Journal of Cellular Biochemistry 100:808–814 (2007) Effects of a Vitamin D 3 Analog on Diabetes in the Bio Breeding (BB) Rat Marcella Pedulla `, 1 Vincenzo Desiderio, 2,3 Antonio Graziano, 2 Riccardo d’Aquino, 2 Andrew Puca, 3 and Gianpaolo Papaccio 2,3 * 1 Dipartimento di Pediatria, Seconda Universita ` degli Studi di Napoli, Italy 2 Dipartimento di Medicina Sperimentale, Sezione di Istologia ed Embriologia, Seconda Universita ` degli Studi di Napoli, Italy 3 SHRO and Department of Biology, Temple University, Center for Biotechnology, Philadelphia, Pennsylvania Abstract Non-hypercalcemic analogs of vitamin D 3 modulate the immune response through antigen-presenting cells (APCs) and activated T-cells. A large population-base case-control showed that vitamin D 3 intake significantly decreases the risk of type 1 diabetes development. The aim of this study was, therefore, to observe the in vivo effects of a vitamin D 3 analog administered to Bio Breeding (BB) rats. 1,25-Dihydroxy-16,23Z-diene-26,27-hexafluoro-19-nor vitamin D 3 (BXL-219, formerly Ro 26-2198) (BioXell, Milan, Italy) was administered in vivo to BB rats from days 42 to 110 of life at 0.2 mg/Kg BW. Control animals received only vehicle (olive oil, 4.8 ml/100 g BW). The animals of these two groups were subjected to insulin treatment as they became diabetic. Insulin (Humulin, 28.6 UI/day) was administered irrespective of diabetes occurrence to another group of rats for comparison. Blood glucose, insulin levels, glycosuria, degree of islet infiltration, and the expression of some antigens were observed. Results showed that the vitamin D 3 analog reduced diabetes incidence, although limitedly, in BB rats while administration of oral insulin increased diabetes incidence. In addition, the vitamin D 3 analog did not stimulate an enhancement in the expression of CD4 and CD25 in BB rats as it does in NOD mice, which may explain the failure of this as well as other antidiabetic treatments in the BB animal model of type 1 diabetes. J. Cell. Biochem. 100: 808 –814, 2007. ß 2006 Wiley-Liss, Inc. Key words: type 1 diabetes; vitamin D3; islets of Langerhans; insulin; cytokines The Bio Breeding (BB) rat is a useful animal model of type 1 diabetes. In fact, these animals spontaneously develop a disease that, under several aspects, resembles that seen in humans. Among the numerous drugs tested by researchers to prevent or suppress the disease, non-hypercalcemic vitamin D 3 analogs have been reported to be capable of modulating the immune response through specific receptors expressed on antigen-presenting cells (APCs) and activated T-cells [Bouillon et al., 1995]. In particular, the non-hypercalcemic D 3 analogs are capable of inhibiting numerous autoimmune diseases in animal models, includ- ing experimental allergic encephalomyelitis [Cantorna et al., 1996], murine lupus [Lemire et al., 1992], collagen-induced arthritis [Larsson et al., 1998], and type 1 diabetes [Mathieu et al., 1994]. In humans, vitamin receptor gene poly- morphism has been associated with type 1 diabetes in different populations [Pani et al., 2000]. Moreover, a large population-base case-control has shown that the intake of vitamin D 3 significantly decreases the risk of type 1 diabetes development [Eurodiab substudy 2 study group, 1999]. Furthermore, vitamin D 3 analogs inhibit IL- 12 production [Lemire et al., 1995], most probably through the inhibition of nuclear factor (NF)-kB [D’ambrosio et al., 1998]. To this regard, we have recently found a biphasic effect ß 2006 Wiley-Liss, Inc. Grant sponsor: Italian Ministry for Research and Uni- versity (Miur). *Correspondence to: Prof. Gianpaolo Papaccio MD, PhD, Department of Experimental Medicine, Section of Histology, Second University of Naples, 5 via L. Armanni, 80138 Naples, Italy. E-mail: gianpaolo.papaccio@unina2.it Received 5 June 2006; Accepted 11 July 2006 DOI 10.1002/jcb.21095