Anti-diabetic properties of a non-conventional radical scavenger, as compared to pioglitazone and exendin-4, in streptozotocin-nicotinamide diabetic mice.

We previously showed that the innovative radical scavenger bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC) improves metabolic dysfunctions in a diabetic mouse model. Here, we compared the in vivoeffects of IAC with those of the anti-diabetic drugs pioglitazone (PIO) and exendin-4 (EX-4). Diabetes wasinduced in C57Bl/6J mice by streptozotocin and nicotinamide administration. Paralleled by healthy controls,diabetic animals (D) were randomly assigned to fourgroups and treated daily for 7 consecutive weeks:Dþsaline,ip;DþIAC 30 mg/kg b.w.,ip;DþPIO 10 mg/kg b.w.per os;andDþEX-4, 50μg/kg b.w.,ip.Ourresults show that IAC reduced basal hyperglycemia and improved glucose tolerance better than PIO or EX-4.Interestingly, in the heart of diabetic mice, IAC treatment normalized the increased levels of GSSG/GSH ratioand thiobarbituric acid reactive substances, indexes of oxidative stress and damage, while PIO and EX-4 wereless effective. As supported by immunohistochemical data, IAC markedly prevented diabetic isletβ-cell reduceddensity, differently from PIO and EX-4 that had only a moderate effect. Interestingly, in diabetic animals, IACtreatment enhanced the activity of pancreatic-duodenal homeobox 1 (PDX-1), an oxidative stress-sensitivetranscription factor essential for maintenance ofβ-cell function, as evaluated by quantification of its nuclearimmunostaining, whereas PIO or EX-4 treatments did not. Altogether, these observations support theimprovement of the general redox balance andβ-cell function induced by IAC treatment in streptozotocin-nicotinamide diabetic mice. Furthermore, in this model, the correction of diabetic alterations was betterobtained by treatment with the radical scavenger IAC than with pioglitazone or exendin-4.