Latent autoimmune diabetes in adults is perched between type 1 and type 2: evidence from adults in...
Transcript of Latent autoimmune diabetes in adults is perched between type 1 and type 2: evidence from adults in...
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Title: Latent autoimmune diabetes (LADA) is perched between type 1 and type 2:
evidence from adults in one region of Spain
Authors: Angels Mollo*1, Marta Hernandez*2,3, Josep R. Marsal4,5,6, Aureli Esquerda7,
Ferran Rius2,3, Francisco Blanco-Vaca8,9, Joan Verdaguer3,10, Paolo Pozzilli11,12, Alberto
de Leiva13,14,15, Didac Mauricio2,3
* These authors contributed equally to the study.
1.- Centre d'Atenció Primària de Cervera, Institut Català de la Salut, Lleida, Spain 2.- Department of Endocrinology and Nutrition, Hospital Universitari Arnau de Vilanova, Lleida, Spain 3.- Institut de Recerca Biomèdica de Lleida, Universitat de Lleida, Lleida, Spain 4.- Unitat de Suport a la Recerca de Lleida, Institut Universitari d'Investigació en Atenció Primària Jordi Gol, Lleida, Spain 5.- Unitat d' Epidemiologia del Servei de Cardiologia. Hospital Universitari Vall d'Hebron, Barcelona, Spain 6.- CIBER en Epidemiología y Salud Pública (CIBERESP). Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain 7.- Clinical Laboratory, Hospital Universitari Arnau de Vilanova, Lleida, Spain 8.- IIB Sant Pau, Barcelona, Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain 9.- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain 10.- Departament de Medicina Experimental, Universitat de Lleida, Lleida, Spain 11.- Department of Endocrinology and Diabetes, University Campus Bio-Medico, Rome, Italy 12.- Centre of Diabetes, Barts and the London School of Medicine, Queen Mary University of London, UK 13.- Department of Endocrinology and Nutrition, Hospital de Sant Pau- IIB-Sant Pau, Barcelona, Spain 14.- CIBER de Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain 15.- Universitat Autònoma de Barcelona, Barcelona, Spain Correspondence to: Didac Mauricio. Department of Endocrinology and Nutrition, Hospital Universitari Arnau de Vilanova, Av Rovira Roure 80, 25198 Lleida, Spain. E-mail: [email protected] Telephone: +34 973705183 Fax: +34 973305189
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/dmrr.2411
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ABSTRACT
Background
The aim of this study was to characterize the clinical characteristics and insulin
secretion in adults with latent autoimmune diabetes (LADA). We also compared these
characteristics in subjects with antibody-negative type 2 diabetes (T2DM) or adult-onset
type 1 diabetes (T1DM) to subjects with LADA.
Methods
In this cross-sectional study, 82 patients with LADA, 78 with T1DM and 485 with
T2DM were studied. Clinical and metabolic data, in particular those that related to
metabolic syndrome, fasting C-peptide and islet-cell autoantibodies (glutamic acid
decarboxylase (GADAb) and IA2 (IA2Ab)) were measured.
Results
The frequency of metabolic syndrome in patients with LADA (37.3%) was higher than
in those with T1DM (15.5%; p = 0.005) and lower than in patients with T2DM (67.2%;
p < 0.001). During the first 36 months of the disease, the C-peptide concentration in
LADA patients was higher than in subjects with T1DM but was lower than in T2DM
patients (p < 0.01 for comparisons). Glycemic control in LADA patients (HbA1c 8.1%)
was worse than in patients with T2DM (HbA1c 7.6%; p =0.007). An inverse association
between GADAb titers and C-peptide concentrations was found in subjects with LADA
(p <0.001). Finally, LADA patients rapidly progressed to insulin treatment.
Conclusions
As in other European populations, patients with LADA in Spain have a distinct
metabolic profile compared with patients with T1DM or T2DM. LADA is also
associated with higher impairment of beta-cell function and worse glycemic control
than in T2DM. Beta cell function is related to GADAb titers in patients with LADA.
Keywords: latent autoimmune diabetes in adults; type 1 diabetes mellitus; type 2
diabetes mellitus; C-peptide; metabolic syndrome; glutamic acid decarboxylase
antibodies.
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INTRODUCTION
The current classification of diabetes mellitus includes the classical form of
autoimmune diabetes, i.e., type 1A diabetes [1]. However, it is clear that not all subjects
with autoimmune-mediated diabetes show the classical type 1A phenotypic features,
especially at the onset of disease [2]. Although there is a controversy about the
convenience of the use of the term, latent autoimmune diabetes in adults (LADA) is
recognized as a form of immune-mediated diabetes that, at least in the initial stages,
masquerades as type 2 diabetes [3-6]. The criteria for diagnosing the condition vary
between studies, mainly with respect to age at onset and time to insulin initiation. The
pathogenic process and the clinical, genetic and immune characteristics of this form of
autoimmune diabetes are still not fully characterized.
LADA accounts for 2 - 12% of all cases of diabetes, according to different
epidemiological data [7]. In addition to contributing to the pathophysiological
knowledge of diabetes, the diagnosis of LADA has been found to influence the
hypoglycemic treatment of choice by physicians; those centers that determine islet cell-
related antibodies tend to start insulin treatment earlier, and this difference could have
consequences for the future management of hyperglycemia [8].
The aim of the study was to further characterize LADA in Spanish subjects in terms of
β-cell autoimmunity, insulin secretion and clinical characteristics. We compared
subjects with LADA to antibody-negative type 2 diabetic subjects from the original
study population (T2DM) and to adult-onset type 1 diabetic subjects (T1DM).
METHODS
This was a cross-sectional study that included diabetic patients over 30 years of age
from two hospital-based centers in northeastern Spain (Barcelona and Lleida). T1DM
and T2DM were diagnosed according to standard criteria [1], and cases of LADA were
defined as patients aged 30 – 70 years at the diagnosis of diabetes who did not require
insulin for at least 6 months after diagnosis, with glutamic acid decarboxylase (GAD)
autoantibody (GADAb) or tyrosine phosphatase autoantibody (IA-2Ab) positivity [9].
The study was initially part of the Action LADA project that was extended locally for
an additional period of 3 years. The selection criteria were those used in the original
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Action LADA Study [10]. Patients were included consecutively if they fulfilled the
inclusion criteria and were willing to participate in the study after they signed the
written informed consent document. The study protocol was approved by the local
Ethics Committee at each center.
For each subject, age, sex, weight, height, body mass index (BMI), waist circumference
and blood pressure were recorded. Blood pressure was measured twice in the sitting
position. Patients were specifically interviewed about smoking habit and treatments for
diabetes, hypertension and dyslipidemia. Time to start of insulin was calculated as the
time between the date of diagnosis and the date of the first insulin treatment.
A fasting blood sample was collected and analyzed locally, using standardized assays to
measure glucose, glycosylated haemoglobin (HbA1c), the lipid profile (including high-
density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and
triglycerides), creatinine and GAD antibody. Serum samples were stored at -80ºC until
the determination of C-peptide and IA-2Ab. C-peptide was measured by a
chemoluminescence assay (Immulite 2000, Siemens Medical Solutions Diagnostics,
Los Angeles, USA), with reference values of 300 - 2.400 pmol/L (interassay coefficient
of variation was less than 5%). The lower detection limit was 30 pmol/L. Any value
below the lower detection limit was assigned a concentration of 29 pmol/L.
Diagnostic criteria for metabolic syndrome
Metabolic syndrome was assessed according to the National Cholesterol Education
Program: Adult Treatment Panel III criteria [11]. All patients in the study fulfilled the
criteria of hyperglycemia. Three of the five criteria (including hyperglycemia) were
required for the diagnosis of metabolic syndrome as previously described [10].
Antibody measurements
Screening for GADAb was performed in all patients. Additionally, stored samples for
IA2 were available from 68 patients with T1DM and 75 patients with LADA.
Antibodies to islet cell antigens (GADA65 and IA-2) were measured with two
commercially available ELISA kits: GAD65 Autoantibody ELISA and IA-2
Autoantibody ELISA (both from DRG Diagnostic, Marburg, Germany), as previously
described [12-13]. Optimal cut-off values for positivity were set at 5 and 15 U/mL for
GADA65 and IA-2, respectively. While the present study was in progress, both assays
showed good performance when tested in the Diabetes Antibody Standardization
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Program (DASP) Workshops. In DASP 2007, sensitivities and specificities were 94%
and 97% for GADAb, respectively, and 66% and 95% for IA2Ab; in DASP 2009 the
figures were 82% and 95% for GADAb, and 60% and 100% for IA2Ab, respectively.
Statistical analysis
Continuous variables were described using the means and standard deviations or
medians and interquartile ranges, and categorical variables were described using
proportions.
Bivariate and multivariate analyses were based on the dependent variable (3 categories:
T1DM, LADA and T2DM). The individual characteristics were tested using a non-
parametric test (Kruskal-Wallis test) or the chi-squared test for differences between the
three groups. A Cox-proportional risk model was used to examine survival in terms of
time to insulin treatment in LADA and patients with type 2 diabetes.
For the purpose of C-peptide secretion analysis, disease duration (in months) was
calculated as the period between the date of diagnosis and the date of the study
assessment. The disease duration was stratified into 3 periods (<12 months, 12-36
months and >36 months) for the three categories analyzed; i.e., LADA, T1DM and
T2DM.
To evaluate the association between GADAb positivity and fasting C-peptide, we
divided GADAb titers into terciles: first (< 30 U/ml), second (30-250 U/ml) and third (>
250 U/ml).
For all analyses, we used the SPSS software (version 15.0; Chicago, USA) and an alpha
value of 0.05 for statistical significance.
RESULTS
A total of 82 consecutive patients with LADA, 78 patients with T1DM and 480 patients
with T2DM were included in the study.
Clinical and metabolic characteristics
Table 1 shows the clinical characteristics of the three study groups. More men than
women were included, with no significant differences between groups. Patients with
LADA were older (53.4 ± 12.3 years) than patients with T1DM (45.5 ± 11.9 years; p <
0.001), but no significant differences were found with patients with T2DM (56.0 ± 11.0
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years; p = 0.076). The median disease duration was longer in LADA patients than in
patients with T1DM (p < 0.001) or T2DM (p = 0.006).
The investigation of metabolic characteristics revealed that subjects with LADA
presented an intermediate phenotype, with adiposity parameters and blood pressure
values that were higher than in patients with T1DM but lower than in those with T2DM.
The triglyceride concentrations of LADA patients were higher than in patients with
T1DM and lower than in patients with T2DM (p = 0.022 and p < 0.001, respectively).
HDL cholesterol concentrations in LADA patients were lower than in patients with
T1DM and higher than in patients with T2DM (p = 0.037 and p < 0.001, respectively).
The prevalence of metabolic syndrome was higher among LADA patients (37.3%) than
in patients with T1DM (15.5%; p = 0.005) but lower than in patients with T2DM
(67.2%; p < 0.001).
In terms of glycemic control, no significant differences were found in fasting plasma
glucose and HbA1c concentrations between both types of autoimmune diabetes, but
both parameters were higher in LADA than in patients with T2DM (p = 0.010 and p =
0.007 for glucose and HbA1c, respectively).
Fasting C-peptide
The LADA subjects displayed lower fasting C-peptide secretion compared with subjects
with T2DM (p < 0.001). Interestingly, when C-peptide concentration was stratified
according to disease duration (Figure 1), this difference remained only up to 36 months
of disease duration (p < 0.01); after 3 years, C-peptide concentration in patients with
LADA overlapped with that of patients with T1DM and T2DM. However, there were
fewer patients in the latter group, resulting in wider confidence intervals.
Insulin treatment, alone or in combination with other hypoglycemic agents, was higher
in LADA patients than in those with type 2 diabetes (45.7% versus 19%, respectively; p
< 0.001). After adjusting for age, weight and time since diagnosis, the hazard ratio for
insulin treatment in LADA compared with type 2 diabetes was 8.34 (4.9 – 13.3; p <
0.001). The faster progression to insulin treatment from the diagnosis of diabetes in
LADA patients compared to patients with T2DM is depicted in Figure 2.
Autoantibodies
The GADAab and IA2Ab data are represented in Figure 3. The frequency of GADAb
positivity was higher in patients with LADA than in patients with T1DM (p < 0.001),
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but no differences were found for IA2Ab positivity (p = 0.126) or for the proportion of
patients with positivity for both antibodies (p = 0.112). GADAb and IA2Ab titers,
expressed as median and interquartile range, were not different between patients with
type 1 diabetes (GADAb: 158 [7-345] U/ml; IA2Ab: 9 [9-60.5]) and those with LADA
(GADAb: 81 [11-251] U/ml; IA2Ab: 9 [9-1.2] U/ml) (p = 0.562 for GADAb and p =
0.697 for IA2Ab).
Figure 4 shows that in LADA patients, C-peptide concentrations were inversely
associated with GADAb levels (p < 0.001 for each tertile). After adjusting for time
since diabetes diagnosis, this difference remained significant (p < 0.001). In contrast,
we did not observe any difference in C-peptide levels in T1DM when stratified by
GADAb titer.
DISCUSSION
In this study, we describe the clinical and biological characteristics of patients
diagnosed with LADA in northeastern Spain, and we compare them with patients with
T1DM and with antibody-negative T2DM. To the best of our knowledge, this is the first
study characterizing patients with LADA from Spain.
Individual components of metabolic syndrome (waist, hypertension and lipid profile) in
LADA patients were intermediate between patients with T1DM and T2DM. Contrary to
our findings, in one of the first studies designed specifically to study the prevalence of
metabolic syndrome among LADA patients [14], no differences were found between
patients with LADA and adult-onset (> 25 years) type 1 diabetic subjects, although they
were present when comparing patients with LADA and T2DM. On the other hand,
Rosario et al. [15] compared 45 adult-onset T1DM patients (age at diagnosis > 35 years)
with 54 LADA patients, and they found a higher prevalence of individual components
of metabolic syndrome in the latter group. Results similar to ours were reported in
GAD-positive subjects in the Botnia [16] and ADOPT [17] studies. In the NIRAD
study, consisting of 83 participating centers in an Italian nationwide survey [18], 193
autoimmune-positive patients showed poorer glycemic control and also a higher
prevalence of several components of metabolic syndrome than patients with negative
autoimmunity. In the Action LADA project [10], in which 40 subjects with LADA from
the current sub-study were included, the results were similar to ours; however, despite a
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higher prevalence of metabolic syndrome in LADA compared to T1DM, individual
components of the metabolic syndrome were not different between both groups. The
differences between the studies may be influenced by the sample size of the groups, the
selection criteria for inclusion, the genetic variability between the included populations
and the settings of the different studies.
The time-course of the derangement of insulin secretion as measured by fasting C-
peptide was faster in LADA patients compared to patients with T2DM. For those
patients less than 3 years from diagnosis, fasting C-peptide concentrations were
intermediate between those of patients with T1DM and T2DM. However, the small
number of subjects with disease duration of more than 3 years for fasting C-peptide
comparisons limits the interpretation of the results. In parallel with these findings,
LADA patients presented with poorer glycemic control and were more frequently
treated with insulin.
Assay of islet-cell autoantibodies revealed no differences in antibody titers between
T1DM and LADA. These data should be interpreted with caution, as both groups were
relatively small and heterogeneous in terms of diabetes duration. Interestingly, we found
that GADAb titers were inversely related to C-peptide concentrations in LADA but not
in T1DM. There are few studies in the literature containing C-peptide and islet cell
autoimmunity data from a considerable number of well-defined LADA patients
compared to T1DM and T2DM patients. Tuomi et al. [16] found an inverse correlation
between fasting C-peptide and GADAb levels in the Botnia study population. In
addition, Radtke et al. [19] found a negative correlation between GADAb titers and C-
peptide in a population of 42 insulin-treated LADA patients, although this correlation
was not observed in 64 non-insulin-treated LADA patients from the same study.
Although we have no data for fasting or stimulated C-peptide, the negative association
between C-peptide concentration and GADAb titers could explain the higher incidence
of insulin treatment found in patients with higher GADAb levels in some studies [20-
21]. In agreement with our results, Buzzetti et al. [18] reported that patients with higher
GADAb titers had more pronounced traits of insulin deficiency. In contrast with these
findings, Maioli et al. [22] did not find high GADAb titers per se to be a major risk
factor for progression to insulin dependence in the ethnically homogeneous population
of Sardinia.
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There are some limitations to our results. The recruitment of diabetic patients in
hospital-based studies may clearly introduce bias in the results. In Spain, patients with
T2DM or LADA are mainly cared for at the primary-care level, and only those with
worse glycemic control or with more severe diabetes-related complications are referred
to hospitals for specialized treatment. It is possible that these results would be different
in a population-based study, in which presumably a higher proportion of patients with a
clinical phenotype closer to that of T2DM would be found. Another important limitation
is the cross-sectional design of the current study, with heterogeneity of diabetes duration
between groups that could influence the autoantibodies and C-peptide secretion results.
With this current design, we cannot draw conclusions about the different islet cell
autoantibody patterns between LADA and T1DM.
In conclusion, our study confirms that LADA patients are metabolically different from
patients with T2DM and that their β-cell function is more severely impaired, a fact that
seems to be related to high GADAb titers. However, further studies are needed for a
better characterization of this type of diabetes, especially studies investigating
autoimmunity and stimulated β-cell function, and its relationship with the genetic
background in different population settings.
ACKNOWLEDGMENTS
We thank the following staff members of the centers involved in the study: Emilia
Belda, Lídia Carrasco, Núria García, Javier Maravall, Antonio Pérez and Anna Ramírez.
Grants: D. Mauricio was supported by a grant from Instituto de Salud Carlos III, Spain
(Project FIS 061104). The Action LADA consortium was supported by the EU (contract
No: QLG1-CT-2002-01886). CIBER de Diabetes y Enfermedades Metabólicas
Asociadas (CIBERDEM) is an ISCIII action. CIBER de Epidemiología y Salud Pública
(CIBERESP) is an ISCIII action. CIBER de Bioingeniería, Biomateriales y
Nanomedicina is an ISCIII action.
Conflict of interest
None declared.
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REFERENCES
[1] American Diabetes Association: Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003; 26 Suppl 1:S5-S20. DOI: 10.2337/diacare.26.2007.S5 [2] Leslie RD, Kolb H, Schloot NC, et al. Diabetes classification: grey zones, sound and smoke: Action LADA 1. Diabetes Metab Res Rev. 2008; 24(7):511-9. DOI: 10.1002/dmrr.877 [3] Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR. Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a noninsulin-dependent onset of disease. Diabetes 1993; 42(2):359–362. [4] Fourlanos S, Dotta F, Greenbaum CJ, et al. Latent autoimmune diabetes in adults (LADA) should be less latent. Diabetologia 2005; 48(11):2206-2212. DOI: 10.1007/s00125-005-1960-7 [5] Gale EA. Latent autoimmune diabetes in adults: a guide for the perplexed. Diabetologia 2005; 48:2195-2199. DOI: 10.1007/s00125-005-1954-5 [6] Rolandsson O, Palmer JP. Latent autoimmune diabetes in adults (LADA) is dead: long live autoimmune diabetes! Diabetologia 2010; 53(7):1250-1253. DOI: 10.1007/s00125-010-1713-0
[7] Stenström G, Gottsäter A, Bakhtadze E, Berger B, Sundkvist G. Latent Autoimmune Diabetes in Adults Definition, Prevalence, β-Cell Function, and Treatment. Diabetes 2005; 54 Suppl 2:S68-S72. DOI: 10.2337/diabetes.54.suppl_2.S68 [8] Brophy S, Davies H, Mannan S, Brunt H, Williams R. Interventions for latent autoimmune diabetes (LADA) in adults. Cochrane Database Syst Rev 2011; 9:CD006165. DOI: 10.1002/14651858.CD006165.pub3 [9] Brophy S, Yderstraede K, Mauricio D, et al. Time to insulin initiation cannot be used in defining latent autoimmune diabetes of the adult. Diabetes Care 2008; 31(3):439-441. DOI: 10.2337/dc07-1308
[10] Hawa MI, Thivolet C, Mauricio D, et al. Metabolic syndrome and autoimmune diabetes: action LADA 3. Diabetes Care 2009; 32(1):160-164. DOI: 10.2337/dc08-1419
[11] Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285:2486–2497. DOI: 10.1001/jama.285.19.2486 [12] Palomer X, Mauricio D, Rodríguez-Espinosa J, et al. Evaluation of two nonisotopic immunoassays for determination of glutamic acid decarboxylase and tyrosine phosphatase autoantibodies in serum. Clin Chem 2004; 50(8):1378-82. DOI: 10.1373/clinchem.2004.031799
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[13] Chen S, Willis J, Maclean C et al. Sensitive non-isotopic assays for autoantibodies to IA-2 and to a combination of both IA-2 and GAD65. Cin Chim Acta 2005;357:74-83. DOI: 10.1016/j.cccn.2005.02.006 [14] Hosszúfalusi N, Vatay A, Rajczy K, et al. Similar genetic features and different islet cell autoantibody pattern of latent autoimmune diabetes in adults (LADA) compared with adult-onset type 1 diabetes with rapid progression. Diabetes Care 2003; 26(2):452-457. DOI: 10.2337/diacare.26.2.452 [15] Rosário PW, Reis JS, Amim R et al. Comparison of clinical and laboratory characteristics between adult-onset type 1 diabetes and latent autoimmune diabetes in adults. Diabetes Care 2005;28(7):1803-4. DOI: 10.2337/diacare.28.7.1803 [16] Tuomi T, Carlsson A, Li H et al. Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 1999; 48:150-157. [17] 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;53:3193-3200. DOI: 10.2337/diabetes.53.12.3193 [18] 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):932-8. DOI: 10.2337/dc06-1696 [19] 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-Trøndelag Health (HUNT) study. Diabetes Care 2009;32(2):245-50. DOI: 10.2337/dc08-1468 [20] Genovese S, Bazzigaluppi E, Gonçalves D, et al. Clinical phenotype and β-cell autoimmunity in Italian patients with adult-onset diabetes. Eur J Endocrinol 2006; 154:441-447. DOI: 10.1530/eje.1.02115 [21] Rosário PW, Reis JS, Fagundes TA, et al. Latent autoimmune diabetes in adults (LADA): usefulness of anti-GAD antibody titers and benefit of early insulinization. Arq Bras Endocrinol Metab 2007;51(1):52-58. [22] 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):541-9. DOI: 10.1530/EJE-10-0427
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Cop
yrig
ht ©
201
3 Jo
hn W
iley
& S
ons,
Ltd.
Tabl
e 1:
Clin
ical
cha
ract
eris
tics,
incl
udin
g fa
stin
g C
-pep
tide
conc
entra
tions
of p
atie
nts w
ith ty
pe 1
dia
bete
s, la
tent
aut
oim
mun
e di
abet
es in
ad
ults
, or t
ype
2 di
abet
es
Sam
ples
for C
-pep
tide
dete
rmin
atio
ns w
ere
avai
labl
e fo
r 77
patie
nts w
ith T
1DM
, 81
patie
nts w
ith L
AD
A a
nd 4
63 p
atie
nts w
ith T
2DM
. Th
e da
ta a
re re
pres
ente
d as
the
mea
ns ±
stan
dard
dev
iatio
n or
n (%
), ex
cept
for d
isea
se d
urat
ion,
whi
ch is
exp
ress
ed a
s med
ians
[in
terq
uant
ile ra
nges
].
TID
M, t
ype
1 di
abet
es; L
AD
A, l
aten
t aut
oim
mun
e di
abet
es in
adu
lts; T
2DM
, typ
e 2
diab
etes
, BM
I, bo
dy m
ass i
ndex
; SB
P, sy
stol
ic b
lood
pr
essu
re; D
BP,
dia
stol
ic b
lood
pre
ssur
e; H
DL,
hig
h-de
nsity
lipo
prot
ein;
LD
L, lo
w-d
ensi
ty li
popr
otei
n; H
bA1c
, gly
cosy
late
d ha
emog
lobi
n.
T1D
M (n
= 7
8)
LA
DA
(n=8
2)
T2D
M (n
=480
)
P va
lue
for
grou
p co
mpa
riso
ns
T1D
M –
L
AD
A
T2D
M -
LA
DA
Se
x (n
, wom
en)
33 (4
2.3%
) 30
(36.
6%)
174
(36.
3%)
0.51
8 1.
000
Age
(yea
rs)
45.5
± 1
1.9
53.4
± 1
2.3
56.0
7 ±
11.0
<0
.001
0.
076
Age
at d
iagn
osis
42
.6 ±
11.
4 49
.2 ±
11.
7 53
.0 ±
10.
5 <0
.001
0.
011
Dis
ease
dur
atio
n (m
onth
s)
10 [6
– 3
9]
38 [6
– 5
9]
24 [6
– 4
7]
<0.0
01
0.00
6 B
MI (
kg/m
2 ) 25
.6 ±
4.9
2 26
.9 ±
4.4
29
.9 ±
5.4
0.
031
<0.0
01
Wai
st (c
m)
90.4
± 1
2.5
94.8
± 1
6.6
101.
6 ±
14.4
0.
003
<0.0
01
SBP
(mm
Hg)
12
3.2
± 24
.0
131.
4 ±
19.1
13
8.6
± 21
.5
0.03
6 0.
002
DB
P (m
mH
g)
74.0
± 1
5.1
79.5
± 9
.9
82.3
± 1
1.7
0.00
1 0.
035
Ant
ihyp
erte
nsiv
e tre
atm
ent
11 (1
4.1%
) 30
(36.
6%)
248
(51.
7%)
0.00
1 0.
012
Trig
lyce
rides
(mg/
dl)
90.7
± 4
8.4
121.
5 ±
84.3
16
3.3
± 12
0.8
0.02
2 <0
.001
To
tal c
hole
ster
ol (m
g/dl
) 19
2.4
± 37
.4
202.
4 ±
61.6
21
8.8
± 37
.9
0.42
0 0.
284
HD
L ch
oles
tero
l (m
g/dl
) 67
.7 ±
23.
2 59
.8 ±
17.
5 50
± 1
5.8
0.03
7 <0
.001
LD
L ch
oles
tero
l (m
g/dl
) 11
3.2
± 33
.5
118.
7 ±
36.0
12
2.3
± 35
.5
0.32
1 0.
192
Met
abol
ic sy
ndro
me
(n, %
) 11
(15.
5%)
28 (3
7.3%
) 30
3 (6
7.2%
) 0.
005
0.00
0 Fa
stin
g gl
ycem
ia (m
g/dl
) 17
8.3
± 80
.7
164.
8 ±
59.8
14
8.8
±56.
3 0.
529
0.01
0 H
bA1c
(%)
8.9
± 2.
7 8.
1 ±
2.1
7.6
± 1.
9 0.
098
0.00
7 C
Pep
tide
(pm
ol/l)
26
1.0
± 23
4.0
587.
0 ±
515.
8 97
8.0
± 48
0.7
<0.0
01
<0.0
01
Insu
lin tr
eatm
ent (
alon
e or
co
mbi
ned
with
oth
er a
gent
s) (n
,%)
78 (1
00.0
%)
37 (4
5.7%
) 91
(19.
00%
) <0
.001
<0
.001
Acc
epte
d A
rticl
e
Copyright © 2013 John Wiley & Sons, Ltd.
Figure 1: C-Peptide concentrations of type 1, LADA, and type 2 diabetic patients divided in three categories according to time since diagnosis: less than 12 months (50, 34, and 269 patients, respectively), 12-36 months (22, 35 and 174 patients, respectively) and over 36 months (5, 12 and 20 patients, respectively). Footnote: Differences between groups were significant in patients with less than 12 months and between 12 and 36 months since diagnosis (p < 0.01). After 36 months of diabetes diagnosis, no differences were found between LADA patients and those with T1DM and T2DM. Vertical lines indicate the 95% confidence intervals (CI). TIDM, type 1 diabetes; LADA, latent autoimmune diabetes in adults; T2DM, type 2 diabetes.
Acc
epte
d A
rticl
e
Copyright © 2013 John Wiley & Sons, Ltd.
Figure 2: Cox proportional hazard model of time to insulin after 6 months since diagnosis in adult patients with latent autoimmune diabetes (dotted line) versus type 2 diabetic patients. Footnote: Time 0 indicates 6 months after diagnosis. LADA, latent autoimmune diabetes in adults; T2DM, type 2 diabetes.
Acc
epte
d A
rticl
e
Copyright © 2013 John Wiley & Sons, Ltd.
Figure 3: Frequency of GADAb and IA2Ab positivity in adult patients with type 1 diabetes or latent autoimmune diabetes Footnote: All patients (78 patients with T1DM and 82 with LADA) were tested for GAD Ab. For IA2-Ab, only 68 T1DM and 75 LADA patients were tested. The data are represented as percentages for antibody positivity. *Theses differences are statistically significant (p < 0.001) TIDM, type 1 diabetes; LADA, latent autoimmune diabetes in adults; GADAb, GAD antibody; IA2Ab, IA2 antibody.
Acc
epte
d A
rticl
e
Copyright © 2013 John Wiley & Sons, Ltd.
Figure 4: Correlation of C-peptide levels and GADAb titers divided into terciles in LADA patients: first (< 30 U/ml), second (30-250 U/ml) and third (> 250 U/ml). Footnote: Vertical lines indicate the 95% CI. GADAb, GAD antibody; LADA, latent autoimmune diabetes in adults.