Article

PDF
Access to the PDF text
Advertising


Free Article !

Diabetes & Metabolism
Vol 33, N° 2  - avril 2007
pp. 153-155
Doi : 10.1016/j.diabet.2006.12.005
Received : 24 mars 2006 ;  accepted : 10 décembre 2006
Familial aggregation of LADA and juvenile type 1 diabetes in a French Caucasian family
 

W. Arnous [1], M.P. Larmaraud [1], S. Bernard [2], C. Thivolet [3], M. Daumont [1]
[1] Service de diabétologie, centre hospitalier L.-Hussel, Vienne, France
[2] Fédération d’endocrinologie, pôle Est, Lyon, France
[3] Service d’endocrinologie–diabète–nutrition, hôpital Édouard-Herriot, Lyon, France

Tirés à part : S. Bernard

Corresponding author. Unité 11, hôpital cardiovasculaire, 69000 Lyon cedex, France.

@@#100979@@
Résumé

Association familiale de diabète de type LADA et de diabète juvénile de type 1 dans une famille caucasienne française.

Nous rapportons l'association inhabituelle de cas de diabètes dans une famille de dix membres. Parmi eux, trois adultes présentaient un diabète de type LADA et un enfant présentait un diabète de type 1 juvénile. Bien que la pathogénie exacte du LADA reste inconnue et pose la question du rôle de l'auto-immunité dans le déficit β cellulaire, l'association familiale de ces deux formes de diabète souligne l'existence de fondements communs, en particulier des mécanismes immunologiques et une susceptibilité génétique. Ce rapport illustre clairement les différences en termes d'auto-immunité (prévalence et titre des anticorps anti-IA2 et anti-GAD) et de génotype HLA entre les patients atteints de LADA et ceux atteints d'un diabète de type 1 juvénile.

Abstract
Abstract

We describe here the unusual aggregation of diabetes cases in a family of 10 subjects. Among them, three adult siblings presented with LADA and one child presented with juvenile type 1 diabetes. Although the exact pathogenesis of LADA is unknown and questions the role of autoimmunity in β cell failure, the familial aggregation of these two forms of diabetes underlines the existence of common roots, i.e. immune mechanisms and genetic susceptibility. This report clearly illustrates the differences in terms of autoimmunity (prevalence and titer of GAD and IA2 antibodies) and HLA class II genotype between patients with LADA and those with juvenile type 1 diabetes.


Mots clés : LADA , Diabète juvénile de type 1 , Anticorps anti-GAD-IA2 , Association familiale

Keywords: LADA , Juvenile type 1 diabetes , GAD-IA2 antibodies , Familial aggregation


The full text of this article is available in PDF format.
Click here to see it.
Introduction

Latent autoimmune diabetes in adults (LADA) type diabetes was defined in 1993 [1] by the presence of specific autoimmune markers (ICA, antibodies to GAD, to insulin and/or to IA-2) in patients with a clinical presentation that mimics type 2 diabetes at the onset of the disease, but a subsequent course toward insulin requirement within a few years [2 et 3]. However, the exact pathogenesis of beta cell failure in this adult form of diabetes is unknown, especially with regard to the role of the pathogenic Th1 cells that has been previously described within insulitis in patients with classical juvenile type 1 diabetes. Furthermore, it is not clear whether LADA is a slowly progressive form of type 1 diabetes or a clinical entity of its own.

Here, we report the prevalence and titer of GAD and IA2 antibodies, and HLA class II genotypes in a large pedigree including three patients with LADA and one patient with juvenile type 1 diabetes.

Case report

A 39-year-old woman (index case) was referred to our hospital for metabolic deterioration of diabetes, which occurred 2 years before and was treated by a combination of metformine and repaglinide. HbA1c levels rose to 10.9% (normal values: 4–6%) without significant weight loss. Blood glucose value at entry was 500 mg/dl, without ketonuria and with normal capillary ketones. She weighed 48 kg for 163 cm (BMI: 18 kg/m2). Clinical examination was normal. No diabetic complications were found. Secondary diabetes was ruled out. The patient mentioned several cases of diabetes in her family, as illustrated in Fig. 1: her mother who had insulin-treated diabetes and died from cardiovascular complications, two brothers treated with insulin after a few years with oral treatment, and a nephew with type 1 diabetes from the age of 7 years. We determined antibodies to GAD and to IA2 (by RIA/cis bio international), to thyroperoxidase (TPO), to gliadine, to transglutaminase and 21-hydroxylase in the four diabetic patients and the unaffected brothers (n = 2) and sisters (n = 4) (Tableau 1). Fasting blood glucose was also determined in the unaffected subjects. HLA class II genotype was assessed by PCR/SSO reverse method in diabetic and unaffected subjects.

Results and discussion

Tableau 1 summarizes the main characteristics of the subjects. The three LADA subjects were lean (BMI < 25 kg/m2) [4] but their birth weights were above 4 kg in the context of gestational diabetes in their mother. Age at onset of diabetes was between 30 and 37 years, which correspond to the characteristics reviewed by Fourlanos who proposed a minimal age of 30 years [2]. As observed in epidemiological studies, requirement for insulin therapy in these patients occurred 2, 4 and 7 years, respectively, after clinical diagnosis of diabetes [5]. Several authors have described two types of LADA [6]. LADA type 1 is characterized by an age at diagnosis below 40 years, a BMI below 25 kg/m2, the absence of android obesity, normal HDL-c and triglycerides, whereas in LADA type 2 diabetes the age at diagnosis was > 40, BMI > 25 kg/m2, android obesity, high triglycerides, and low HDL-c levels could be observed. In the reported family, the index case and the two affected brothers had the clinical features of LADA type 1 diabetes. Four of the unaffected subjects were lean but three had a birth weight above 4 kg. All subjects had normal lipid parameters, except one unaffected brother (MD) who had low HDL-c and slightly elevated fasting blood glucose in association with high BMI (28.4 kg/m2).

All diabetic patients had antibodies to GAD. Only the index case and the patient with juvenile type 1 were also positive for IA2 antibodies. In contrast to their diabetic siblings, none of the unaffected subjects were positive for anti-GAD or IA2 antibodies. In the patient with juvenile type 1 diabetes, the titer of GAD antibodies was lower than in the three patients with LADA. In the UKPDS, the presence of GAD antibodies was a strong predictor of insulino-dependency in this type 2 diabetes population [5]. Our index case had both GAD and IA2 antibodies, and the progression to insulin requirement was more rapid (2 years) than in the two affected brothers (5 and 7 years) who were only GAD positive. Other autoimmune diseases have been reported in LADA [7]. Only one LADA type patient had antibodies to TPO and was treated for Graves' disease. The diabetic child had antibodies to gliadine but not to transglutaminase and had no clinical features of celiac disease. None of the family members had antibodies to 21 hydroxylase and to transglutaminase, but two of the unaffected subjects had antibodies to TPO, which have a high prevalence in the general population.

Islet cell antibodies and GAD antibodies are strongly associated with DR4-DQB1*0302 haplotype in early adulthood type 1 diabetes, but not after the age of 55 years in the UKPDS study [8]. In this family, the DR4-DQB1*0302 haplotype was found in the three LADA patients but not in the child with type 1 diabetes. The DR4-DQB1*0302 haplotype was also found in the unaffected subjects but in association with the protective DQB1*0602 allele in four subjects. In conclusion, aggregation of these two forms of autoimmune diabetes (juvenile type 1 and LADA type diabetes which may be the ends of a continuous spectrum), within the same family with individuals exposed to similar environmental factors, reinforces the idea that HLA status may modulate the autoimmune response and therefore the age of onset of diabetes.

References

[1]
Tuomi T, Groop LC, Zimmet PZ, et al. Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes 1993;42:359-362.
[2]
Fourlanos S, Dotta F, Greenbaum CJ, et al. Latent autoimmune diabetes in adults (LADA) should be less latent. Diabetologia 2005;48:2206-2212.
[3]
Stenstrom G, Gottsater A, Bakhtadze E, Berger B, Sundkvist G. Latent autoimmune diabetes in adults: definition, prevalence, β-cell function, and treatment. Diabetologia 2005;54:68-72.
[4]
Pozzilli P, Di Mario U. Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adults): definition, characterization, and potential prevention. Diabetes Care 2001;24:1460-1467.
[5]
Turner R, Stratton I, Horton V, et al. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamine acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group. Lancet 1997;350:1288-1293.
[6]
Lohmann T, Kellner K, Verlohren HJ, et al. Titre and combination of ICA and autoantibodies to glutamic acid decarboxylase discriminate two clinically distinct types of latent autoimmune diabetes in adults (LADA). Diabetologia 2001;44:1005-1010.
[7]
Kucera P, Novakova D, Behanova M, et al. Endomysial and thyroid antibodies in patients with latent autoimmune diabetes of adults (LADA). Clin Exp Immunol 2003;33:139-143.
[8]
Horton V, Straton I, Bottazzo GF, et al. Genetic heterogeneity of autoimmune diabetes: age of presentation in adults is influenced by HLA DRB1 and DQB1 genotypes (UKPDS 43). Diabetologia 1999;42:608-616.




© 2006 Elsevier Masson SAS. Tous droits réservés.
EM-CONSULTE.COM is registrered at the CNIL, déclaration n° 1286925.
As per the Law relating to information storage and personal integrity, you have the right to oppose (art 26 of that law), access (art 34 of that law) and rectify (art 36 of that law) your personal data. You may thus request that your data, should it be inaccurate, incomplete, unclear, outdated, not be used or stored, be corrected, clarified, updated or deleted.
Personal information regarding our website's visitors, including their identity, is confidential.
The owners of this website hereby guarantee to respect the legal confidentiality conditions, applicable in France, and not to disclose this data to third parties.
Close
Article Outline
You can move this window by clicking on the headline