Endocrinology and Metabolic Disorders

There has been a recent explosion of interest in the notion that metaflammation and activation of the innate immune system are closely involved in the pathogenesis of type 2 diabetes mellitus (T2DM). Hence, we assessed the potential antidiabetic effect of leflunomide (10 mg/kg every other day) and sulfasalazine (100 mg/kg/day), in a comparison with pioglitazone (5 mg/ kg/day) as a reference drug, using neonatal STZ animal model. All treatments were gavaged for 8 weeks. Leflunomide and sulfasalazine lowered significantly the n5-STZ-induced elevation in body weight, blood glucose, and HOMA index. Moreover, they amended successfully serum lipid profile and increased serum insulin level. Additionally, leflunomide and sulfasalazine showed antioxidant (Nrf2, keap1), anti-inflammatory (NF-κB, TNF-α) and anti-apoptotic (caspase-3, cytochrome c) capabilities. Both drugs showed comparable effects on almost all the parameters, however, pioglitazone effect was superior to both. On the molecular level, drugs have improved the hepatic insulin (glucokinase, p-insulin receptor, p-Akt, IRS-1), lipogenic (SREBP-1c, PGC-1α) and Wnt/β-catenin (p-GSK-3β, β-catenin, FOXO) signaling pathways. All treatments also showed decreases in the hepatic 8-oxoguanine content. The present results clearly proved that altered immune responses play a key role in T2DM and that the immunomodulatory drugs can gain insights as prospective antidiabetic agents.