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Diabetes & Metabolism
Vol 27, N° 1  - mars 2001
p. 59
Doi : DM-02-2001-27-1-1262-3636-101019-ART9
Case reports

bCell autoimmunity in a child with M.O.D.Y. (Maturity Onset Diabetes in the Young)
 

E. Ortega-Rodriguez [1], C. Levy-Marchal [1], S. Guillermine [1], M. Polak [1]
[1] Pediatric Endocrine and Diabetes Unit, INSERM U457, Robert Debré Hospital, Paris, France.

Abstract

We present the case of a well characterised M.O.D.Y. type 2 diabetes family in which one of the children associated bcell autoimmunity and a HLA DQB1 at risk for immune-mediated type 1 diabetes mellitus. The search for autoantibodies against bcell should be considered in cases of genetically defined form of diabetes mellitus to exclude the possibility of a concomitant risk to develop type 1 diabetes mellitus.

Abstract
Autoanticorps anti-cellule bchez un enfant atteint de M.O.D.Y. (Maturity Onset Diabetes in the Young)

Nous rapportons le cas d'un enfant atteint d'un diabète de type MODY 2, qui présentait simultanément des signes d'auto-immunité dirigée contre la cellule b. De plus le typage HLA révélait un génotype de susceptibilité majeure au diabète de type 1 auto-immun. La question est posée de l'utilité de rechercher systématiquement des signes d'auto-immunité anti-pancréatique dans le diabète de type MODY.


Mots clés : MODY. , diabète de type 1. , auto-immunité anti-cellule b.

Keywords: MODY. , type 1 diabetes. , bcell autoimmunity.


We evaluated two brothers of French origin who had a family history of M.O.D.Y. 2. Their mother had been diagnosed with diabetes at 18 years of age and treated by diet. However insulin was required during pregnancies. Maternal grandfather and great-grandfather had had non insulindependent diabetes mellitus. M.O.D.Y. was suspected on the basis of the clinical and the family history of diabetes over three generations. A mutation (G 279A) in exon 7 codon 249 of the glucokinase gene was found in the mother.

The older child was born at 38 weeks of gestation with a weight of 3790 g (75

th

percentile) and a height of 48 cm (50

th

percentile). On the occasion of a minor surgery, when he was 4 years old, fasting blood glucose was measured at 7.9 mmol/l and glycated haemoglobin (HbA1c) at 6.2 % (normal < 5.7 %). He had the same mutation in the glucokinase gene as his mother. At the time of the first visit he was 6 years old. He showed impaired glucose tolerance: fasting glucose 6.6 mmol/l, and glucose 9.6 mmol/l at 120 minutes during an oral glucose tolerance test (OGTT). No

b

cell autoimmunity was detected. HLA DQB1 analysis detected a low susceptibility genotype for type 1 autoimmune diabetes [ [1]].

His brother was 2 years 11 months old at the first visit. Birth weight (3790 g) and height (52 cm) were below the 90

th

percentile for gestational age (38 weeks). Impaired glucose tolerance was detected during OGTT with fasting glucose levels at 6.3 mmol/l and 8.8 mmol/l after 120 minutes. HbA1c level was 6.2 %. The same mutation in glucokinase gene was detected. Surprisingly, immunological studies performed in a systematic way showed ICA (Islet Cell Cytoplasmic Antibodies) positivity at 3 Juvenile Diabetes Foundation (JDF) units. Dietary exclusion of simple carbohydrate sugar was recommended. At 4 years of age the first phase insulin secretion, assessed as insulin at 1 plus 3 minutes after intravenous glucose load (IVGTT), was 16.4

m

U/ml (two-fold lower than the 5

th

percentile of our reference population). Normal insulin release could be obtained under glucagon stimulation (Table I)

. HLA typing showed the high risk genotype for type 1 diabetes DQB1 0201-0302. Over the following 3 years he maintained stable HbA1c levels in the range of 6.2-6.4 %. However ICA antibodies title raised to 63 JDF units; autoantibodies directed towards GAD 65 (glutamic acid decarboxilase) and insulin were strongly positive at 108.1 U/ml and 35.5 % (more than 30 times the threshold for positivity of both) but anti-IA2 (tyrosine-phosphatase) remained negative.

M.O.D.Y. is defined by an autosomic dominant inheritance of diabetes before 25 years of age [ [2]]. M.O.D.Y. 2 is due to mutations in the glucokinase gene which encodes for the "glucose sensing" enzyme of the

b

cell [ [3]]. These patients maintain mild fasting hyperglycaemia and rarely need specific treatment such as oral hypoglycaemic agents in childhood. M.O.D.Y. is not thought classically to be associated with

b

cell autoimmunity. The presence of autoantibodies against

b

cell reflects pancreatic autoimmunity. The high level of autoantibodies and the HLA DQB1 genotype in our patient make him prone to develop type 1 autoimmune diabetes mellitus. His young age, multiple autoantibodies positivity and high risk HLA typing would confer a risk greater than 80 % to develop type 1 autoimmune diabetes in the next 5 years if he was a first degree relative of type 1 autoimmune diabetes patient [ [4], [5]]. The follow-up of this patient is a crucial point for the high risk to develop type 1 diabetes.

Therefore we presented here the unexpected association of a non immune monogenic form of diabetes mellitus and

b

cell autoimmunity. We believe that the search for autoantibodies against

b

cell should be considered in cases of genetically defined form of diabetes mellitus to exclude the possibility of a concomitant

b

cell autoimmunity with a high risk to develop type 1 diabetes mellitus.

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Références

[1]
Veijola R, Reijonen H, Vasalo P, et al. HLADQB1-defined genetic susceptibility, beta cell autoimmunity and metabolic characteristics in familial and non-familial insulin dependent diabetes mellitus. Childhood diabetes in Finland (DiMe) study group. J Clin Invest, 1996, 98, 2489-2495.
[2]
Velho G, Froguel P. Genetic, metabolic and clinical characteristics of maturity onset diabetes of the young. Eur J Endoc, 1998, 138, 233-239.
[3]
Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, et al. Familial hyperglycemia due to mutations in glucokinase. Definition of subtype of diabetes mellitus. N Engl J Med, 1993, 328, 697-702.
[4]
Kulmala P, Savola K, Petersen JS, Vahasalo P, Karjalainen J, Lopponen T, et al. Prediction of insulin-dependent diabetes mellitus in siblings of children with diabetes. A population-based study. The childhood Diabetes in Finland Study Group. J Clin Invest, 1998, 101, 327-336.
[5]
Polak M, Eisenbarth GS. Human autoimmune diabetes. In: Bona CA, Siminovitch K, Theofilopoulos AN, Zanetti M, editors. The Molecular Pathology of Autoimmunity. Harwood Academic Publishers, 1993, 610-618.


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