Elevated glucose levels in the presence of insulin are indicative of type 2 diabetes and the more inclusive metabolic syndrome. Alleles conferring susceptibility to these and other common conditions may be adaptations to past environments. It is possible that other mammals exhibiting environmental diversity harbor similar variants; therefore, we assessed glucose regulation in two species of deer mice (Peromyscus), a diverse endemic North American group. The prairie deer mouse, P. maniculatus bairdii (BW), and the Oldfield mouse, P. polionotus subgriseus (PO) differ in sexual dimorphism, behavior and habitat. PO animals exhibit better regulatory ability than BW animals, particularly among males, although both species display equivalent insulin levels/responses and non-fasted glucose levels. Hybrid males exhibit a PO glucose challenge response and subsequent analysis of consomic animals implicates Y chromosome variation as the genetic cause. Two pieces of evidence indicate that the male glucose regulatory differences are mediated by stress response: (1) fasting and handling alone account for most of the variation; (2) an inhibitor of glucocorticoid (GC) stress hormone synthesis eliminates these differences. PO males have GC levels that are twice those of BW males, indicating the presence of alleles that attenuate the GC response. We hypothesize that the interspecific physiological and behavioral differences are interrelated and that similar human variants exist.