Induction of diabetes in cynomolgus monkeys with high-dose streptozotocin: adverse effects and early responses

OBJECTIVES: Streptozotocin (STZ) has been widely used to induce diabetes in nonhuman primates, although it has been found difficult to achieve complete diabetes without serious adverse effects. We have investigated different types and dosages of STZ to find a way to safely induce complete diabetes in cynomolgus monkeys.

METHODS: After adequate hydration, 10 monkeys received STZ. Five monkeys received conventional STZ (Sigma) at a dosage of 1250 mg/m ("high dose"; n = 4) or 60 mg/kg ("low dose"; n = 1; Group 1). Five monkeys received Zanosar STZ (Sicor Pharmaceuticals, Irvine, CA) at 150 mg/kg (high dose; n = 5; Group 2).

RESULTS: High-dose Group 1 monkeys became completely diabetic (n = 4), but a protein-losing nephropathy was observed in 3 of the 4 monkeys. The monkey that received 60 mg/kg STZ failed to become fully diabetic (C-peptide, > 1.86 ng/mL). Group 2 (high-dose Zanosar-treated) monkeys became completely diabetic but with no apparent adverse effects. A triphasic blood glucose response to STZ was documented in all the high-dose STZ-treated monkeys. Low-dose STZ failed to result in a triphasic response.

CONCLUSIONS: (1) High-dose Zanosar STZ induced diabetes safely in cynomolgus monkeys without adverse effects. (2) A triphasic blood glucose response suggested the complete induction of diabetes.