Type 2 diabetes is a chronic metabolic disorder characterized by elevated glucose levels, which can lead to severe complications such as cardiovascular disease and neuropathy. Suppressing liver glucose production is an attractive therapeutic approach to control hyperglycemia in diabetic patients. However, current methods that target this pathway have resulted in adverse effects such as hepatic steatosis (fatty liver) and in rare cases, lactic acidosis. In these studies, we have designed anti-diabetic small molecules that inhibit liver glucose production by selective targeting the gluconeogenic enzyme PCK1. These small molecules re-direct specific metabolite routes that can selectively suppress liver glucose production without promoting lipid synthesis. Small molecules-induced PCK1 lysine acetylation reverses its catalytic activity promoting synthesis of oxaloacetate from phosphoenolpyruvate. This enzymatic shift results in increased glucose and lactate oxidation through the TCA cycle, suppressing glucose production, without promoting lipid synthesis and fatty liver. Together, our studies show that these small molecules re-direct glucose and lactate metabolic fluxes to complete oxidation and causing an anti-diabetic therapeutic action that could be used for the treatment of type 2 diabetes.