Remote ischemic preconditioning (RIPC: the phenomenon whereby brief episodes of ischemia in a distant organ render the heart resistant to infarction): 1) has been extensively documented in healthy preclinical models; and 2) may be triggered by exosome-mediated humoral communication of the cardioprotective signal from the remote organ to the heart. However, in cohorts displaying clinically relevant comorbidities - in particular, type-2 diabetes - the infarct-sparing effect of RIPC may be confounded for as-yet unknown reasons. To address this issue, Zucker Fatty rats (displaying hyperglycemia and obesity) and age-matched Zucker Lean (normoglycemic) rats were randomized to receive RIPC (4 5-min episodes of hindlimb ischemia) or a matched control period. In Protocol 1, all animals underwent 45 min coronary artery occlusion + 2 hrs reperfusion. Infarct size (delineated by tetrazolium staining and expressed as a % of the risk region) was, as expected, significantly reduced by RIPC in Zucker lean rats (**p<0.01 vs matched controls). However, RIPC failed to confer protection in Zucker Fatty rats (Figure-left). To establish whether the inability of RIPC to reduce infarct size was associated with defective humoral communication (Protocol 2), serum was collected after the RIPC stimulus and ultracentrifuged to obtain exosome-rich and exosome-depleted fractions. The protective efficacy of each fraction was then probed in cultured HL-1 cardiomyocytes subjected to simulated ischemia + reoxygenation. Exosome-rich serum from Zucker Lean rats attenuated HL-1 cell death (*p<0.05 vs volume-matched buffer), while the exosome-poor fraction had no effect. In contrast, exosome-rich serum from Zucker Fatty rats was not protective, and the exosome-poor fraction was cytotoxic (Figure-right). These data provide novel evidence that RIPC fails to reduce infarct size in this established model of type-2 diabetes, an effect that may be due in part to defects in humoral communication.