The in vivo ınvestigation of the usage of proteasome inhibitor bortezomib in type 1 diabetes treatment.

Tip 1 diabet is a otoimmüne disease that is characterizied as the infiltration of inflamatuar cells to pancreas langerhans islets and destruction of the insulin secreting β cells. The leukocytes, which is infiltrated to inner parts of islet, secrete proinflamatuar cytokines like IL-β, TNF-α and IFN-γ that causes death of the β cells. In most studies both in vitro and in vivo, it is showed that Nuclear Factor Kappa-B (NF-κB) pathway has a role in β cell death that is triggered by those cytokines. The objective of this these is investigate usability of bortezomib, a Proteozome inhibitor, whose effectiveness in clinical practise depends on NF-kB inhibition and which is nowadays used in treatment of multiple myeloma, in treatment of Type-1 Diabetes Mellitus in vivo. For this purpose, female Sprague Dawley rats which were not obese were comprised. These were the control group, the diabetes group for which streptozotocin (STZ) was injected (Group II), the group for which bortezomib was administered (Group III), the group for which STZ and bortezomib were administered simultaneously (Group IV) and the treatment group in which bortezomib was administered to the rats which were confirmed to be diabetic following STZ administration (Group V). Bortezomib was administered totally as three (0th, 3rd and 7th days) with 3-day interval, as it is used in clinical practice. Following drug administration, all islets which were cultured for 24 hours, cell viability was determined under fluorescence microscopy. In conclusion of this study, the fact that STZ causes apoptozis in insulin-secreting beta cells of pancreas was confirmed by increase in blood glucose levels, decrease in viability of islets and investigation of expression levels of apoptotic genes (bax/bcl-2=3.14 /1.99). The fact that bortezomib dosage that was administered alone was not cytotoxic for β cells (91%) did not demonstrate any alteration compared to the control group. When apoptotic gene expression levels were investigated in this group, it was determined that Bortezomib had anti-apoptotic effect. In group IV, in which STZ and BOR were administered simultaneously, although blood glucose increased with administration of STZ, the fact that Bortezomib had anti-apoptotic effect on β cells was determined by evaluating bax/bcl-2 (3.84/4.68) ratio. In group V, in which Bortezomib was administered following STZ, it was determined that there was no improvement in terms of neither blood glucose nor number of islets. In group V, when apoptotic gene expression levels were investigated (bax/bcl-2=4.45/3.30), as is in the Group II, it pro-apoptotic effect was determined. In conclusion, it was concluded that in diabetic rats whose islets were not completely destructed, Bortezomib may prevent cells to undergo apoptozis by inhibiting NF-kB signalling pathway.