Aim: Insulin resistance represents the core component of the so-called Metabolic Syndrome, ultimately promoting glucose intolerance, pancreatic beta cell failure, and overt type 2 diabetes. Based on substantial side effects of existing pharmacological approaches, efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications. The goal of this study is to characterize the role of Transforming Growth Factor beta-like Stimulated Clone (TSC) 22 D4 protein in insulin resistance and diabetes. Materials and methods: In order to investigate the metabolic function of TSC22D4 in vivo, we employed liver-specific TSC22D4 knockdown and overexpression approaches both in wild type and diabetic mouse models (db/db and NZO mice). Results: We identified TSC22D4 as a critical molecular determinant of insulin signaling and glucose handling. Hepatic TSC22D4 knockdown enhanced insulin signaling in liver, while hepatic TSC22D4 overexpression blunted insulin signaling. Consequently, hepatic TSC22D4 inhibition both prevented and reversed hyperglycemia, glucose intolerance, and insulin resistance in diabetic mouse models (db/db and NZO mice). In addition, we found that TSC22D4 exerts its effects on systemic glucose homeostasis -in large parts- through the transcriptional regulation of the small secretory protein lipocalin (LCN) 13 as demonstrated by in vivo chromatin recruitment and genetic rescue experiments. Conclusion: In support of our hypothesis and findings, diabetic human patients have elevated hepatic TSC22D4 levels correlating with decreased insulin sensitivity and hyperglycemia. Thus, our results establish TSC22D4 as a promising and attractive target for the treatment of diabetes mellitus.