Latent Autoimmune Diabetes of Adults in Latakia, Syria

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Article Information:


Group: 2010
Subgroup: Volume 8, Issue 1, Winter
Date: January 2010
Type: Original Article
Start Page: 13
End Page: 21

Authors:

  • AA Al-Farwi
  • Department of Laboratory Medicine and bEndocrinology Division, Tishreen University, Latakia, Syria
  • MI Khayat
  • Department of Laboratory Medicine and bEndocrinology Division, Tishreen University, Latakia, Syria
  • M Muhsen Al-Mehri
  • Department of Laboratory Medicine and bEndocrinology Division, Tishreen University, Latakia, Syria

      Correspondence:

      Affiliation: Department of Laboratory Medicine and bEndocrinology Division, Tishreen University
      City, Province: Latakia,
      Country: Syria
      Tel:
      Fax:
      E-mail: myownlab@yahoo.com

Abstract:


This study aimed at assessing the frequency of latent autoimmune diabetes of adults (LADA) and its laboratory and clinical characteristics at the Diabetic Center of Latakia, Syria. Materials and Methods: Based on glutamic acid decarboxylase autoantibodies positivity, a population of 254 type 2 diabetic males and females, aged 35 to 75 years, were subdivided and studied in terms of the laboratory and clinical characteristics. Results: Glutamic acid decarboxylase autoantibodies (GADAs) were positive (GADA+) in 45 diabetic patients versus 209 type 2 diabetics with GADA negative (GADA-). In both subgroups, GADA+ and GADA-, no significant differences were observed in terms of anthropometric and clinical features except for body mass index (BMI) which was significantly lower in GADA+ subgroup (27.6±4.8 vs. 29.8±5.9; P= 0.02). Significant poor glycemic control was detected in terms of fasting blood sugar (FBS) (221.6±77.9 vs 182±66.7; P=0.001), glucosuria (60% vs. 41.6%; P=0.025), and ketonuria (22.2% vs. 3.8%; P<0.0001) in LADA patients (GADA+) versus type 2 diabetic patients (GADA-). By subdividing the studied sample into tertiles of type 2 diabetes, GADA- <5 IU/ml , GADA+ ≤50 IU/ml, and GADA+ >50 IU/ml, the tertile with high GADA titers (>50 IU/ml) presented significantly low BMI (P=0.012) and c-peptide levels (P<0.002) in comparison with type 2 and GADA≤ 50 IU/ml tertiles. Conclusion: Overall the prevalence of LADA was 17.7% in the type 2 diabetics studied. LADA patients showed similar laboratory and clinical features as type 2 diabetics, except for low BMI levels and poor glycemic control.

Keywords: LADA;Type 2 diabetes;GADA;Cpeptide;BMI

Manuscript Body:


Introduction

In 1977, Irvine and others outlined a subset of type 2 diabetics, which were positive for islet cell autoantibody (ICA) and failed to respond to sulphonylurea treatment1. Later on, autoimmune diabetes of adults was reported in 19862, leading to ongoing arguments in terms of its nomenclature, classification, and management. The name of latent autoimmune diabetes of adults (LADA) was launched3 after discovering circulating glutamic acid decarboxylase autoantibodies (GADAs) in 19904. Since then, many eponyms (Table 1) were introduced to state the disease criteria in terms of slow progressive rather than rapid onset type1 diabetes in adults22, 28-30.Although LADA shares some clinical, immune, and genetic similarities with type 1 diabetes16,22,30-32, it is still a crucial issue that25, 33-37 is not only misclassified as type 2diabetes12-13,16,31,38, but is sometimes presented with incompatible criteria of type 1 diabetes12, 39. Therefore, considering the lack of standard clinical features, LADA needs to patients17, 18,27, but it also mirrored the be identified carefully.Overall, the positivity of at least one circulating autoantibody such as ICA, insulinization proved to protect or delay islet GADA, protein tyrosine phosphatase β-cell deterioration26,31,42,43). Plasma cautoantibody (IA-2), or insulin autoantibody peptide was reported to reflect the degree of (IAA) against pancreatic islet β-cell antigens endogenous insulin secretion by islet β-cell is enough to define LADA. GADA has been 19,28,40,43,44 and to fall more rapidly in type 1 confirmed to be a sensitive autoimmune rather than in LADA22, 44. marker to diagnose LADA3,10,13,27,31,38,40-43 and This paper aims to determine the epidemiological data have demonstrated that prevalence of LADA in Latakia based on the the prevalence of LADA, based on GADA positivity of GADAs among type 2 diabetic positivity, ranged from 2.8% to 16% in type patients, and investigates further the clinical2 diabetics10,13,18, 31, 38, 41. According to GADAand laboratory characteristics of LADA titers, not only was LADA was subdivided based on GADA titers.

Table 1. Eponyms for latent autoimmune diabetes of adults based on the first article that utilized this
terminology

Eponym Year
Slowly progressive insulin-dependent diabetes mellitus (SPIDDM)5 1984
Type 1.5 diabetes/ Type 1 1/2 diabetes6 1985
Latent type 1 diabetes2 1986
Progressive insulin-dependent diabetes mellitus (PIDDM)7 1992
Latent autoimmune diabetes in adults3
1993
Autoimmune diabetes in adults (ADA)8
1996
Slow-onset insulin-dependent diabetes mellitus9
1997
Slowly progressive type 1 diabetes10
1998
Latent-onset type 1 diabetes1
1999
Antibody-positive non-insulin-dependent diabetes11
1999
Slowly progressing autoimmune type 1 diabetes12
1999
Type 2 diabetes with glutamic acid decarboxylase antibodies13
1999
Slow type 1 diabetes14
1999
Slow onset autoimmune diabetes15
2000
Slowly progressing autoimmune diabetes15
2000
Autoimmune diabetes not requiring insulin at diagnosis16
2001
Latent autoimmune diabetes of adults –type 1 and –type 2 17-18
2001
Slowly progressive β-cell failure19
2001
Slowly progressive autoimmune diabetes in adult patients20
2001
Antibody-positive phenotypic type 2 diabetes with obesity21
2003
Slowly progressive adult-onset type 1 diabetes22
2003
Latent autoimmune diabetes of adulthood23
2003
Type 2 with islet cell autoimmunity24
2004
Adult-onset latent autoimmune diabete18
2004
Autoimmune diabetes in adults with slowly progressive b-cell failure (ADASP)25
2005
Antibody-positive slowly progressive type 1 diabetes26
2005
Non insulin requiring autoimmune diabetes (NIRAD)27
2007

 

Materials and Methods

Patients

A group of 254 (equally divided in gender) type 2 diabetics, aged 35 to 75 years enrolled in the diabetic center of the National Health Services of Latakia, were recruited in this study during the period of January 2008 to February 200912-13,16-17,22,24-25,30,38,41. Each patient was provided with the date and a pre-analytical preparation notice for an interview. Seventeen patients were excluded from the study and the exclusion criteria were malignancy, autoimmune diseases, known abnormal thyroid function at the time of the study, use of NSAIDS or acetylsalicylic acid, or infections in the previous two weeks before the start of the study; in addition, patients with type 1 diabetes requiring insulin after 6 months of diagnosis were also excluded13,22,25,34. Ninety-three diabetic patients (36.6%) of our cohort were insulin treated. A hundred and forty-five patients were on oral hypoglycemic drugs while 16 patients were on a diet; some of them refused to have treatment. These subgroups of patients were studied in terms of the clinical characteristics, biochemical laboratory assessment, and determination of GADAs concentrations.

Clinical assessment

The recruited patients visited the Diabetic Center frequently (every 2 months) for general clinical evaluation. All patients were examined by the same endocrinologist and newly diagnosed patients were referred to the related clinics for further assessment of the diabetic complications. Personal and clinical characteristics (Table 3) of type 2 GADA-subgroup were compared with misdiagnosed type 2 GADA+ subgroup (LADA) in terms of gender, age, duration of diabetes (in years), body mass index (BMI), and family history of diabetes. Also, diabetic complications including peripheral neuropathy, retinopathy, cardiovascular disease, and peripheral vascular disease in both subgroups (type 2 GADA- patients versus GADA+ diabetics) were assessed according to the Diabetics Center records. Nephropathy evaluation was done by laboratory tests (urea, creatinine, and Macro-or Micro- proteinuria) and hypertension was considered abnormal if a subject took antihypertensive drugs or had blood pressure >140/90 mmHg. Metabolic syndrome was evaluated for each subject according to the World Health Organization (WHO) 1999 criteria29.
 

Biochemical laboratory methods

After a 12-hour overnight fasting, plasma heparin samples were used for all tests except LDL-C and HBA1c for which we used serum for LDL-C and plasma EDTA for HGBA1c. The amount of the anticouagulants are international standards for 5ml tubes. Samples were drawn after interviewing patients between 8 and 10 am at the diabetic center of Latakia. In addition, a morning midstream urine specimen was collected from every patient for chemical urinalysis (protein, glucose, ketones, and microalbuminuria) according to the pre-analytical notice that was given to each patient previously. The blood and urine analysis were run in the department of Laboratory Medicine at Al-Assad Hospital of Latakia. Glucose, cholesterol (total, High density lipoprotein (HDL-C), and Low density lipoprotein (LDL-C), triglycerides, urea, and creatinine (modified kinetic Jafe’ method) were tested by enzymatic methods while HbA1c was analyzed by ion exchange chromatographic method. HDL and LDL cholesterol were precipitated by phosphotungstate/magnesium and polyvinyl sulphate/polyethyleneglycol methods, respectively. Normal and abnormal controls were run with every tested sample for all the above mentioned tests, and all the above mentioned materials were commercially supplied by BioSystems S. A., Spain. Microalbuminuria was determined by turbidimetric latex method (BioSystems S. A.) and albuminuria levels >20 mg/L were considered microalbuminuria, according to WHO 2002 criteria45. Ketones, glucose, and protein in urine were tested using urine strip tests (Analyticon® Biotechnologies AG). Urine controls level 1 and level 2 were applied in each run (DiaSys Diagnostic Systems GmbH). C-peptide (ng/mL) was tested by two-site immunoluminometric assay (DiaSorin S. P. A, Italy).Determination of GAD65 autoantibodies: Glutamic acid decarboxylase 65 (GAD65) autoantibodies were tested on the serum samples using enzyme immunoassay method and the kits were supplied commercially by Medipan Diagnostica, Germany. The manufacturer’s reference value of ≥ 5.0 IU/mL was considered positive with 92.3 % sensitivity and 98.6 % specificity. The commercial assay was calibrated against the WHO reference preparation National Istitute of Biological Standards and Control (NIBSC) 97/550 and the concentration was, therefore, expressed in IU/ml. The threshold for positivity (≥ 5.0 units/mL) was further confirmed in our laboratory as the 96.6th percentile from a healthy control group (n =48) according to WHO criteria; only normal subjects with normal glucose tolerance test were included in this study.

Statistical analysis

The results are statistically expressed as mean ± standard deviation (SD). Differences between GADA- versus GADA+ subgroups were analyzed with Student t-test (continuous variables) and χ2 test (dichotomous variables). One way ANOVA was used to show the differences of c-peptide and BMI variables according to subgroups of diabetics with GADA- <5 IU/mL (type 2), GADA+ ≤50 IU/mL, or GADA+ >50 IU/mL. Level of significance was 0.05.

Results

This study showed that GADA+ was prevalent in 45 (17.7 %) patients out of 254 type 2 diabetics. In Table 2 the clinical comparison of GADA+ patients (n=45) versus individuals with GADA- (n=209) showed that there were no significant differences with respect to personal, anthropometric and clinical features including gender, age at diagnosis, family history for diabetes, and disease duration with the exception of BMI which was significantly lower in the GADA+ subgroup compared with results of the GADA-subgroup (27.6±4.8 vs. 29.8±5.9; P=0.02). Furthermore, no difference was noticed with respect to the metabolic syndrome and the clinical complications of diabetes in both GADA- and GADA+ subgroups, although the frequency of metabolic syndrome and the family history of diabetes were high (> 50%) in both subgroups, GADA+ and GADA- diabetics (Table 2).

 

Table 2. Personal and clinical characteristics of patients without Glutamic acid decarboxylase autoantibodies versus those with Glutamic acid decarboxylase autoantibodies diabetics misdiagnosed as having typen 2 diabetes

Variable GADA-* GADA+
  n(209) n(45)
Gender; F/M (%) 48.8/51.2 55.6/44.4
Age (years)
52.8±9.9 54.0±9.8
Duration of diabetes (years)
8.1±7.1 9.9±6.7
Body mass index (kg/m2)
29.8±5.9 27.6±4.8†
Family History of diabetes
(%) 66 51.1
Neuropathy
(%) 39.7 44.4
Retinopathy
(%) 17.7 15.5
Nephropathy
(%) 3.35 2.2
Hypertension
(%) 30.6 20
Cardiovascular disease
(%) 12 17.7
Peripheral vascular disease
(%) 3.35 0
Metabolic syndrome
(%) 64.6 62.2

*Glutamic acid decarboxylase autoantibodies, continuous variables are presented with mean±SD, †P=0.02

Comparing blood and urinary laboratory tests (table 3) showed significant laboratory differences in terms of the glycemic control variables such as FBS, glucosuria, and ketonuria between GADA- and GADA+ female with respect to the presence or subgroups. The FBS was significantly higher absence of GAD autoantibodies. Urinary in the GADA+ diabetics (221.6±77.9) than tests showed that glucosuria and ketonuria in GADA- subgroup (182±66.7), (P=0.001). were significantly different between GADA+ However, there no differences were observed and GADA- subgroups with P=0.025 and in HBA1c, c-peptide, lipids (total cholesterol, P<0.0001, respectively. triglycerides, HDL-C, LDL-C) in male and Based on GADA levels, the studied IU/mL, and GADA+ >50 IU/mL. As seen in sample was further subdivided into tertiles of figure 1, there were significantly lower c-type 2 ,GADA- <5 IU/mL, GADA+ ≤50 peptide concentrations between the subgroups (P =0.002), diabetic patients with GADA+ >50 IU/mL had significantly lower c-peptide concentrations in comparison to those detected in the type 2 and GADA+ ≤50 subgroups.

Table 3. Laboratory results of patients without Glutamic acid decarboxylase autoantibodies versus
those with glutamic acid decarboxylase autoantibodies diabetics misdiagnosed as having type 2 diabetes

Variable GADA-*
n (209)
GADA+
n (45)
P value
Fasting blood glucose (mg/dL) 182±66.7 221.6±77.9 0.001
HBA1c (%) 7.4±1.3 7.7±1.3 ns†
C-peptide (ng/mL) 1.7±1.1 1.6±0.9 ns
Total Cholesterol (mg/dL)      
 females 223±49.3 228.3±51.7 ns
 males 205.4±43.9 203.8±41.3 ns
Triglycerides(mg/dL)      
 female 193.9±97.2 178.6±112 ns
 male 181.7±123.3 185.1±122.1 ns
High density lipopro1tein cholesterol(mg/dL)      
 female 38.1±11.2 42.6±16.21 ns
 male 31.2±8.9 29.6±8.4 ns
Low density lipoprotein cholesterol (mg/dL)      
 female 137.4±34.1 150.5±41.8 ns
 male 134.1±39.7 136.1±36.6 ns
Urine (% positivity)      
 Protein  8.6  8.9  ns
 Glucose  41.6  60  0.025
 Ketones  3.8  22.2  <0.0001

* Glutamic acid decarboxylase autoantibodies; † non significant; continus variables are presented with mean±SD

 

Fig. 1. C-peptide concentrations (ng/mL) intertiles of diabetic patients with type 2,GADA+ ≤50 IU/mL, and GADA+ >50 IU/mL(CI 95%).

 

Fig. 2. Body mass index (kg/m2) values in tertilesof diabetics with type 2, GADA+ ≤50IU/ml, and GADA+ >50 IU/mL (CI 95%)

Also, as seen in figure 2, BMI in the subgroup of GADA+ >50 IU/mL was significantly lower than that found in type 2 patients (p=0.012). However, no significant differences were detected between GADA+ ≤50 IU/ml subgroup and both of type 2 and GADA+ >50 IU/ml subgroups.

Discussion

Based on GADA positivity, the findings of this study showed that 17.7% of type 2 diabetic patients, aged 35 to 75 years, were diagnosed as having LADA. The prevalence of LADA in Latakia was higher than that observed by extensive studies in Europe and North America that reported LADA in less than 10% of the type 2 diabetics studied31, 41. Moreover, the classification of LADA is further emphasized in this study by islet cell autoantibody screening in agreement with WHO and American Diabetic Association reports28,29 rather than the clinical judgment in the subgroup of misdiagnosed type 2 diabetics.In LADA subjects, the clinical presentation ranged across the classical features of type 1 and type 2 diabetes, in agreement with other studies17,18 in relation with the GADA titers. Regardless of BMI, the clinical picture in our cohort illustrated that GADA+ patients (n=45) have similar clinical features as classical GADA- type 2 diabetes, with no significant differences in terms of gender, age at diagnosis, family history for diabetes, and disease duration. Isomaa and his colleagues12 reported no significant differences in terms of the clinical complications of diabetes between LADA and type 2 subjects. Different studies reported that the metabolic syndrome was significantly different in LADA with type 2 diabetics regardless of GADA titers12-13,18-19, 27,38,41,46. Our results showed no significant differences between LADA patients and GADA- type 2 diabetic patients; nonetheless, more than 50% of patients in both subgroups have metabolic syndrome parameters. However, the majority of our cohort with high GADA titers (>50 IU/mL) had lower frequencies of metabolic syndrome components, in agreement with data reportedby other studies12-13, 18-19, 27.In agreement with several previous studies3,13,17-18,22, 27, 31, the findings concerning BMI presented significantly lower levels in LADA versus type 2 diabetic subjects, but in both subgroups patients were overweight or obese, which could be related to the high prevalence of obesity worldwide47. Fourlanos et al showed that using BMI as a single variable to identify LADA resulted in 30% sensitivity, since LADA patients were overweight or obese48. However, patients with high GADA levels (> 50 IU/ml) were found to present with normal or lean weight, in comparison with type 2 diabetics similar to those seen in classical type 1 diabetes22,17,27,42,49.In comparison with GADA- type 2 subjects, LADA patients metabolically presented with poorly controlled glycemia, estimated by significantly observed high levels of FBS, glucosuria, and ketonuria; some of these were treated with oral hypoglycemic drugs, especially those who showed advanced stages of β-cell failure. Many researchers agree on commencing insulin early with GADA+ subjects13,19,31,39,42. Early diagnosis of LADA based on detecting GADA and c-peptide will help to preserve insulin secretory capacity by β-cell.Turner and his colleagues noticed that almost 50% of LADA patients required insulin after6 years31 while others showed that better glycemic control was accomplished with the insulinization of GADA+ diabetic subjects between from 2 to 4 years after diagnosis50,51. Based on c-peptide in patients with GADA+ >50 IU/mL, the data presents significant low levels of c-peptide and shows complete deterioration of islet β-cell in comparison with type 2 and GADA+ ≤50 IU/ml subgroups in which both showed relatvely more preserved β-cell funtion.In conclusion, it seems that LADA is a prevalent public health problem in Syria and it has to be considered at the national level in terms of islet β-cell autoimmune screening. LADA patients showed similar laboratory and clinical features as type 2 diabetics with the exception of low BMI levels and poor glycemic control.

Acknowledgements

Dr. Nada Shiek Yousef and all the academic staff at the Diabetic Center of National Health Services in Latakia for their excellent technical assistance; Mrs. Roula Alkattib and Mrs. Kafa Ahmad for their laboratory technical assistance at Al-Assad Teaching Hospital in Latakia; Dr Imad Abo Assali who has kindly contributed to my study with c-peptide controls level 1 and 2, and Dr. Mouhannad Hassan and the Faculty of Medicine at Tishreen University for its sponsorship.

References: (51)

  1. Irvine WJ, McCallum CJ, Gray RS, Duncan LJ.Clinical and pathogenic significance of pancreaticislet-cell antibodies in diabetics treated with oral hypoglycemic agents. Lancet 1977: 1025-7.
  2. Groop LC, Bottazzo GF, Doniac D. Islet cell antibodiesidentify latent type 1 diabetes in patients aged 35–75 years at diagnosis. Diabetes 1986; 35:237-41.
  3. Tuomi T, Groop LC, Zimmet PZ, Rowley MJ,Knowles W, Mackay IR. Antibodies to glutamicacid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulindependent onset of disease. Diabetes 1993; 42:359-62.
  4. Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A,Solimena M, Cascalho M, et al. Identification ofthe 64K autoantigen in insulin-dependent diabetesas the GABA-synthesizing enzyme glutamic aciddecarboxylase. Nature 1990; 347: 151-6.
  5. Kobayashi T, Sawano S, Sugimoto T, Itoh T, KosakaK. Risk factors of slowly progressive insulindependent(type I) diabetes mellitus. J Steroid Biochem1984; 20: 1488.
  6. No authors listed. Insulin-dependent? Lancet1985; 2: 809-10.
  7. Harris M, Zimmet P. Classification of diabetesmellitus and other categories of glucose intolerance.In: Alberti K, De Fronzo R, Keen H, ZimmetP, editors. International Textbook of DiabetesMellitus. Chichester: John Wiley & Sons Ltd,1992. p. 3-18.
  8. Björk E, Berne C, Kämpe O, Wibell L, Oskarsson P, Karlsson FA. Diazoxide treatment at onset preserves residual insulin secretion in adults with autoimmune diabetes. Diabetes 1996; 45: 1427-30.
  9. Lohmann T, Sessler J, Verlohren HJ, Schröder S, Rötger J, Dãhn K, et al. Distinct genetic and immunological features in patients with onset of IDDM before and after age 40. Diabetes Care 1997; 20: 524-9.
  10. Seissler J, de Sonnaville JJ, Morgenthaler NG, Steinbrenner H, Glawe D, Khoo-Morgenthaler UY, et al. Immunological heterogeneity in type I diabetes: presence of distinct autoantibody patternsin patients with acute onset and slowly progressivedisease. Diabetologia 1998; 41: 891-7.
  11. Juneja R, Palmer JP. Type 1 1/2 diabetes: myth or reality? Autoimmunity 1999; 29: 65-83.
  12. Isomaa B, Almgren P, Henricsson M, TaskinenMR, Tuomi T, Groop L, et al. Chronic complicationsin patients with slowly progressing autoimmunetype 1 diabetes (LADA). Diabetes Care1999; 22: 1347-53.
  13. Tuomi T, Carlsson A, Li H, Isomaa B, MiettinenA, Nilsson A, et al. Clinical and genetic characteristicsof type 2 diabetes with and without GADantibodies. Diabetes 1999; 48: 150 -7.
  14. Zimmet P, Turner R, Mc Carty D, Rowley M,Mackay I. Crucial points at diagnosis: type 2 diabetesor slow type 1 diabetes. Diabetes Care1999; 22: 59-64.
  15. Carlsson A, Sundkvist G, Groop L, Tuomi T. Insulinand glucagon secretion in patients with slowlyprogressing autoimmune diabetes (LADA). JClin Endocrinol Metab 2000; 85:76–80.
  16. Pozzilli P, Di Mario U. Autoimmune diabetes notrequiring insulin at diagnosis (latent autoimmunediabetes of the adult): definition, characterization,and potential prevention. Diabetes Care 2001; 24:1460-7.
  17. Lohmann T, Kellner K, Verlohren HJ, Krug J,Steindorf J, Scherbaum WA, et al. Titre and combinationof ICA and autoantibodies to glutamic aciddecarboxylase discriminate two clinically distincttypes of latent autoimmune diabetes in adults(LADA). Diabetologia 2001; 44: 1005-10.
  18. Li X, Zhou ZG, Huang G, Yan X, Yang L, ChenXY, et al. Optimal Cutoff Point of Glutamate DecarboxylaseAntibody Titers in DifferentiatingTwo Subtypes of Adult-Onset Latent AutoimmuneDiabetes. Ann N Y Acad Sci 2004; 1037: 122-6.
  19. Borg H, Gottsäter A, Landin-Olsson M, FernlundP, Sundkvist G. High levels of antigen-specific isletantibodies predict future beta-cell failure in patientswith onset of diabetes in adult age. J ClinEndocrinol Metab 2001; 86: 3032-8.
  20. Schernthaner G, Hink S, Kopp HP, Muzyka B,Streit G, Kroiss A. Progress in the characterizationof slowly progressive autoimmune diabetes inadult patients (LADA or type 1.5 diabetes).ExpClin Endocrinol Diabetes 2001; 109 Suppl 2: S94-108.
  21. Palmer JP, Hirsch IB. What’s in a name: latent autoimmunediabetes of adults, type 1.5, adult-onset,and type 1 diabetes. Diabetes Care 2003; 26: 536-8.
  22. Hosszufalusi N, Vatay A, Rajczy K, Prohaszka Z,Pozsonyi E, Horvath L, et al. Similar genetic featuresand different islet cell autoantibody patternof latent autoimmune diabetes in adults (LADA)compared with adult-onset type 1 diabetes withrapid progression. Diabetes Care 2003; 26: 452-7.
  23. Behme MT, Dupre J, Harris SB, Hramiak IM,Mahon JL. Insulin resistance in latent autoimmunediabetes of adulthood. Ann N Y Acad Sci 2003;1005: 374-7.
  24. Barinas-Mitchell E, Pietropaolo S, Zhang YJ,Henderson T, Trucco M, Kuller LH, et al. Isletcell autoimmunity in a triethnic adult populationof the Third National Health and Nutrition ExaminationSurvey. Diabetes 2004; 53: 1293-302.
  25. Stenström G, Gottsäter A, Bakhtadze E, Berger B,Sundkvist G. Latent autoimmune diabetes inadults: definition, prevalence, beta-cell function,and treatment. Diabetes 2005; 54: 68-72.
  26. Matsumoto M, Satou S. Small doses of insulinmay prevent the decrease of intrinsic insulin secretionin anti-GAD, ICA and IA-2 antibody-positiveslowly progressive type 1 diabetes. Journal of theJapan Diabetes Society 2005; 48: 257-61(Japanese).
  27. Buzzetti R, Di Pietro S, Giaccari A, Petrone A,Locatelli M, Suraci C, et al. Non Insulin RequiringAutoimmune Diabetes Study Group.. High Titerof Autoantibodies to GAD Identifies a SpecificPhenotype of Adult- Onset Autoimmune Diabetes.Diabetes Care 2007; 30: 932-8.
  28. The Expert Committee on the Diagnosis and Classificationof Diabetes Mellitus: Report of the ExpertCommittee on the Diagnosis and Classificationof Diabetes Mellitus. Diabetes Care 1997; 20:1183-97.
  29. World Health Organization, editor. Report of aWHO Consultation. Definition, Diagnosis andClassification of Diabetes Mellitus and its Complications.Part 1: Diagnosis and Classification ofDiabetes Mellitus. World Health Organization,Department of Noncommunicable Disease Surveillance:Geneva; 1999.
  30. Rosário PW, Reis JS, Amim R, Fagundes TA,Calsolari MR, Silva SC, et al. Comparison ofClinical and Laboratory Characteristics BetweenAdult-Onset Type 1 Diabetes and Latent AutoimmuneDiabetes in Adults. Diabetes Care 2005; 28:1803-4.
  31. Turner R, Stratton I, Horton V, Manley S, ZimmetP, Mackay IR, et al; UK Prospective Diabetes Study (UKPDS) Group. cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. Lancet 1997; 350:1288-93.
  32. Horton V, Stratton I, Bottazzo GF, Shattock M,Mackay I, Zimmet P, et al. Genetic heterogeneityof autoimmune diabetes: age of presentation inadults is influenced by HLA DRB1 and DQB1 genotypes(UKPDS 43). UK Prospective DiabetesStudy (UKPDS) Group. Diabetologia 1999; 42: 608-16.
  33. Palmer JP, Hampe CS, Chiu H, Goel A, Brooks-Worrell BM. Is latent autoimmune diabetes inadults distinct from type 1 diabetes or just type 1diabetes at an older age? Diabetes 2005; 54: 62-7.
  34. Fourlanos S, Dotta F, Greenbaum CJ, Palmer JP,Rolandsson O, Colman PG, et al. Latent autoimmunediabetes in adults (LADA) should be less latent.Diabetologia 2005; 48: 2206-12.
  35. Gale EA. Latent autoimmune diabetes in adults: aguide for the perplexed. Diabetologia 2005; 48:2195-9.
  36. Leslie RD, Williams R, Pozzilli P. Clinical review:Type 1 diabetes and latent autoimmune diabetesin adults: one end of the rainbow. J ClinEndocrinol Metab 2006; 91: 1654-9.
  37. Groop L, Tuomi T, Rowley M, Zimmet P, MackayIR. Zimmet. Latent autoimmune diabetes in adults(LADA)- more than a name. Diabetologia 2006;49: 1996-8.
  38. Römkens TE, Kusters GC, Netea MG, Netten PM.Prevalence and clinical characteristics of insulintreated,anti-GAD-positive, type 2 diabetic subjectsin an outpatient clinical department of aDutch teaching hospital. Neth J Med 2006; 64:114-8.
  39. Takeda H, Kawasaki E, Shimizu I, Konoue E, FujiyamaM, Murao S, et al. Clinical, autoimmune,and genetic characteristics of adult-onset diabeticpatients with GAD autoantibodies in Japan (EhimeStudy). Diabetes Care 2002; 25: 995-1001.
  40. Borg H, Gottsater A, Fernlund P, Sundkvist G. A12-year prospective study of the relationship betweenislet antibodies and β-cell function at andafter diagnosis in patients with adult-onset diabetes.Diabetes 2002; 51: 1754-62.
  41. Zinman B, Kahn SE, Haffner SM, O'Neill MC,Heise MA, Freed MI; ADOPT Study Group. Phenotypiccharacteristics of GAD antibody-positiverecently diagnosed patients with type 2 diabetes inNorth America and Europe. Diabetes 2004; 53:3193-200.
  42. Rosário PW, Reis JS, Fagundes TA, CalsolariMR, Amim R, Silva SC, et al. Latent AutoimmuneDiabetes in Adults (LADA): Usefulness of Anti-GAD Antibody Titers and Benefit of Early Insulinization.Arq Bras Endocrinol Metabol 2007; 51:52-8.
  43. Maruyama T, Tanaka S, Shimada A, Funae O,Kasuga A, Kanatsuka A, et al. Insulin interventionin slowly progressive insulin-dependent (type 1)diabetes mellitus. J Clin Endocrinol Metab 2008;93: 2115-21.
  44. Palmer JP, Fleming GA, Greenbaum CJ, HeroldKC, Jansa LD, Kolb H, et al. C-peptide Is the AppropriateOutcome Measure for Type 1 DiabetesClinical Trials to Preserve {beta}-Cell Function:Report of an ADA Workshop. Diabetes 2004; 53:250-64.
  45. Reinauer H, Home PD, Kanagasabapathy AS,Heuck CC; World Health Organization, editors.Laboratory Diagnosis and Monitoring of DiabetesMellitus. World Health Organization: Geneva;2002.
  46. Hawa MI, Thivolet C, Mauricio D, Alemanno I,Cipponeri E, Collier D, et al; Action LADAGroup. Metabolic syndrome and autoimmune diabetes:action LADA 3. Diabetes Care 2009; 32:160-4.
  47. Abelson P, Kennedy D. The obesity epidemic.Science 2004; 304: 1413.
  48. Fourlanos S, Perry C, Stein MS, Stankovich J,Harrison LC, Colman PG. A clinical screeningtool identifies autoimmune diabetes in adults. DiabetesCare 2006; 29: 970-5.
  49. Maruyama T, Oak S, Shimada A, Hampe CS.GAD65 autoantibody responses in Japanese latentautoimmune diabetes in adult patients. DiabetesCare 2008; 31: 1602-7.
  50. Alvarsson M, Sundkvist G, Lager I, HenricssonM, Berntorp K, Fernqvist- Forbes E, et al. Beneficialeffects of insulin versus sulphonylurea on insulinsecretion and metabolic control in recentlydiagnosed type 2 diabetic patients. Diabetes Care2003; 26: 2231-7.
  51. Alvarsson M, Sundkvist G, Lager I, HenricssonM, Berntorp K, Fernqvist-Forbes E, et al. Effectsof insulin vs. glibenclamide in recently diagnosedtype 2 diabetic patients. Diabetologia 2004; 47:A56 (Abstract).