reduction rate of sigma C-peptide in group 1 (patients with GADAb titer ≥10 AU/mL [≥180 WHO U/mL]), group 2 (patients with GADAb titer <10 AU/mL [<180 WHO U/mL]), group 3 (patients without GADAb and with islet cell antibodies [ICA], group 4 (patients without GADAb or ICA antibodies and with insulin-associated antigen 2 antibodies [IA-2A]), and group 5 (patients with T2D without GADAb, ICA, or IA-2A antibodies).

Note: Copyright © 2015. Japan Diabetes Society. Reproduced from Tanaka S, Okubo M, Nagasawa K, et al. Predictive value of titer of GAD antibodies for further progression of beta cell dysfunction in slowly progressive insulin-dependent (type 1) diabetes (SPIDDM). Diabetol Int. 2016;7(1):42–52.³³

Table 1 Genes Associated Or Not Associated With SPIDDM Or LADA

	Gene	dbSNP ID (Rs Number)	Association	Odds Ratio (95% CI)	Comparator	Reference
HLA	DR3	2187668	Positive	3.37 (2.92–3.90)	Healthy subjects	^Citation57
	DR4	660,895	Positive	3.34 (2.94–3.81)	Healthy subjects	^Citation57
	DQA1*0301-DQB1*0401-DRB1*0405 (DR4)	N/A	Positive	2.9 (N/A)	Healthy subjects	^Citation3
	DQA1*0103-DQB1*0601-DRB1*1502 (DR2)	N/A	Protective	0.08 (N/A)	Healthy subjects	^Citation3
	DQA1*0301-DQB1*0302-DRB1*0802 (DR8)	N/A	No association	N/A	Healthy subjects	^Citation3
	DQA1*0301-DQB1*0303-DRB1*0901 (DR9)	N/A	No association	N/A	Healthy subjects	^Citation3
	DQA1*05_DQB1*0201_DRB1*0301	N/A	Positive	2.65 (1.93–3.65)	Healthy subjects	^Citation61
	DQA1*03_DQB1*0401_DRB1*0405	N/A	Positive	2.02 (1.48–2.76)	Healthy subjects	^Citation61
	DQA1*03_DQB1*0303_DRB1*0901	N/A	Positive	1.61 (1.34–1.93)	Healthy subjects	^Citation61
	DQA1*03_DQB1*0303_DRB1*0803	N/A	Protective	1.61 (1.34–1.93)	Healthy subjects	^Citation61
	DQA1*0601g_DQB1*0301_DRB1*1202	N/A	No association	N/A	Healthy subjects	^Citation61
	DQA1*0101g_DQB1*0502_DRB1*1401	N/A	No association	N/A	Healthy subjects	^Citation61
	DQA1*03_DQB1*0303	N/A	Positive	N/A	Healthy subjects	^Citation39
	DQA1*03_DQB1*0401	N/A	Positive	N/A	Healthy subjects	^Citation39
	DQA1*05_DQB1*0201	N/A	Positive	N/A	Healthy subjects	^Citation39
	DQA1*05_DQB1*0201	N/A	Positive	N/A	T2D subjects	^Citation39
	DQA1*0102_DQB1*0602	N/A	Protective	N/A	T2D subjects	^Citation39
	DQA1*05_DQB1*0201_DRB1*0301	N/A	Protective	0.55 (0.42–0.72)	AT1D subjects	^Citation61
	DQA1*03_DQB1*0401_DRB1*0405	N/A	No association	N/A	AT1D subjects	^Citation61
	DQA1*03_DQB1*0303_DRB1*0901	N/A	No association	N/A	AT1D subjects	^Citation61
	DQA1*0601g_DQB1*0301_DRB1*1202	N/A	Positive	2.79 (1.71–4.57)	AT1D subjects	^Citation61
	DQA1*0101g_DQB1*0502_DRB1*1401	N/A	Positive	8.19 (2.47–27.12)	AT1D subjects	^Citation61
	DQB1*0401-DRB1*0405 (DR4)	N/A	Positive	2.5 (N/A)	Healthy subjects	^Citation59
	DQB1*0303-DRB1*0901 (DR9)	N/A	Positive	1.9 (N/A)	Healthy subjects	^Citation59
	DQB1*0601-DRB1*1502 (DR2)	N/A	Protective	0.14 (N/A)	Healthy subjects	^Citation59
	DQB1*0302-DRB1*0802	N/A	No association	N/A	Healthy subjects	^Citation59
	DQB1*0602-DRB1*1501	N/A	No association	N/A	Healthy subjects	^Citation59
	DQB1 *0201_DRB1 *0301	N/A	Positive	3.08 (2.32–4.12)	Healthy subjects	^Citation60
	DQB1 *0302_DRB1 *0401	N/A	Positive	2.57 (1.80–3.73)	Healthy subjects	^Citation60
	DQB1 *0602_DRB1 *1501	N/A	Protective	0.21 (0.13–0.34)	Healthy subjects	^Citation60
	DQB1 *0602_DRB1 *1501	N/A	Protective	N/A	Healthy subjects	^Citation64
	DQB1 *0301_DRB1 *1101(04)	N/A	Protective	0.25 (0.12–0.48)	Healthy subjects	^Citation60
	DQB1	9273368-A	Positive	3.115 (2.855–3.398)	Healthy subjects	^Citation63
	DQB1	1049107	Protective	0.27 (0.13–0.56)	Healthy subjects	^Citation59
	DQB1*0401_DRB1*0405	N/A	Positive	N/A	Healthy subjects	^Citation64
	DQB1 low risk	N/A	Positive	2.26 (1.17–4.36)	Healthy subjects	^Citation65
	DQB1 moderate risk	N/A	Positive	3.49 (1.15–10.61)	Healthy subjects	^Citation65
	DQB1 high risk	N/A	Positive	3.92 (1.12–13.79)	Healthy subjects	^Citation65
	DQB1	9273368-A	Positive	2.439 (2.222–2.676)	T2D subjects	^Citation63
	DQB1 *0302/*02, 0302/X	N/A	Positive	N/A	T2D subjects	^Citation62
	DQB1	9273368-A	Protective	0.335 (0.256–0.385)	AT1D subjects	^Citation63
	DOB	2071554	Protective	0.28 (0.15–0.54)	Healthy subjects	^Citation59
	A24	N/A	No association	N/A	Healthy subjects	^Citation3
CTLA4	49 GG	N/A	Positive	5.93 (2.21–15.86)	Healthy subjects	^Citation65
	49 AG	N/A	Positive	2.74 (1.12–6.69)	Healthy subjects	^Citation65
	AG	N/A	Positive	2.47 (1.27–4.81)	Healthy subjects	^Citation66
	AA	N/A	Protective	0.40 (0.20–0.80)	Healthy subjects	^Citation66
	G>A	3087243	Protective	0.75 (0.68–0.83)	Healthy subjects	^Citation57
	N/A	N/A	No association	N/A	Healthy subjects	^Citation58
	CT60	3087243	No association	N/A	T2D subjects	^Citation62
PTPN22	1858 C>T	2476601	Positive	1.7 (1.1–2.7)	Healthy subjects	^Citation55
	1858 C>T	2476601	Positive	1.717 (1.539–1.915)	Healthy subjects	^Citation63
	1858 C>T	2476601	Positive	1.77 (1.53–2.06)	Healthy subjects	^Citation57
	1858 C>T	2476601	Positive	N/A	Healthy subjects	^Citation55
	1858 C>T	2476601	No association	N/A	Healthy subjects	^Citation69
	1858 C>T	2476601	Positive	N/A	T2D subjects	^Citation62
	1858 C>T	2476601	Positive	1.529 (1.380–1.693)	T2D subjects	^Citation63
	A>C	6679677	Positive	1.469 (1.427–1.510)	Healthy subjects	^Citation58
	1123 G>C	2488457	No association	N/A	Healthy subjects	^Citation69
	2740 C>T	1217412	No association	N/A	Healthy subjects	^Citation69
	T>C	478582	No association	N/A	Healthy subjects	^Citation57
	G>C	45450798	No association	N/A	Healthy subjects	^Citation57
INS	VNTR T>A	689	Positive	1.265 (1.234–1.296)	Healthy subjects	^Citation58
	VNTR AA	689	Positive	1.7 (1.2–2.6)	Healthy subjects	^Citation55
	VNTR T>A	689	Positive	1.483 (1.363–1.613)	Healthy subjects	^Citation63
	VNTR A>T	689	Protective	0.47 (0.42–0.54)	Healthy subjects	^Citation57
	VNTR T>A	689	positive	1.473 (1.352–1.605)	T2D subjects	^Citation63
	VNTR A/T	689	No association	N/A	T2D subjects	^Citation62
	VNTR	3842755	Positive	1.6 (1.1–2.5)	Healthy subjects	^Citation55
	VNTR	N/A	Positive	2.34 (1.25–4.38)	Healthy subjects	^Citation65
Vitamin D receptor	BB genotype	N/A	Positive	N/A	Healthy subjects	^Citation71
Interleukin 2 receptor	A>G	12722495	Protective	0.70 (0.58–0.83)	Healthy subjects	^Citation57
	IL-2 receptor-alpha (IL2RA)(CD25)	706778	No association	N/A	Healthy subjects	^Citation72
	IL-2 receptor-alpha (IL2RA)(CD25)	3118470	No association	N/A	Healthy subjects	^Citation72
	IL2RA	N/A	No association	N/A	Healthy subjects	^Citation58
TCF7L2	CT/TT	7903146	Positive	1.5 (1.2–1.9)	Healthy subjects	^Citation55
	T	7903146	Positive	1.44 (1.18–1.77)	Healthy subjects	^Citation73
	T/C	7903146	No association	N/A	Healthy subjects	^Citation58
	T/C	7903146	Protective	N/A	T2D subjects	^Citation58
	GT/TT	12,255372	Positive	1.5 (1.1–1.9)	Healthy subjects	^Citation55
	G>T	12,255372	No association	N/A	Healthy subjects	^Citation57
ZMIZ1	A	12571751	Positive	1.35 (1.15–1.60)	Healthy subjects	^Citation73
SH2B3	C/G	7310615	Positive	1.284 (1.193–1.383)	Healthy subjects	^Citation63
	C/G	7310615	Positive	1.240 (1.151–1.336)	T2D subjects	^Citation63
	A>G	3184504	Positive	1.35 (1.22–1.50)	Healthy subjects	^Citation57
	C/T	3184504	Positive	1.24 (1.151–1.336	T2D subjects	^Citation63
	G/A	17696736	Positive	1.277 (1.250–1.304)	Healthy subjects	^Citation58
PFKFB3	C/T	1983890	Positive	1.16 (1.14–1.32)	Healthy subjects	^Citation63
TNF	N/A	1800610	Positive	2.17 (1.51–3.11)	Healthy subjects	^Citation59
MHC	A/G	9272,346	Positive	1.455 (1.427–1.483)	Healthy subjects	^Citation58
HNFIA	G/C	12427353	Positive	1.291 (1.256–1.326)	Healthy subjects	^Citation58
STAT4	G>T	7574865	Positive	1.23 (1.09–1.39)	Healthy subjects	^Citation57
STAT	N/A	N/A	No association	N/A	Healthy subjects	^Citation58
ERBB3	C>A	2292239	Positive	1.20 (1.08–1.33)	Healthy subjects	^Citation57
CLEC16A	A>G	12708716	Protective	0.83 (0.75–0.93)	Healthy subjects	^Citation57
	N/A	N/A	No association	N/A	Healthy subjects	^Citation58
SMARCE1	N/A	7221109	Protective	N/A	AT1D subjects	^Citation58

Abbreviations: dbSNP ID, The Single Nucleotide Polymorphism Database; CI, confidence interval; HLA, human leukocyte antigen; CTLA4, cytotoxic T lymphocyte-associated antigen 4; PTPN22, protein tyrosine phosphatase, non-receptor 22 gene; INS, insulin gene; VNTR, variable number of tandem repeats; TCF7L2, transcription factor 7 like 2; ZMIZ1, zinc finger MIZ-type containing 1, SH2B3, SH2B adaptor protein 3; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; TNF, tumor necrosis factor; MHC, major histocompatibility complex; HNF1A, HNF1 homeobox A; STAT4 signal transducer and activator of transcription 4; ERBB3, erb-b2 receptor tyrosine kinase 3; CLEC16A, C-type lectin domain containing 16A; SMARCE1, SWI/SNF related, matrix associated, actin-dependent regulator of chromatin, subfamily e, member 1; T2D, type 2 diabetes; AT1D, acute type 1 diabetes.

Table 2 Prevalence Of Islet Cell Autoantibody Positivity Among Patients With Diabetes

Author (Study), Year	Region	Location	AA Positivity (%)	Sample Size (n)	Type Of Study	Measured AA	Refs
Takeda et al (Ehime study), 2002	Asia	Japan	3.8	4980	Clinical-based study	GAD	^Citation64
Lee et al, 2009		Korea	5.1	1370	Clinical-based study	GAD, IA-2	^Citation84
Qi et al, 2011		China	9.2	8109	Population-based study.	GAD	^Citation85
Zhou et al (LADA China study), 2013		China	5.9	4880	Clinical-based study	GAD	^Citation39
Turner et al (UKPDS 25), 1997	Europe	U.K.	12	3672	Clinical-based study	GAD, ICA	^Citation26
Tuomi et al (Botnia study), 1999		Finland	9.3	1122	Population-based study.	GAD, IA-2, ICA	^Citation37
Bosi et al (Cremona study), 1999		Italy	2.8	2076	Population-based study.	GAD, IA-2	^Citation86
Zinman et al (ADOPT), 2004		Europe, US, Canada	4.2	4357	Clinical-based study	GAD	^Citation87
Buzzetti et al (NIRAD study), 2007		Italy	4.5	4250	Clinical-based study	GAD, IA-2	^Citation35
Radtke et al (HUNT study), 2009		Norway	10.1	1049	Population-based study.	GAD	^Citation88
Maioli et al, 2010		Italy	4.9	5568	Clinical-based study	GAD	^Citation38
Hawa et al (Action LADA 7), 2013		Europe	9.7	6156	Clinical-based study	GAD, IA-2, ZnT8	^Citation32
Maddaloni et al, 2015	Middle Eastern	United Arab Emirates	2.6	17,072	Clinical-based study	GAD, IA-2	^Citation44

Abbreviations: LADA, latent autoimmune diabetes in adults; ADOPT, A Diabetes Outcome Progression Trial; NIRAD, Non-Insulin Requiring Autoimmune Diabetes; UKPDS, United Kingdom Prospective Diabetes Study; HUNT, Nord-Trøndelag Health; AA, autoantibody; GAD, glutamic acid decarboxylase; IA-2, tyrosine phosphatase IA-2; ZnT8, zinc transporter 8; ICA, islet-cell antibody.

Table 3 Clinical Characteristics Of SPIDDM Compared With AT1D And T2D

	AT1D	SPIDDM	T2D
Age at diagnosis	Childhood to adolescence	Any age	Adulthood
Onset	Acute	Intermediate	Slow
Acute complications (e.g. ketosis) at diagnosis	Frequently	Rare	Rare
Micro/macro-vascular complications at diagnosis	Rare	Rare	Sometimes
Family history of diabetes	Sometimes	Sometimes	Frequently
Family history of autoimmune disease	Frequently	Frequently	Rare
Autoimmunity	Severely increased	increased	no change
Other autoimmune disease	Frequently	Frequently	Rare
HLA	Strongly associated	Associated	Not associated
BMI	Low to normal	Normal to high	High
Mets or its components	Rare	Sometimes	Frequently
Beta cell function	Severely decreased	Decreased	No change or increased
Decline in beta cell function	<3 months	>3 months	>years

Abbreviations: AT1D, acute-onset type 1 diabetes; SPIDDM, Slowly progressive type 1 (insulin-dependent) diabetes mellitus; T2D, type 2 diabetes mellitus; HLA, human leukocyte antigen; BMI, body mass index; Mets, metabolic syndrome.

Table 4 Diagnostic Criteria For Slowly Progressive Insulin-Dependent Type 1 Diabetes Mellitus (2012)

Requirements
1. Presence of glutamic acid decarboxylase antibodies (GADAb) and/or islet cell antibodies (ICA) at some time during the disease course a 2. Absence of ketosis or ketoacidosis at onset (or diagnosis) of diabetes mellitus and no need for insulin treatment to correct hyperglycemia immediately after diagnosis b Determination: “‘Slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM)’” should be diagnosed if the conditions described in 1 and 2 above are met
Notes
1) As the course progresses, insulin secretory capacity gradually decreases, and insulin therapy becomes necessary more than 3 months after onset (or diagnosis) of diabetes mellitus, and insulin dependence frequently develops 2) In the field of pediatrics, at the time diabetes mellitus is diagnosed, insulin treatment at low doses (B0.5 U/kg body weight) is sometimes started immediately. Even in the field of internal medicine, if GADAb-positive findings are confirmed, patients are sometimes started immediately on insulin therapy, in consideration of preventing decreased insulin secretion 3) GADAb and/or ICA sometimes become negative during the disease course in many cases 4) In rare cases with GADAb and/or ICA, insulin dependence does not develop until 10 years and more after onset (or diagnosis) of diabetes mellitus, because of extremely gradual or no change in insulin secretory capacity, irrespective of the titer of GADAb and ICA
a Because there is insufficient evidence for insulinoma-associated antigen-2 antibodies (IA-2Ab), insulin autoantibodies (IAA), or zinc transporter 8 antibodies (ZnT8Ab), the presence of these antibodies was excluded from the required diagnostic criteria b This limitation does not apply when soft drink ketosis (ketoacidosis) has occurred at onset of diabetes mellitus

Figure 3 Longitudinal changes in the C-peptide response to the oral glucose tolerance test for 48 months in patients treated with sitagliptin in the Tokyo study. Patients with 48 months of follow-up are shown. Data are expressed as the mean ± SEM. In both the ∑C-peptide values (A) and change ratios from baseline (B), a repeated-measures analysis of variance revealed a significant interaction between time and treatment assignment (sitagliptin or insulin; p = 0.030 and p = 0.014, respectively) as well as between time and treatment assignment (sitagliptin or sulfonylurea; p = 0.00004 and p = 0.007, respectively) in the longitudinal changes.

Note: Reproduced from Awata T, Shimada A, Maruyama T, et al. Possible Long-Term Efficacy of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, for Slowly Progressive Type 1 Diabetes (SPIDDM) in the Stage of Non-Insulin Dependency: An Open-Label Randomized Controlled Pilot Trial (SPAN-S). Diabetes Ther. 2017;8(5):1123-1134. Creative commons license and disclaimer available from: http://creativecommons.org/licenses/by/4.0/legalcode.¹⁴

Aida K , Fukui T , Jimbo E , et al. Distinct inflammatory changes of the pancreas of slowly progressive insulin-dependent (Type 1) Diabetes. Pancreas . 2018;47(9):1101–1109. doi:10.1097/MPA.0000000000001144 30192315

 PubMed Web of Science ®Google Scholar

Tanaka S , Okubo M , Nagasawa K , et al. Predictive value of titer of GAD antibodies for further progression of beta cell dysfunction in slowly progressive insulin-dependent (type 1) diabetes (SPIDDM). Diabetol Int . 2016;7(1):42–52. doi:10.1007/s13340-015-0211-5 30603242

 PubMedGoogle Scholar

Howson JM , Rosinger S , Smyth DJ , Boehm BO , Todd JA . Genetic analysis of adult-onset autoimmune diabetes. Diabetes . 2011;60(10):2645–2653. doi:10.2337/db11-0364 21873553

 PubMed Web of Science ®Google Scholar

Kobayashi T , Tamemoto K , Nakanishi K , et al. Immunogenetic and clinical characterization of slowly progressive IDDM. Diabetes Care . 1993;16(5):780–788. doi:10.2337/diacare.16.5.780 8098691

 PubMed Web of Science ®Google Scholar

Luo S , Lin J , Xie Z , et al. HLA genetic discrepancy between latent autoimmune diabetes in adults and type 1 diabetes: LADA China study no. 6. J Clin Endocrinol Metab . 2016;101(4):1693–1700. doi:10.1210/jc.2015-3771 26866570

 PubMed Web of Science ®Google Scholar

Zhou Z , Xiang Y , Ji L , et al. 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):543–550. doi:10.2337/db12-0207 23086039

 PubMed Web of Science ®Google Scholar

Kawabata Y , Ikegami H , Awata T , et al. Differential association of HLA with three subtypes of type 1 diabetes: fulminant, slowly progressive and acute-onset. Diabetologia . 2009;52(12):2513–2521. doi:10.1007/s00125-009-1539-9 19812988

 PubMed Web of Science ®Google Scholar

Desai M , Zeggini E , Horton VA , et al. An association analysis of the HLA gene region in latent autoimmune diabetes in adults. Diabetologia . 2007;50(1):68–73. doi:10.1007/s00125-006-0513-z 17143607

 PubMed Web of Science ®Google Scholar

Takeda H , Kawasaki E , Shimizu I , et al. Clinical, autoimmune, and genetic characteristics of adult-onset diabetic patients with GAD autoantibodies in Japan (Ehime Study). Diabetes Care . 2002;25(6):995–1001. doi:10.2337/diacare.25.6.995 12032105

 PubMed Web of Science ®Google Scholar

Cousminer DL , Ahlqvist E , Mishra R , et al. First genome-wide association study of latent autoimmune diabetes in adults reveals novel insights linking immune and metabolic diabetes. Diabetes Care . 2018;41(11):2396–2403. doi:10.2337/dc18-1032 30254083

 PubMed Web of Science ®Google Scholar

Haller K , Kisand K , Pisarev H , et al. Insulin gene VNTR, CTLA-4 +49A/G and HLA-DQB1 alleles distinguish latent autoimmune diabetes in adults from type 1 diabetes and from type 2 diabetes group. Tissue Antigens . 2007;69(2):121–127. doi:10.1111/tan.2007.69.issue-2 17257313

 PubMedGoogle Scholar

Andersen MK , Lundgren V , Turunen JA , et al. Latent autoimmune diabetes in adults differs genetically from classical type 1 diabetes diagnosed after the age of 35 years. Diabetes Care . 2010;33(9):2062–2064. doi:10.2337/dc09-2188 20805278

 PubMed Web of Science ®Google Scholar

Cosentino A , Gambelunghe G , Tortoioli C , Falorni A . CTLA-4 gene polymorphism contributes to the genetic risk for latent autoimmune diabetes in adults. Ann N Y Acad Sci . 2002;958:337–340. doi:10.1111/j.1749-6632.2002.tb03000.x 12021137

 PubMed Web of Science ®Google Scholar

Mishra R , Chesi A , Cousminer DL , et al. Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes. BMC Medicine . 2017;15(1):88. doi:10.1186/s12916-017-0846-0 28438156

 PubMed Web of Science ®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):1433–1437. doi:10.2337/db07-0299 18310307

 PubMed Web of Science ®Google Scholar

Kawasaki E , Awata T , Ikegami H , et al. Systematic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): association between a promoter polymorphism and type 1 diabetes in Asian populations. Am J Med Genet A . 2006;140(6):586–593. doi:10.1002/ajmg.a.31124 16470599

 PubMed Web of Science ®Google Scholar

Shimada A , Kanazawa Y , Motohashi Y , et al. Evidence for association between vitamin D receptor BsmI polymorphism and type 1 diabetes in Japanese. J Autoimmunity . 2008;30(4):207–211. doi:10.1016/j.jaut.2007.09.002 17959356

 PubMed Web of Science ®Google Scholar

Kawasaki E , Awata T , Ikegami H , et al. Genetic association between the interleukin-2 receptor-alpha gene and mode of onset of type 1 diabetes in the Japanese population. J Clin Endocrinol Metab . 2009;94(3):947–952. doi:10.1210/jc.2008-1596 19106270

 PubMed Web of Science ®Google Scholar

Andersen MK , Sterner M , Forsen T , et al. Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes. Diabetologia . 2014;57(9):1859–1868. doi:10.1007/s00125-014-3287-8 24906951

 PubMed Web of Science ®Google Scholar

Lee SH , Kwon HS , Yoo SJ , et al. Identifying latent autoimmune diabetes in adults in Korea: the role of C-peptide and metabolic syndrome. Diabetes Res Clin Pract . 2009;83(2):e62–e65. doi:10.1016/j.diabres.2008.11.031 19166794

 PubMedGoogle Scholar

Qi X , Sun J , Wang J , et al. 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. doi:10.2337/dc10-0488 20876205

 PubMed Web of Science ®Google Scholar

Turner R , Stratton I , Horton V , et al. 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):1288–1293. doi:10.1016/S0140-6736(97)03062-6 9357409

 PubMed Web of Science ®Google Scholar

Tuomi T , Carlsson A , Li H , et al. Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes . 1999;48(1):150–157. doi:10.2337/diabetes.48.1.150 9892237

 PubMed Web of Science ®Google Scholar

Bosi EP , Garancini MP , Poggiali F , Bonifacio E , Gallus G . Low prevalence of islet autoimmunity in adult diabetes and low predictive value of islet autoantibodies in the general adult population of northern Italy. Diabetologia . 1999;42(7):840–844. doi:10.1007/s001250051235 10440126

 PubMed Web of Science ®Google Scholar

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 . 2004;53(12):3193–3200. doi:10.2337/diabetes.53.12.3193 15561950

 PubMed Web of Science ®Google Scholar

Buzzetti R , Di Pietro S , Giaccari A , et al. High titer of autoantibodies to GAD identifies a specific phenotype of adult-onset autoimmune diabetes. Diabetes Care . 2007;30(4):932–938. doi:10.2337/dc06-1696 17392553

 PubMed Web of Science ®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):245–250. doi:10.2337/dc08-1468 19001190

 PubMed Web of Science ®Google Scholar

Maioli M , Pes GM , Delitala G , et al. 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):541–549. doi:10.1530/EJE-10-0427 20603341

 PubMed Web of Science ®Google Scholar

Hawa MI , Kolb H , Schloot N , et al. Adult-onset autoimmune diabetes in Europe is prevalent with a broad clinical phenotype: action LADA 7. Diabetes Care . 2013;36(4):908–913. doi:10.2337/dc12-0931 23248199

 PubMed Web of Science ®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. doi:10.1371/journal.pone.0131837 26252955

 PubMed Web of Science ®Google Scholar

Awata T , Shimada A , Maruyama T , et al. Possible long-term efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, for Slowly Progressive Type 1 Diabetes (SPIDDM) in the stage of non-insulin-dependency: an open-label randomized controlled pilot trial (SPAN-S). Diabetes Ther . 2017;8(5):1123–1134. doi:10.1007/s13300-017-0299-7 28929327

 PubMed Web of Science ®Google Scholar