I will discuss two areas of diabetes treatment that are of great interest to our research: hepatic insulin resistance and pancreatic b cell failure. Hepatic insulin resistance is a hallmark of diabetes and an unmet clinical need. Insulin inhibits hepatic glucose production and promotes lipogenesis by suppressing FOXO1-dependent activation of Glucose-6-phosphatase (G6pc) and inhibition of Glucokinase (Gck), respectively. The tight coupling of these events poses a dual conundrum: mechanistically, as the FOXO1 corepressor of Gck is unknown; and clinically, as inhibition of FOXO-dependent glucose production increases lipogenesis. The FOXO1 corepressor acting on Gck is unknown. We have recently discovered that SIN3a is the FOXO1 corepressor of Gck. Using a variety of cellular and biochemical assays, we have shown that SIN3a recruits FOXO1 to the Gck promoter to inhibit Gck expression. Moreover, genetic ablation of SIN3a in the liver abolishes regulation of Gck by fasting and refeeding, without affecting other FOXO1 target genes, and causes hypoglycemia without concurrent steatosis. Using this knowledge, we undertook to identify selective FOXO1 inhibitors that would suppress FOXO1-dependent glucose production without affecting lipogenesis. We screened small-compound libraries and identified two series of FOXO1 inhibitors: pan-inhibitors with insulin-like effects to suppress G6pc and activate Gck; and selective inhibitors devoid of Gck-activating function. In addition to discovering a pathway for the dual actions of insulin on gene transcription, these data raise the possibility of developing selective modulators of unliganded transcription factors to dial out potential adverse effects of insulin sensitizers. In a second area of research, we sought to identify pathways associated with diabetic β cell failure. We have previously demonstrated a role of β cell dedifferentiation in b cell dysfunction. However, in order to design new treatments for this condition, we needed to identify the key mediators of this process. To this end, we undertook an integrated approach in which we examined gene expression and genome-wide chromatin changes associated with the onset of diabetes. The integration of gene expression and genome-wide histone modification profiles indicates that β cell dysfunction can be explained by a relatively small subset of genes. I will discuss how this small number of genes can cause a global failure to adapt to physiologic stressors, with increased repression of gene expression and failure to activate stress-response programs. We show that as β cells fail, they become more similar to immature progenitor cells and activate α cell-specific genes. We tested the idea that β cell failure entails a progressive acquisition of α cell features. I will illustrate results from human islet single cell RNA sequencing that support this hypothesis to propose a new mechanism of b cell failure.