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1.  Heterogeneity of Patients With Latent Autoimmune Diabetes in Adults: Linkage to Autoimmunity Is Apparent Only in Those With Perceived Need for Insulin Treatment 
Diabetes Care  2009;32(2):245-250.
OBJECTIVE—Subjects with the diagnosis of latent autoimmune diabetes in adults (LADA) are more prone to need insulin treatment than those with type 2 diabetes. However, not all patients with LADA develop the need for insulin treatment, indicating the heterogeneity of LADA. We investigated this heterogeneity by comparing phenotypes of LADA with and without perceived need for insulin treatment (data obtained at times when diagnosis of LADA was not investigated) and also compared LADA and type 2 diabetes phenotypes.
RESEARCH DESIGN AND METHODS—We used data from the all population–based Nord-Trøndelag Health study (n = 64,931), performed in 1995–1997. Data were assembled for individuals with LADA (n = 106) and type 2 diabetes (n = 943).
RESULTS—In the comparison of individuals with LADA both with and without the need for insulin, insulin-treated subjects had higher titers of GAD antibodies (P < 0.001) and lower fasting C-peptide levels (P < 0.001). GAD antibodies and C-peptide correlated negatively (r = −0.40; P = 0.009). In the comparison of individuals with LADA and type 2 diabetes, all without the need for insulin, markers of metabolic syndrome were equally prevalent and pronounced. Age, C-peptide, and glucose levels were also similar. In the comparison of insulin-treated individuals with LADA and type 2 diabetes, more patients with LADA received insulin (40 vs. 22%, P < 0.001) and C-peptide levels were lower (P < 0.001). Patients with LADA were leaner but were still overweight (mean BMI 28.7 vs. 30.9 kg/m2 in type 2 diabetes, P < 0.001). In the comparison of type 2 diabetic patients with and without insulin, insulin-treated subjects were more obese and had higher A1C and lower C-peptide levels (P < 0.001).
CONCLUSIONS—Our conclusions are that 1) the need for insulin treatment in LADA is linked to the degree of autoimmunity and β-cell failure, 2) subjects with LADA and type 2 diabetes without the need for insulin treatment are phenotypically similar, and 3) insulin treatment in type 2 diabetic patients is associated with both insulin resistance and β-cell insufficiency.
doi:10.2337/dc08-1468
PMCID: PMC2628687  PMID: 19001190
2.  Latent autoimmune diabetes in adults in a population-based cohort of Polish patients with newly diagnosed diabetes mellitus 
Introduction
Latent autoimmune diabetes in adults (LADA) is a slowly developing form of autoimmune diabetes characterized by the presence of type 1 diabetes-associated autoantibody. The aim of this study was to determine the incidence and characteristics of LADA in a population-based cohort of Polish patients with newly-diagnosed diabetes.
Material and methods
The study cohort was taken from the resident population of the city Białystok, Poland, during the period 1 January to 31 December 2003, aged 20-64 years. During this period we identified 231 cases of diabetes. We measured glutamic acid decarboxylase (GADA) and insulin antibody (IAA), insulin, C peptide and glycated hemoglobin (HbA1c). Diagnosis of LADA was made according to Immunology Diabetes Society and Action LADA criteria.
Results
The incidence of LADA was 10 per year per 100 000 people. The proportion of patients with LADA was 8.9% among newly diagnosed cases with diabetes. Patients with LADA were younger at diagnosis (48.5 ±9.4 years vs. 54.8 ±10.6 years, p < 0.01), had lower body mass index (26.9 ±9.3 kg/m2 vs. 29.5 ±5.2 kg/m2, p < 0.05), C peptide (126 ±127 pmol/l vs. 446 ±592 pmol/l, p < 0.001), and were less insulin resistant (HOMA IR 0.94 ±0.85 vs. 3.6±4.4, p < 0.001) compared to patients with type 2 diabetes. Glycated hemoglobin and fasting glucose were similar in patients with LADA and type 2 diabetes.
Conclusions
In addition to GAD, anti-insulin antibodies are useful for diagnosing autoimmune diabetes in adults. Patients with LADA have similar glucose control parameters (HbA1c) compared to patients with type 2 diabetes, although they are usually younger and have a lower body mass index. Patients with LADA make up a significant proportion of newly diagnosed people with diabetes mellitus in a Polish population.
doi:10.5114/aoms.2012.29405
PMCID: PMC3400915  PMID: 22852005
latent autoimmune diabetes in adults; incidence; Poland; anti-glutamic acid decarboxylase antibody; anti-insulin autoantibodies
3.  Frequency, Immunogenetics, and Clinical Characteristics of Latent Autoimmune Diabetes in China (LADA China Study) 
Diabetes  2013;62(2):543-550.
Adult non–insulin requiring diabetes includes latent autoimmune diabetes of adults (LADA), distinguished from type 2 diabetes by the presence of islet autoantibodies. LADA China determined the characteristics of Chinese LADA. This nationwide, multicenter, clinic-based cross-sectional study was conducted in 46 university-affiliated hospitals in 25 Chinese cities. All 4,880 ketosis-free diabetic patients (<1 year postdiagnosis, without insulin therapy for >6 months, aged ≥30 years) had GAD antibody (GADA) and HLA-DQ genotype measured centrally with clinical data collected locally. GADA-positive subjects were classified as LADA. Of the patients, 5.9% were GADA positive with LADA. LADA showed a north-south gradient. Compared with GADA-negative type 2 diabetes, LADA patients were leaner, with lower fasting C-peptide and less metabolic syndrome. Patients with high GADA titers are phenotypically different from those with low GADA titers, while only a higher HDL distinguished the latter from those with type 2 diabetes. HLA diabetes–susceptible haplotypes were more frequent in LADA, even in those with low-titer GADA. HLA diabetes-protective haplotypes were less frequent in LADA. Our study implicates universal immunogenetic effects, with some ethnic differences, in adult-onset autoimmune diabetes. Autoantibody positivity and titer could be important for LADA risk stratification and accurate therapeutic choice in clinical practice.
doi:10.2337/db12-0207
PMCID: PMC3554388  PMID: 23086039
4.  Genetic Heterogeneity in Latent Autoimmune Diabetes Is Linked to Various Degrees of Autoimmune Activity 
Diabetes  2009;59(1):302-310.
OBJECTIVE
Previous studies have indicated that the latent autoimmune diabetes in adults (LADA) phenotype is heterogeneous and that LADA patients share features of type 1 and type 2 diabetes in various proportions. We tested for association of known type 1 and type 2 diabetes susceptibility genes in LADA subjects and analyzed relationships to a marker of autoimmune activity (titers of anti-GAD) and a phenotypic risk factor of type 2 diabetes (BMI).
RESEARCH DESIGN AND METHODS
Data were assembled from the Nord-Trøndelag Health Study (HUNT) study, which comprises the adult population of an entire county in Norway. We genotyped 60 single nucleotide polymorphisms (SNPs) known to be associated with type 1 or type 2 diabetes, including 14 tag SNPs used for HLA haplotyping in 120 type 1 diabetic, 126 LADA, and 1,090 type 2 diabetic patients and 1,503 age- and sex-matched nondiabetic subjects.
RESULTS
The majority of the strongly associated HLA haplotypes for type 1 diabetes were significantly associated with LADA in general, but mainly with high anti-GAD LADA patients. Two distinct HLA haplotypes were associated only with LADA and mainly in low anti-GAD LADA patients. There were no associations of non-HLA type 1 diabetes loci with LADA. Of type 2 diabetes–associated genes, the CC/CT genotypes of rs7961581 (TSPAN8) and the obesity-linked AA/AC genotypes of rs8050136 (FTO) were associated with LADA in general, but mainly in low anti-GAD LADA patients (P = 0.004 and P = 0.004, respectively).
CONCLUSIONS
Genetic heterogeneity in LADA is linked to various degrees of autoimmune activity and may be partly distinct from both type 1 and type 2 diabetes.
doi:10.2337/db09-0923
PMCID: PMC2797937  PMID: 19833889
5.  Metabolic Syndrome and Autoimmune Diabetes: Action LADA 3  
Diabetes Care  2009;32(1):160-164.
OBJECTIVE—The purpose of this study was to estimate whether prevalence of metabolic syndrome in adult European diabetic patients is associated with type of diabetes.
RESEARCH DESIGN AND METHODS—A consecutive series of patients attending hospital-based diabetes clinics were assessed for the frequency of metabolic syndrome and compared with population-based control subjects as part of the Action LADA study. In total, 2,011 subjects (aged 30–70 years) were studied, including 1,247 patients with recent-onset type 2 diabetes without glutamic acid decarboxylase autoantibodies (GADAs), 117 non–insulin-requiring patients with GADAs who had not received insulin therapy for at least 6 months after diagnosis (designated latent autoimmune diabetes of adults [LADA]), 288 type 1 diabetic patients, and 359 normal subjects.
RESULTS—Frequency of metabolic syndrome was significantly different in patients with type 1 diabetes (31.9%) and LADA (41.9%) (P = 0.015) and in both conditions was less frequent than in type 2 diabetic patients (88.8%) (P < 0.0001 for each). Eliminating glucose as a variable, the prevalence of metabolic syndrome was similar in patients with autoimmune diabetes (type 1 diabetes and/or LADA) (17.3%) and control subjects (23.7%) but remained more common in type 2 diabetic patients (47.8%) (P = 0.001 for all groups). In both type 1 diabetic patients and those with LADA, individual components of metabolic syndrome were similar but less common than in type 2 diabetic patients (P < 0.0001 for each).
CONCLUSIONS—The prevalence of metabolic syndrome is significantly higher in type 2 diabetic patients than in patients with LADA or adults with type 1 diabetes. Excluding glucose as a variable, metabolic syndrome is not more prevalent in patients with autoimmune diabetes than in control subjects. Metabolic syndrome is not a characteristic of autoimmune diabetes.
doi:10.2337/dc08-1419
PMCID: PMC2606853  PMID: 18945926
6.  Adult-Onset Autoimmune Diabetes in Europe Is Prevalent With a Broad Clinical Phenotype 
Diabetes Care  2013;36(4):908-913.
OBJECTIVE
Specific autoantibodies characterize type 1 diabetes in childhood but are also found in adult-onset diabetes, even when initially non–insulin requiring, e.g., with latent autoimmune diabetes (LADA). We aimed to characterize adult-onset autoimmune diabetes.
RESEARCH DESIGN AND METHODS
We consecutively studied 6,156 European diabetic patients attending clinics within 5 years of diagnosis (age range, 30–70 years) examined cross-sectionally clinically and for GAD antibodies (GADA) and antibodies to insulinoma-associated antigen-2 (IA-2A) and zinc-transporter 8 (ZnT8A).
RESULTS
Of 6,156 patients, 541 (8.8%) had GADA and only 57 (0.9%) IA-2A or ZnT8A alone. More autoantibody-positive than autoantibody-negative patients were younger, leaner, on insulin (49.5 vs. 13.2%), and female (P < 0.0001 for each), though LADA patients (9.7% of total) did not show categorically distinct clinical features from autoantibody-negative type 2 diabetes. Similarly, more GADA patients with high (>200 World Health Organization IU) (n = 403) compared with low (n = 138) titer were female, lean, and insulin treated (54.6 vs. 39.7%) (P < 0.02 for each). Autoantibody-positive patients usually had GADA (541 of 598; 90.5%) and had LADA more often than type 1 autoimmune diabetes (odds ratio 3.3).
CONCLUSIONS
Adult-onset autoimmune diabetes emerges as a prevalent form of autoimmune diabetes. Our results indicate that adult-onset autoimmune diabetes in Europe encompasses type 1 diabetes and LADA in the same broad clinical and autoantibody-positive spectrum. At diagnosis, patients with adult-onset autoimmune diabetes are usually non–insulin requiring and clinically indistinguishable from patients with type 2 diabetes, though they tend to be younger and leaner. Only with screening for autoantibodies, especially GADA, can they be identified with certainty.
doi:10.2337/dc12-0931
PMCID: PMC3609504  PMID: 23248199
7.  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.
OBJECTIVE
We studied differences between patients with latent autoimmune diabetes in adults (LADA), type 2 diabetes, and classical type 1 diabetes diagnosed after age 35 years.
RESEARCH DESIGN AND METHODS
Polymorphisms in HLA-DQB1, INS, PTPN22, and CTLA4 were genotyped in patients with LADA (n = 213), type 1 diabetes diagnosed at >35 years of age (T1D>35y; n = 257) or <20 years of age (T1D<20y; n = 158), and type 2 diabetes.
RESULTS
Although patients with LADA had an increased frequency of HLA-DQB1 and PTPN22 risk genotypes and alleles compared with type 2 diabetic subjects, the frequency was significantly lower compared with T1D>35y patients. Genotype frequencies, measures of insulin secretion, and metabolic traits within LADA differed according to GAD antibody (GADA) quartiles, but even the highest quartile differed from type 1 diabetes. Having two or more risk genotypes was associated with lower C-peptide concentrations in LADA.
CONCLUSIONS
LADA patients differed genetically and phenotypically from both T1D>35y and type 2 diabetic patients in a manner dependent on GADA levels.
doi:10.2337/dc09-2188
PMCID: PMC2928363  PMID: 20805278
8.  GAD65 Autoantibody Responses in Japanese Latent Autoimmune Diabetes in Adult Patients  
Diabetes Care  2008;31(8):1602-1607.
OBJECTIVE—To determine whether development of insulin requirement in patients with latent autoimmune diabetes in adults (LADA) is accompanied with the emergence of a type 1 diabetes–like autoimmune response.
RESEARCH DESIGN AND METHODS—We correlated β-cell–specific autoimmunity reflected in autoantibodies to the 65-kDa isoform of GAD (GAD65) with insulin requirement. We determined GAD65Ab epitope specificities in type 1 diabetic patients, LADA patients without insulin requirement (nonprogressed), and LADA patients that had developed insulin requirement (progressed).
RESULTS—Recognition of a type 1 diabetes–specific GAD65Ab epitope was more pronounced in type 1 diabetic patients than in nonprogressed (P < 0.001) or progressed (P < 0.01) LADA patients, with no significant differences between the two LADA cohorts. These differences were particularly pronounced in samples with GAD65Ab titers <1,000 units/ml, with no differences in epitope specificities in samples with higher GAD65Ab titers. Disease duration (initial diabetes diagnosis until sample collection or development of insulin requirement) in nonprogressed and progressed LADA patients, respectively, was not correlated with epitope specificity, suggesting lack of epitope maturation. This was supported by epitope analyses of longitudinal samples from LADA patients during progression to insulin requirement.
CONCLUSIONS—First, the GAD65Ab-specific autoimmune reaction in type 1 diabetic patients with low and moderate GAD65Ab titers differs from that in LADA patients, irrespective of insulin requirement. Second, the GAD65Ab-specific autoimmune response in LADA patients does not change after their initial diabetes diagnosis. Finally, LADA patients with high GAD65Ab titers resemble type 1 diabetic patients in their GAD65Ab epitope specificity.
doi:10.2337/dc08-0235
PMCID: PMC2494628  PMID: 18487477
9.  Six-year follow-up of pancreatic β cell function in adults with latent autoimmune diabetes 
AIM: To investigate the characteristics of the progression of islet β cell function in Chinese latent autoimmune diabetes in adult (LADA) patients with glutamic acid decarboxylase antibody (GAD-Ab) positivity, and to explore the prognostic factors for β cell function.
METHODS: Forty-five LADA patients with GAD-Ab positivity screened from phenotypic type 2 diabetic (T2DM) patients and 45 T2DM patients without GAD-Ab matched as controls were followed-up every 6 mo. Sixteen patients in LADA1 and T2DM1 groups respectively have been followed-up for 6 years, while 29 patients in LADA2 and T2DM2 groups respectively for only 1.5 years. GAD-Ab was determined by radioligand assay, and C-peptides (CP) by radioimmune assay.
RESULTS: The percentage of patients whose fasting CP (FCP) decreased more than 50% compared with the baseline reached to 25.0% at 1.5th year in LADA1 group, and FCP level decreased (395.8±71.5 vs 572.8±72.3 pmol/L, P<0.05) at 2.5th year and continuously went down to the end of follow-up. No significant changes of the above parameters were found in T2DM1 group. The average decreased percentages of FCP per year in LADA and T2DM patients were 15.8% (4.0-91.0%) and 5.2% (-3.5 to 35.5%, P = 0.000) respectively. The index of GAD-Ab was negatively correlated with the FCP in LADA patients (rs = -0.483, P = 0.000). The decreased percentage of FCP per year in LADA patients were correlated with GAD-Ab index, body mass index (BMI) and age at onset (rs = 0.408, -0.301 and -0.523 respectively, P<0.05). Moreover, GAD-Ab was the only risk factor for predicting β cell failure in LADA patients (B = 1.455, EXP (B) = 4.283, P = 0.023).
CONCLUSION: The decreasing rate of islet β cell function in LADA, being highly heterogeneous, is three times that of T2DM patients. The titer of GAD-Ab is an important predictor for the progression of islet β cell function, and age at onset and BMI could also act as the predictors.
doi:10.3748/wjg.v11.i19.2900
PMCID: PMC4305656  PMID: 15902725
Latent autoimmune diabetes in adults; Type 2 diabetes; Islet β cell function; Glutamic acid decarboxylase antibody
10.  Prevalence and Correlates of Latent Autoimmune Diabetes in Adults in Tianjin, China 
Diabetes Care  2010;34(1):66-70.
OBJECTIVE
Data on latent autoimmune diabetes in adults (LADA) from population-based studies are sparse. We sought to investigate the prevalence and correlates of LADA.
RESEARCH DESIGN AND METHODS
A total of 8,109 participants, who were aged ≥15 years and living in Tianjin, China, were assessed to identify individuals with type 2 diabetes (American Diabetes Association Criteria, 1997) and further to detect patients with LADA. LADA was ascertained by 1) the presence of type 2 diabetes and age ≥35 years, 2) the lack of a requirement for insulin at least 6 months after the diagnosis of type 2 diabetes, and 3) serum GAD antibody positivity. Data were analyzed using multinomial logistic regression with adjustment for potential confounders.
RESULTS
Of all participants, 498 (6.1%) were patients with type 2 diabetes. Of them, 46 (9.2%) were found to have LADA. The prevalence of LADA was 0.6% (46 of 8,109), and tended to increase with age up to 50–59 years in all participants. The odds ratios (95% CI) of LADA related to hypertension, family history of diabetes, waist-to-hip ratio ≥0.85, and major stressful events were 1.93 (1.02–3.65), 17.59 (9.08–34.06), 5.37 (2.31–12.49), and 4.09 (1.75–9.52), respectively.
CONCLUSIONS
The prevalence of LADA is ∼9% in patients with type 2 diabetes. Hypertension, family history of diabetes, central obesity, and major stressful events may be associated with the occurrence of LADA.
doi:10.2337/dc10-0488
PMCID: PMC3005491  PMID: 20876205
11.  Insulin secretion in patients with latent autoimmune diabetes (LADA): half way between type 1 and type 2 diabetes: action LADA 9 
Background
The study of endogenous insulin secretion may provide relevant insight into the comparison of the natural history of adult onset latent autoimmune diabetes (LADA) with types 1 and 2 diabetes mellitus. The aim of this study was to compare the results of the C-peptide response to mixed-meal stimulation in LADA patients with different disease durations and subjects with type 2 and adult-onset type 1 diabetes.
Methods
Stimulated C-peptide secretion was assessed using the mixed-meal tolerance test in patients with LADA (n = 32), type 1 diabetes mellitus (n = 33) and type 2 diabetes mellitus (n = 30). All patients were 30 to 70 years old at disease onset. The duration of diabetes in all groups ranged from 6 months to 10 years. The recruitment strategy was predefined to include at least 10 subjects in the following 3 disease onset categories for each group: 6 to 18 months, 19 months to 5 years and 5 to 10 years.
Results
At all time-points of the mixed-meal tolerance test, patients with LADA had a lower stimulated C-peptide response than the type 2 diabetes group and a higher response than the type 1 diabetes group. The same results were found when the peak or area under the C-peptide curve was measured. When the results were stratified by time since disease onset, a similar pattern of residual insulin secretory capacity was observed.
Conclusions
The present study shows that the magnitude of stimulated insulin secretion in LADA is intermediate between that of type 1 and type 2 diabetes mellitus.
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6823-15-1) contains supplementary material, which is available to authorized users.
doi:10.1186/1472-6823-15-1
PMCID: PMC4297398  PMID: 25572256
Latent autoimmune diabetes in adults; Type 1 diabetes mellitus; Type 2 diabetes mellitus; Insulin secretion; C-peptide
12.  Prevalence and Clinical Characteristics of Recently Diagnosed Type 2 Diabetes Patients with Positive Anti-Glutamic Acid Decarboxylase Antibody 
Diabetes & Metabolism Journal  2012;36(2):136-143.
Background
Latent autoimmune diabetes in adults (LADA) refers to a specific type of diabetes characterized by adult onset, presence of islet auto-antibodies, insulin independence at the time of diagnosis, and rapid decline in β-cell function. The prevalence of LADA among patients with type 2 diabetes varies from 2% to 20% according to the study population. Since most studies on the prevalence of LADA performed in Korea were conducted in patients who had been tested for anti-glutamic acid decarboxylase antibody (GADAb), a selection bias could not be excluded. In this study, we examined the prevalence and clinical characteristics of LADA among adult patients recently diagnosed with type 2 diabetes.
Methods
We included 462 patients who were diagnosed with type 2 diabetes within 5 years from the time this study was performed. We measured GADAb, fasting insulin level, fasting C-peptide level, fasting plasma glucose level, HbA1c, and serum lipid profiles and collected data on clinical characteristics.
Results
The prevalence of LADA was 4.3% (20/462) among adult patients with newly diagnosed type 2 diabetes. Compared with the GADAb-negative patients, the GADAb-positive patients had lower fasting C-peptide levels (1.2±0.8 ng/mL vs. 2.0±1.2 ng/mL, P=0.004). Other metabolic features were not significantly different between the two groups.
Conclusion
The prevalence of LADA is 4.3% among Korean adult patients with recently diagnosed type 2 diabetes. The Korean LADA patients exhibited decreased insulin secretory capacity as reflected by lower C-peptide levels.
doi:10.4093/dmj.2012.36.2.136
PMCID: PMC3335895  PMID: 22540050
Diabetes mellitus, type 1; Diabetes mellitus, type 2; Glutamate decarboxylase
13.  An association analysis of the HLA gene region in latent autoimmune diabetes in adults 
Diabetologia  2006;50(1):68-73.
Aims/hypothesis
Pathophysiological similarities between latent autoimmune diabetes in adults (LADA) and type 1 diabetes indicate an overlap in genetic susceptibility. HLA-DRB1 and HLA-DQB1 are major susceptibility genes for type 1 diabetes but studies of these genes in LADA have been limited. Our aim was to define patterns of HLA-encoded susceptibility/protection in a large, well characterised LADA cohort, and to establish association with disease and age at diagnosis.
Materials and methods
Patients with LADA (n=387, including 211 patients from the UK Prospective Diabetes Study) and non-diabetic control subjects (n=327) were of British/Irish European origin. The HLA-DRB1 and -DQB1 genes were genotyped by sequence-specific PCR.
Results
As in type 1 diabetes mellitus, DRB1*0301_DQB1*0201 (odds ratio [OR]=3.08, 95% CI 2.32–4.12, p=1.2× 10−16) and DRB1*0401_DQB1*0302 (OR=2.57, 95% CI 1.80–3.73, p=4.5×10−8) were the main susceptibility haplotypes in LADA, and DRB1*1501_DQB1*0602 was protective (OR=0.21, 95% CI 0.13–0.34, p=4.2×10−13). Differential susceptibility was conferred by DR4 subtypes: DRB1*0401 was predisposing (OR=1.79, 95% CI 1.35–2.38, p=2.7×10−5) whereas DRB1*0403 was protective (OR=0.37, 95% CI 0.13–0.97, p=0.033). The highest-risk genotypes were DRB1*0301/DRB1*0401 and DQB1*0201/DQB1*0302 (OR=5.14, 95% CI 2.68–10.69, p=1.3×10−8; and OR=6.88, 95% CI 3.54–14.68, p=1.2×10−11, respectively). These genotypes and those containing DRB1*0401 and DQB1*0302 associated with a younger age at diagnosis in LADA, whereas genotypes containing DRB1*1501 and DQB1*0602 associated with an older age at diagnosis.
Conclusions/interpretation
Patterns of susceptibility at the HLA-DRB1 and HLA-DQB1 loci in LADA are similar to those reported for type 1 diabetes, supporting the hypothesis that autoimmune diabetes occurring in adults is an age-related extension of the pathophysiological process presenting as childhood-onset type 1 diabetes.
doi:10.1007/s00125-006-0513-z
PMCID: PMC3076207  PMID: 17143607
Age of diagnosis; Genetic susceptibility; Protection; Type 1 diabetes
14.  Adiponectin levels in people with Latent Autoimmune Diabetes-a case control study 
BMC Research Notes  2010;3:317.
Background
To examine adiponectin levels in people with Latent Autoimmune Diabetes in Adults using a matched pair case control study.
Findings
Patients with LADA (n = 64), were matched for sex with type 2 diabetic and non-diabetic controls. A matched paired T-test was used to examine average adiponectin levels in the LADA patients' versus controls. The average adiponectin level for the LADA patients was 9.96 μg/ml compared to 6.4 μg/ml for Type 2 matched controls and 9.6 μg/ml for non-diabetic controls. Mean difference for the LADA-type 2 comparison was calculated after data was log transformed and showed a difference of 1.58 μg/ml (95%CI: 1.28-1.95, p = 0.0001). There was no significant difference between LADA and non-diabetic controls (p = 0.54).
Conclusions
Adiponectin levels are higher among people with LADA compared to those with type 2 diabetes and are equivalent to levels seen in non-diabetic controls. This suggests that risk of complications in LADA, as with type 1 diabetes may be related more to glycaemic control rather than to factors of the metabolic syndrome.
doi:10.1186/1756-0500-3-317
PMCID: PMC3000423  PMID: 21092154
15.  Alcohol and the risk for latent autoimmune diabetes in adults: results based on Swedish ESTRID study 
European Journal of Endocrinology  2014;171(5):535-543.
Objective
Moderate alcohol consumption is associated with a reduced risk of type 2 diabetes. Our aim was to investigate whether alcohol consumption is associated with the risk of latent autoimmune diabetes in adults (LADA), an autoimmune form of diabetes with features of type 2 diabetes.
Design
A population-based case–control study was carried out to investigate the association of alcohol consumption and the risk of LADA.
Methods
We used data from the ESTRID case–control study carried out between 2010 and 2013, including 250 incident cases of LADA (glutamic acid decarboxylase antibodies (GADAs) positive) and 764 cases of type 2 diabetes (GADA negative), and 1012 randomly selected controls aged ≥35. Logistic regression was used to estimate the odds ratios (ORs) of diabetes in relation to alcohol intake, adjusted for age, sex, BMI, family history of diabetes, smoking, and education.
Results
Alcohol consumption was inversely associated with the risk of type 2 diabetes (OR 0.95, 95% CI 0.92–0.99 for every 5-g increment in daily intake). Similar results were observed for LADA, but stratification by median GADA levels revealed that the results only pertained to LADA with low GADA levels (OR 0.85, 95% CI 0.76–0.94/5 g alcohol per day), whereas no association was observed with LADA having high GADA levels (OR 1.00, 95% CI 0.94–1.06/5 g per day). Every 5-g increment of daily alcohol intake was associated with a 10% increase in GADA levels (P=0.0312), and a 10% reduction in homeostasis model assessment of insulin resistance (P=0.0418).
Conclusions
Our findings indicate that alcohol intake may reduce the risk of type 2 diabetes and type 2-like LADA, but has no beneficial effects on diabetes-related autoimmunity.
doi:10.1530/EJE-14-0403
PMCID: PMC4190680  PMID: 25117461
16.  HLA-DR, HLA-DQB1 and PTPN22 gene polymorphism: association with age at onset for autoimmune diabetes 
Introduction
Autoimmune diabetes has different clinical manifestations related to the age at onset. It is divided into several subtypes, including “classical” type 1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA). The LADA is considered a slowly progressing subtype of autoimmune diabetes, although the clinical picture is more similar to type 2 diabetes.
Material and methods
The aim of this study is to investigate whether genetic predisposition influences age at onset in autoimmune diabetes. We studied rs2476601 PTPN22 gene polymorphism and HLA DR, HLA-DQB1 in 175 patients with classical type 1 diabetes, 80 LADA, and 151 control subjects from north-east Poland.
Results
The frequencies of the PTPN22 TT genotype were higher in the group of patients with classical type 1 diabetes (6.3%) and LADA (11.3%) than in control subjects (0.7%) (p = 0.02 and p = 0007, respectively). In patients with classical type 1 diabetes we observed an increasing trend in frequencies of genotype TT dependent on age at onset (3.9% (0-5 year olds), 6.0% (6-15 year-olds), 8.2% (16-25 year olds), p = 0.048). The incidence of predisposing human leukocyte antigen (HLA) genotypes HLA DR3/DQB1*02 and DR4/DQB1*0302 was found to decrease in the group with type 1 diabetes in relation to age at onset and LADA (HLA DR3/DQB1*02 – 69.2% (0-5 year olds), 57.0% (6-15 year olds), 51.0% (16-25 year olds), 46.3% (LADA), p = 0.032; HLA DR4/DQB1*0302 – 80.8% (0-5 year olds), 63.0% (6-15 year olds), 51.0% (16-25 year olds), 43.8% (LADA), p = 0.0003), and to increase for the protective allele DQB1*0602 (0.0% (0-5 year olds), 1.0% (6-15 year olds), 2.0% (16-25 year olds), 6.3% (LADA), p = 0.029).
Conclusions
Thus, age at onset for autoimmune diabetes appears to be related to a combination of predisposing and protective HLA alleles. Against a background of HLA genetic predisposition, other non-HLA loci may influence age at onset for late autoimmune diabetes.
doi:10.5114/aoms.2012.31619
PMCID: PMC3506241  PMID: 23185198
type 1 diabetes; latent autoimmune diabetes in adults; PTPN22; HLA
17.  Heterogeneity of Altered Cytokine Levels Across the Clinical Spectrum of Diabetes in China 
Diabetes Care  2011;34(7):1639-1641.
OBJECTIVE
To determine the relationship between selected cytokines and diabetes in Chinese subjects.
RESEARCH DESIGN AND METHODS
Adult patients with recent-onset type 1 diabetes (n = 53), latent autoimmune diabetes in adults (LADA) (n = 250), and type 2 diabetes (n = 285) from multiple centers were compared with normal subjects (n = 196). We centrally tested serum GAD antibodies (GADAs), interleukin-6 (IL-6), lipocalin 2 (LCN2), high-sensitivity C-reactive protein (hs-CRP), and adiponectin.
RESULTS
After adjustment for age, sex, and BMI, all diabetes types had increased IL-6 and LCN2 (P < 0.01), and all four cytokines were increased in LADA (P < 0.01). In type 1 diabetes, adiponectin but not hs-CRP was increased (P < 0.01), whereas in type 2 diabetes, hs-CRP but not adiponectin was increased (P < 0.01). Adiponectin was correlated positively with GADA titer and negatively with hs-CRP (P < 0.01 for both).
CONCLUSIONS
In China, inflammatory markers are increased in all three major types of diabetes, but probably for different reasons, even in autoimmune diabetes.
doi:10.2337/dc11-0039
PMCID: PMC3120206  PMID: 21617097
18.  β‐cell autoantibodies in children with type 2 diabetes mellitus: subgroup or misclassification? 
Archives of Disease in Childhood  2006;91(6):473-477.
Background
In adults, a fraction of diabetic individuals with β‐cell autoantibodies has initially non‐insulin requiring diabetes clinically appearing as type 2 diabetes mellitus (T2DM), named latent autoimmune diabetes in adulthood (LADA). The occurrence of β‐cell autoantibodies in European children and adolescents with T2DM has not been reported so far.
Methods
The frequency of β‐cell autoantibodies (anti‐GAD, anti‐IA‐2, and anti‐ICA) was determined in 7050 diabetic children and adolescents. The type of diabetes was classified by paediatric diabetic specialists based on the clinical presentation. Children with non‐insulin dependent T2DM over a one year period were studied separately.
Results
A total of 6922 children were clinically classified as having type 1 diabetes (T1DM) and 128 children as having T2DM. Thirty six per cent of the children with T2DM had at least one detectable β‐cell autoantibody. These children did not differ significantly from the children with T2DM and without autoantibodies in respect of age, gender, weight status, lipids, blood pressure, C‐peptide, glucose, and HbA1c at manifestation, as well as frequency of anti‐thyroidal antibodies and insulin treatment during follow up. In the subgroup of the 38 children with T2DM without insulin requirement over a one year period, autoantibodies occurred in 32%. These 12 children were predominantly obese (67%), female (67%), and in the pubertal age range.
Conclusion
β‐cell autoantibodies were detectable in a subgroup of initially non‐insulin dependent diabetic children and adolescents with the clinical appearance of T2DM. Following the terminology “latent autoimmune diabetes in adulthood (LADA)”, this subgroup might be classified as “LADY” (latent autoimmune diabetes in youth).
doi:10.1136/adc.2005.088229
PMCID: PMC2082766  PMID: 16449253
type 2 diabetes mellitus; type 1 diabetes mellitus; differential diagnosis; β‐cell autoantibodies; thyroidal antibodies
19.  Latent autoimmune diabetes in adults: A distinct but heterogeneous clinical entity 
World Journal of Diabetes  2010;1(4):111-115.
Latent autoimmune diabetes in adults (LADA) accounts for 2%-12% of all cases of diabetes. Patients are typically diagnosed after 35 years of age and are often misdiagnosed as type II Diabetes Mellitus (DM). Glycemic control is initially achieved with sulfonylureas but patients eventually become insulin dependent more rapidly than with type II DM patients. Although they have a type II DM phenotype, patients have circulating beta (β) cell autoantibodies, a hallmark of type I DM. Alternative terms that have been used to describe this condition include type 1.5 diabetes, latent type I diabetes, slowly progressive Insulin Dependent Diabetes Mellitus, or youth onset diabetes of maturity. With regards to its autoimmune basis and rapid requirement for insulin, it has been suggested that LADA is a slowly progressive form of type I DM. However, recent work has revealed genetic and immunological differences between LADA and type I DM. The heterogeneity of LADA has also led to the proposal of criteria for its diagnosis by the Immunology of Diabetes Society. Although many workers have advocated a clinically oriented approach for screening of LADA, there are no universally accepted criteria for autoantibody testing in adult onset diabetes. Following recent advances in immunomodulatory therapies in type I DM, the same strategy is being explored in LADA. This review deals with the contribution of the genetic, immunological and metabolic components involved in the pathophysiology of LADA and recent approaches in screening of this distinct but heterogeneous clinical entity.
doi:10.4239/wjd.v1.i4.111
PMCID: PMC3083891  PMID: 21537436
Latent autoimmune diabetes in adults; Glutamic acid decarboxylase autoantibodies; Type 1 diabetes; Type 2 diabetes
20.  Fatty fish consumption and risk of latent autoimmune diabetes in adults 
Nutrition & Diabetes  2014;4(10):e139-.
Objective:
It has been suggested that intake of fatty fish may protect against both type 1 and type 2 diabetes. Hypotheses rest on the high marine omega-3 fatty acid eicosapentaenoic acid+docosahexaenoic acid (EPA+DHA) and vitamin D contents, with possible beneficial effects on immune function and glucose metabolism. Our aim was to investigate, for the first time, fatty fish consumption in relation to the risk of latent autoimmune diabetes in adults (LADA).
Methods:
Analyses were based on data from a Swedish case–control study with incident cases of LADA (n=89) and type 2 diabetes (n=462) and randomly selected diabetes-free controls (n=1007). Diabetes classification was based on the onset of age (⩾35), glutamic acid decarboxylase autoantibodies, and C-peptide. A validated food frequency questionnaire was used to derive information on previous intake of fish, polyunsaturated long-chain omega-3 fatty acids (n-3 PUFA) and supplementation of fish oil and vitamin D. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using logistic regression, adjusted for age, gender, body mass index (BMI), family history of diabetes, physical activity, smoking, education, and consumption of alcohol, fruit, vegetables and red meat.
Results:
Weekly fatty fish consumption (⩾1 vs <1 serving per week), was associated with a reduced risk of LADA but not type 2 diabetes (OR 0.51, 95% CI 0.30–0.87, and 1.01, 95% CI 0.74–1.39, respectively). Similar associations were seen for estimated intake of n-3 PUFA (⩾0.3 g per day; LADA: OR 0.60, 95% CI 0.35–1.03, type 2 diabetes: OR 1.14, 95% CI 0.79–1.58) and fish oil supplementation (LADA: OR 0.47, 95% CI 0.19–1.12, type 2 diabetes: OR 1.58, 95% CI 1.08–2.31).
Conclusions:
Our findings suggest that fatty fish consumption may reduce the risk of LADA, possibly through effects of marine-originated omega-3 fatty acids.
doi:10.1038/nutd.2014.36
PMCID: PMC4216999  PMID: 25329601
21.  Latent autoimmune diabetes of adults: From oral hypoglycemic agents to early insulin 
Approximately 10% of phenotypic type 2 diabetics have islet autoantibodies and are referred to as having latent autoimmune diabetes of adults (LADA), and they land on early sulfonylurea failure and require insulin. Diagnosing LADA has treatment implications because of high risk of progression to insulin dependency. But often there is delay in insulin therapy, as there are no recommendations for islet antibody testing in adult-onset diabetes currently. LADA clinical risk score can identify adults at high risk who may benefit from antibody testing. The optimal treatment of LADA is not established. Early insulin therapy helps to achieve good metabolic control and better long-term outcomes by preserving β-cells and endogenous C-peptide secretion. Sulfonylureas are better avoided as they exhaust β-cells; glitazones and exenatide have favorable outcomes, whereas metformin needs to be used with caution. Understanding LADA will also bring new windows in managing type 1 diabetes. Information acquisition was done by reviewing the medical literature published since 1987, with particular attention to the natural history, genetic factors, and treatment of LADA.
doi:10.4103/2230-8210.94257
PMCID: PMC3354922  PMID: 22701843
Autoimmune; insulin; islet autoantibodies; latent autoimmune diabetes of adults; sulfonylurea failure
22.  Distinct clinical and laboratory characteristics of latent autoimmune diabetes in adults in relation to type 1 and type 2 diabetes mellitus 
World Journal of Diabetes  2014;5(4):505-510.
Ever since its first appearance among the multiple forms of diabetes, latent autoimmune diabetes in adults (LADA), has been the focus of endless discussions concerning mainly its existence as a special type of diabetes. In this mini-review, through browsing important peer-reviewed publications, (original articles and reviews), we will attempt to refresh our knowledge regarding LADA hoping to enhance our understanding of this controversial diabetes entity. A unique combination of immunological, clinical and metabolic characteristics has been identified in this group of patients, namely persistent islet cell antibodies, high frequency of thyroid and gastric autoimmunity, DR3 and DR4 human leukocyte antigen haplotypes, progressive loss of beta cells, adult disease onset, normal weight, defective glycaemic control, and without tendency to ketoacidosis. Although anthropomorphic measurements are useful as a first line screening, the detection of C-peptide levels and the presence of glutamic acid decarboxylase (GAD) autoantibodies is undoubtedly the sine qua non condition for a confirmatory LADA diagnosis. In point of fact, GAD autoantibodies are far from being solely a biomarker and the specific role of these autoantibodies in disease pathogenesis is still to be thoroughly studied. Nevertheless, the lack of diagnostic criteria and guidelines still puzzle the physicians, who struggle between early diagnosis and correct timing for insulin treatment.
doi:10.4239/wjd.v5.i4.505
PMCID: PMC4127585  PMID: 25126396
Latent autoimmune diabetes in adults; Type 1 diabetes mellitus; Type 2 diabetes mellitus; Autoantibodies; Glutamic acid decarboxylase 65
23.  Randomized, controlled, parallel-group prospective study to investigate the clinical effectiveness of early insulin treatment in patients with latent autoimmune diabetes in adults 
Background
Latent autoimmune diabetes in adults [LADA] is a type 1 diabetes that is slowly developing. This means many people are treated as having type 2 diabetes at diagnosis as they are adults who are not immediately insulin dependent. LADA can be distinguished from type 2 diabetes by antibody tests. Patients who are antibody positive have an autoimmune reaction which is similar to that of type 1 diabetes and is not found in type 2 diabetes. We would like to examine the best way of treating LADA in the early phase of the conditions, with tablets (similar to type 2 diabetes) or with insulin (similar to type 1 diabetes).
Methods/design
This is an open parallel group prospective randomised trial. Participants need to have a GAD antibody test results of 101 WHO units or more and a diagnosis of diabetes not requiring insulin at diagnosis. Participants will need to have been diagnosed within 12 months and not treated with insulin at study entry. They will be randomised to receive either insulin (NovoMix 30) or tablets (diet treated followed by metformin followed by glitazone (with or without metformin) followed by insulin). Primary outcome assessment will be for change in HbA1c and change in fasting C-peptide over 24 months. Secondary outcome measures will include Quality of life, GAD antibody levels, adverse events, inflammatory markers, insulin resistance, and markers of the metabolic syndrome.
Discussion
This study seeks the best treatment for early LADA in terms of maintaining glycaemic control and maintaining natural insulin production.
Trial registration
ISRCTN63815121
doi:10.1186/1472-6823-8-8
PMCID: PMC2496905  PMID: 18652676
24.  Characteristics and Prevalence of Latent Autoimmune Diabetes in Adults (LADA) 
ISRN Pharmacology  2012;2012:580202.
Diabetes, one of the most commonly seen metabolic disorders, is affecting a major area of population in many developing as well as most of the developed countries and is becoming an alarming concern for the rising cost of the healthcare system. Latent Autoimmune Diabetes in Adults (LADA) is a form of diabetes which is less recognized and underdiagnosed type of diabetes which appears to have characteristics of both type 1 (autoimmune in nature) and type 2 diabetes (adult age at onset and initial response to oral hypoglycemic agents). An epidemiological study was carried out on 500 patients in the western region of India. Various parameters such as age at onset, duration of diabetes, gender, basal metabolic index (BMI), type of diabetes, family history, HbA1c levels, cholesterol levels, and current treatment regimen were evaluated and correlated with type 1 and type 2 diabetes. Moreover, diagnostic markers for LADA, namely, GAD autoantibodies and C-peptide levels, were determined for 80 patients selected from the epidemiological study. Some of the results obtained were found to be consistent with the literature whereas some results were found to be contradictory to the existing data.
doi:10.5402/2012/580202
PMCID: PMC3339117  PMID: 22577577
25.  β-cell function and metabolic control in latent autoimmune diabetes in adults with early insulin versus conventional treatment: a 3-year follow-up 
European Journal of Endocrinology  2011;164(2):239-245.
Objectives
The optimal treatment of latent autoimmune diabetes in adults (LADA) is not established. We explored whether early insulin treatment, which has shown beneficial effects in rodents and in human pilot studies, would result in better preservation of β-cell function or metabolic control, compared with conventional treatment.
Subjects and methods
Glucagon-stimulated C-peptide and HbAlc were evaluated at baseline and after 12, 24 and 36 months in 37 patients recently diagnosed with diabetes, aged ≥30 years, non-insulin-requiring and GADAb and/or ICA positive. Twenty patients received early insulin and 17 received conventional treatment (diet±oral hypoglycaemic agents (OHA), metformin, some and/or sulfonylurea) and insulin when necessary.
Results
Level of metabolic control, HbAlc, was preserved in the early insulin treated, while it significantly deteriorated in the conventionally treated. There was no significant difference between the groups in C-peptide after 12, 24 or 36 months, or in the decline of C-peptide. Only baseline C-peptide predicted a C-peptide of ≥0.5 nmol/l at 36 months. Gender, body mass index, antibody titres or HbAlc did not influence the levels of C-peptide or HbAlc at baseline or end-of-study, or the decline in C-peptide. Among the diet±OHA-treated, 5/17 (30%) developed insulin dependency during the follow-up. No major hypoglycaemic events occurred.
Conclusions
Early insulin treatment in LADA leads to better preservation of metabolic control and was safe. Superior preservation of C-peptide could not be significantly demonstrated. Only baseline level of C-peptide significantly influenced C-peptide level after 3 years. Further studies exploring the best treatment in LADA are warranted.
doi:10.1530/EJE-10-0901
PMCID: PMC3022338  PMID: 21088056

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