Lessons from the NOD mouse for the pathogenesis and immunotherapy of human Type 1 (insulin-dependent) diabetes mellitus

Suitable animal models of human Type 1 (insulin-dependent) diabetes mellitus have long been sought, in particular a model that would permit detailed histological and immunological investigation of changes in the islet preceding the metabolic disorder. This would allow hypotheses as to pathogenesis of the condition to be examined and interventions such as immunotherapy to be tested. The most widely studied models include the low-dose streptozotocin induced diabetic mouse and the BB rat, but both differ in important respects from the human disease. In this review we describe one highly successful model, the non obese diabetic mouse. Selected aspects of pathogenesis and immunotherapy are presented and analogies with human Type 1 diabetes discussed

Raised temperature reduces the incidence of diabetes in the NOD mouse

An association between the incidence of childhood Type 1 (insulin-dependent) diabetes mellitus and the average yearly temperature in different countries has been reported, the incidence being higher in countries with a lower mean temperature. We have studied the effect of environmental temperature on the incidence of diabetes in an animal model of Type 1 diabetes, the non-obese diabetic (NOD) mouse. Female NOD mice were divided at weaning, with one group placed at a higher temperature (mean 23.7±1.7° C) and the other at a lower temperature (21.0±1.8° C). At 20 weeks of age 6 of 16 mice at lower temperature and 1 of 17 mice at higher temperature had developed diabetes (p < 0.02); at 30 weeks 10 of 16 and 5 of 17 mice had developed diabetes (p < 0.05). Non-diabetic animals in the low temperature group had a higher food intake than those in the high temperature group between 13–15 weeks of age (28.0±1.2 g/week vs 24.8± 0.7 g/week, P < 0.05). In a parallel experiment, histological examination showed that there were similar degrees of insulitis in the high and low temperature groups at seven weeks of age. We conclude that environmental temperature can affect the incidence of diabetes in the NOD mouse and that this may be related to alterations in food intake

Combined screening for antoantibodies to IA-2 and antibodies to glutamic acid decarboxylase in first degree relatives of patients with IDDM

To determine the value of antibodies to the intracytoplasmic domain of the tyrosine phosphatase IA-2 (anti-IA-2 ic) and glutamic acid decarboxylase (GADA) for identification of subjects at risk for insulin-dependent diabetes mellitus (IDDM) we investigated 1238 first degree relatives of patients with IDDM for the presence of anti-IA-2 ic and GADA and compared the results with cytoplasmic islet cell antibodies (ICA). Anti-IA-2 ic were observed in 54 (4.4 %) first degree relatives, in 51 of 86 (59.3 %) ICA positive relatives and in 3 of 4 individuals who developed overt IDDM within a follow-up period of 1 to 28 months. GADA were found in 78 of 1238 (6.3 %) first degree relatives. They were detected in 22 of 35 (62.9 %) sera with ICA alone and in 1 of 3 subjects with anti-IA-2 ic in the absence of ICA. Of the 1238 subjects 37 (3.0 %) sera were positive for all three antibodies. Both anti-IA-2 ic and GADA were positively correlated with high levels of ICA. Anti-IA-2 ic and GADA were detected in 39.1 and 47.8 % of subjects with ICA of less than 20 Juvenile Diabetes Foundation units (JDF-U) but in 66.7 and 76.2 % of individuals with ICA of 20 JDF-U or more, respectively (p < 0.05). The levels of ICA and GADA in first degree relatives with at least one additional marker were significantly higher than in subjects with ICA alone (p < 0.005) or GADA alone (p < 0.03). The combination of anti-IA-2 ic and GADA identified 84.9 % of all ICA positive subjects and 93.7 % of individuals with high level ICA (≥ 20 IDF-U). All 4 individuals who progressed to IDDM had either IA-2 ic or GADA. Our data indicate that primary screening for anti-IA-2 ic and GADA provides a powerful approach with which to identify subjects at risk for IDDM in large-scale population studies which may represent the basis for the design of new intervention strategies