Data on the influences of diabetes mellitus on the severity of ischemic damage to the myocardium are contradictory. We report here experiments using a model based on in vivo myocardial infarcts resulting from coronary occlusion to study the resistance of the myocardium in rats with alloxan-induced insulin-dependent diabetes mellitus to prolonged ischemia, along with studies of the infarct-limiting efficacy of ischemic preconditioning. The results showed that after diabetes mellitus for six weeks, the relative size of infarcts was significantly less than in controls (39.8 +/- 8.8 and 62.3 +/- 6.6% of the size of the anatomical risk zone respectively, p < 0.01). In addition, animals with diabetes mellitus developed ischemic ventricular tachyarrhythmia significantly less often than controls. A single episode of ischemic preconditioning in animals with diabetes mellitus had a less marked infarct-limiting effect than the same procedure in controls. Thus, these data support the existence of an endogenous cardioprotective phenotype (metabolic preconditioning) in experimental diabetes. On the other hand, the efficacy of ischemic preconditioning was sharply decreased in diabetes.