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Simple Summary: There is increasing evidence that Type-2 diabetes and pre-diabetes may increase cancer risk; however, the biology that links these diseases is poorly understood. Epigenetics is the biological study of how DNA can be modified without mutations; epigenetic changes link medical, social, and environmental changes with cancer. Here, we investigated whether insulin resistance (pre-diabetes) may result in epigenetic changes that increase cancer risk. We discovered that women with insulin resistance have epigenetic changes that increase inflammation and perhaps accelerated aging. Our study is important because the inflammatory changes we see are associated with an increased risk for heart disease, kidney disease, and cancer. Background: Epigenetic changes link medical, social, and environmental factors with cardiovascular and kidney disease and, more recently, with cancer. The mechanistic link between metabolic health and epigenetic changes is only starting to be investigated. In our in vitro and in vivo studies, we performed a broad analysis of the link between hyperinsulinemia and chromatin acetylation; our top "hit" was chromatin opening at H3K9ac. Methods: Building on our published preclinical studies, here, we performed a detailed analysis of the link between insulin resistance, chromatin acetylation, and inflammation using an initial test set of 28 women and validation sets of 245, 22, and 53 women. Results: ChIP-seq identified chromatin acetylation and opening at the genes coding for TNFα and IL6 in insulin-resistant women. Pathway analysis identified inflammatory response genes, NFκB/TNFα-signaling, reactome cytokine signaling, innate immunity, and senescence. Consistent with this finding, flow cytometry identified increased senescent circulating peripheral T-cells. DNA methylation analysis identified evidence of accelerated aging in insulin-resistant vs. metabolically healthy women. Conclusions: This study shows that insulin-resistant women have increased chromatin acetylation/opening, inflammation, and, perhaps, accelerated aging. Given the role that inflammation plays in cancer initiation and progression, these studies provide a potential mechanistic link between insulin resistance and cancer. [ABSTRACT FROM AUTHOR]