**5. Drug-induced diabetic mellitus and their mechanisms of action**

The most common drugs that are currently being used for the experimental induction of diabetes are alloxan and streptozotocin (STZ). Streptozotocin (STZ) is a synthetic antineoplas‐ tic agent that is classified as an anti-tumour antibiotic and is chemically related to other nitrosureas used in cancer chemotherapy [37]. Intra-venous injection of 60mg/kg dose of streptozotocin in adult Wistar rats, makes pancreas swell and at last causes degeneration in Langerhans islet beta cells and induces experimental diabetes mellitus in 2-4 days [37]. Both alloxan and STZ have been extensively documented for the induction of diabetes via free radical generation and depletion of antioxidant defense system [38-40]. STZ has been reported to significantly decrease the activity of erythrocytes antioxidative enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) [38-39]. Several drugs, with pharmacological properties including theophylline, aspirin, isoniazid and nalidixic acid can cause transient hyperglycaemia in over dosage, but only streptozotocin, alloxan and the rodenticide vacor are likely to cause permanent diabetes. Alloxan and the product of its reduction, dialuric acid, establish a redox cycle with the formation of superoxide radicals that undergo dismutation to produce hydrogen peroxide via Fenton reaction [41]. Similarly, the reactive oxygen species results in simultaneous massive increase in cytosolic calcium concen‐ tration causes rapid destruction of B cells. In the same vein, streptozotocin enters the B cell via a glucose transporter (GLUT2) and causes alkylation of DNA. DNA damage induces activation of poly ADP-ribosylation, a process that is more important for the diabetogenicity of strepto‐ zotocin than DNA damage itself. More so, Poly ADP-ribosylation leads to depletion of cellular NAD+ and ATP [41]. Enhanced ATP dephosphorylation after streptozotocin treatment supplies a substrate for xanthine oxidase resulting in the formation of superoxide radicals. Also, streptozotocin liberates toxic amounts of nitric oxide that inhibits aconitase activity and participates in DNA damage [41].
