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P. Gargiulo, U. Di Mario, O. Zuccarini, F. Troili, C. Tiberti, U. Nicolini, A. Pachi, G. Gerlini and F. Fallucca

Abstract. Very little immunological research has been undertaken in pregnant diabetic women in relation to insulin therapy.

We investigated the relations between treatment with insulins of varied immunogenic character and the presence of immune factors such as insulin antibodies, immune complexes and insulin antiinsulin complexes as well as some maternal and neonatal complications of diabetic pregnancy.

128 insulin treated diabetic pregnant women and 121 of their newborns were included in the study.

The incidence of insulin antibodies, immune complexes and insulin antiinsulin complexes was lower in patients treated with highly purified insulins than in those treated with conventional insulins.

The insulin antibody levels were significantly related to the occurrence of maternal and neonatal morbibity.

The presence of insulin antiinsulin complexes in the cord blood of infants of diabetic mothers was related to the presence of these complexes in their mothers.

Our results seem to indicate that the use of highly purified insulin could favour the outcome of diabetic pregnancy.

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E Anastasi, E Ponte, R Gradini, A Bulotta, P Sale, C Tiberti, H Okamoto, F Dotta and UD Mario

OBJECTIVE: To evaluate the existence of beta-cell differentiation and proliferation in the low-dose streptozotocin (ld-STZ) mouse model of autoimmune diabetes. DESIGN: We studied the expression of Reg protein and cytokeratin 20 (CK20), the presence of proliferative phenomena (judged by the incorporation of bromodeoxyuridine (BrdU)), and the co-expression of Reg, CK20 or BrdU with insulin. MATERIALS AND METHODS: Diabetes was induced in male C57Bl6/J mice by administration of ld-STZ. The animals were killed at days 10 and 23 from the beginning of the induction of disease. Five animals were used at each time point and each group was evaluated for blood glucose concentrations, insulitis, expression of Reg and CK20 pancreatic proteins and BrdU incorporation, together with staining for insulin by immunohistochemistry and laser confocal microscopy. RESULTS: All mice treated with ld-STZ were hyperglycemic and histological investigation showed a mild or severe insulitis both at day 10 and at day 23. At day 10, immunochemistry revealed an intense expression of Reg and CK20 in pancreatic ducts in ld-STZ mice, but not in control mice. Reg and CK20 immunoreactive cells were also positive for insulin. In contrast, at day 23, pancreatic sections reacted weakly with anti-Reg and anti-CK20 antibody; co-localization with insulin was observed for both Reg and CK20. The incorporation of BrdU was observed only in insulin-positive cells in pancreatic sections from mice killed at day 10. CONCLUSIONS: These observations show an islet regeneration mechanism in response to an autoimmune attack, and that the ld-STZ mouse is a suitable model in which to evaluate intervention strategies.

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F Dotta, S Dionisi, V Viglietta, C Tiberti, MC Matteoli, M Cervoni, C Bizzarri, G Marietti, M Testi, G Multari, L Lucentini and U Di Mario

The target molecules of the T-cell response in type 1 diabetes, despite their pathogenic importance, remain largely uncharacterized, especially in humans. Interestingly, molecules such as insulin and glutamic acid decarboxylase (GAD) have been shown to be a target not only of autoantibodies, but also of autoreactive T-lymphocytes both in man and in the non-obese diabetic (NOD) mouse. In the present study we aimed to determine the existence of a specific T-cell response towards the insulinoma-associated protein 2 (IA-2) islet tyrosine phosphatase, a recently identified autoantigen which is the target of autoantibodies strongly associated with diabetes development. Human recombinant IA-2 produced in Escherichia coli, was tested for its reactivity with peripheral blood lymphocytes obtained from 16 newly diagnosed type 1 diabetic patients and from 25 normal controls, 15 of whom were HLA-DR-matched. A T-cell proliferation assay was performed in triplicate employing freshly isolated cells in the absence or in the presence of the antigen to be tested (at two different concentrations: 2 microg/ml and 10 microg/ml). A specific T-cell proliferation (defined as a stimulation index (S.I.) >/=3) was observed against IA-2 used at a concentration of 10 microg/ml (but not of 2 microg/ml) in 8/16 diabetic patients, in 1/15 HLA-DR-matched control subjects (P<0.01 by Fisher exact test) and in 0/10 of the remaining normal individuals. A statistically significant difference (P<0.003 by Mann-Whitney U test) was also observed in S.I. values between patients (3.1+/-1.4) and HLA-DR-matched controls (1.7+/-0.54) employing IA-2 at a concentration of 10 microg/ml. However, when IA-2 was used at a concentration of 2 microg/ml, the difference in S. I. between patients (1.65+/-0.8) and controls (1.0+/-0.3) did not reach statistical significance. In conclusion, these data show the presence of a specific, dose-dependent T-lymphocyte response against the IA-2 islet tyrosine phosphatase at the onset of type 1 diabetes. Consequently, this molecule appears to be a target not only at the B-lymphocyte but also at the T-lymphocyte level, reinforcing the potential pathogenic role of this autoantigen in the islet destructive process.

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E Ferretti, ML Jaffrain Rea, C Asteria, D Di Stefano, V Esposito, L Ferrante, P Daniele, C Tiberti, M Gallucci, C Bosman, E Alesse, A Gulino, P Beck-Peccoz and G Tamburrano

OBJECTIVE: Pituitary adenomas are usually sporadic, although rare familial cases have been described. Here we report two first degree female cousins with giant pituitary adenoma and overweight. Both presented with secondary amenorrhoea, occasional headache and weight gain. MATERIALS AND METHODS: In both patients clinical, morphological and genetic studies were performed. Both patients underwent surgery and post-operative medical therapy with somatostatin analogues and dopamine agonist, followed by a conventional radiotherapy course. RESULTS: Clinical examination at presentation revealed an acromegaloid habitus only in the second patient. Basal and dynamic hormonal evaluation showed high serum GH and serum IGF-I values, higher in the second than in the first patient, and a mild hyperprolactinaemia only in the first patient. On optical and electron microscopy, both tumours were oncocytic adenomas, immunopositive for GH in the first patient and GH/prolactin in the second. The genetic analysis for germ-line mutations of the multiple endocrine neoplasia type 1 gene was negative. Two years after radiotherapy a remarkable shrinkage of both tumours was observed, whereas the overweight worsened in both patients, accompanied by high plasma leptin values. CONCLUSION: To our knowledge, this is the first report of familial pituitary adenomas including one case of a clinically silent GH-secreting adenoma. In addition, it provides further evidence that familial pituitary tumours can occur as a multiple endocrine neoplasia type 1 unrelated disease.