Cardiovascular disease involves changes in inflammatory markers. Since insulin/insulin-like growth factor 1 receptor (IGF-1R) can activate vascular endothelial growth factor to promote vascular growth, reduced IGF-1R signaling in the type I diabetic heart could be detrimental, leading to reduced, collateral blood vessel growth. This study assessed whether diabetes can induce an inflammatory phenotype to regulate molecules in the IGF-1 signaling cascade, thus mediating apoptosis. Rats were made diabetic using streptozotocin (to render them type I diabetic) for 2 months with no insulin treatment. At 2 months, rats were sacrificed under anesthesia, and the left ventricle was immediately removed and placed into cold lysis buffer for protein analyses. Western blotting, immunoprecipitation, and enzyme-linked immunosorbent assay analyses were completed to evaluate protein levels. Diabetes increased TNF-alpha, interleukin-6 (IL-6), and IL-1alpha levels in the heart. JNK and p42/p44 activity was significantly increased in the diabetic heart, while IGF-1R phosphorylation, IRS-2 tyrosine phosphorylation, and Akt activities were reduced. A significant increase in Bad protein levels and the cleavage of caspase 3 was observed in the diabetic heart. These results suggest that diabetes activates multiple inflammatory markers in the heart, which then signal a decrease in the activities of key players in the insulin-signaling cascade, namely IGF-1R, IRS-2, and Akt, to regulate apoptosis.