The rewarding effects of nicotine have been previously shown to be enhanced in rodent models of diabetes. It is presently unclear whether the enhanced nicotine reward observed in the diabetes models are mediated via an insulin or glucose mechanism. This study examined whether the enhanced rewarding effects of nicotine observed in streptozotocin (STZ)-treated rats are insulin-mediated. Male and female rats were treated with STZ and the rewarding effects of nicotine (0.2mg/kg) were measured using the conditioned place preference (CPP) procedure. Some STZ-treated animals received insulin supplementation via subcutaneous pellets immediately after STZ administration, while other rats received daily injections of dapagliflozin (10mg/kg), a sodium-glucose cotransporter-2 inhibitor. Both male and female STZ-treated rats displayed hyperglycemia, and their blood glucose levels (BGLs) were normalized to control levels following insulin supplementation or dapagliflozin administration. STZ-treated male rats displayed higher nicotine CPP relative to vehicle-treated controls. This effect was abolished in rats that received insulin supplementation or dapagliflozin administration. STZ-treated female rats displayed reduced levels of nicotine CPP as compared to male rats, regardless of treatment condition. These results suggest that glucose plays a major role in modulating the rewarding effects of nicotine in male rats treated with STZ.