Dietary protein/amino acid restriction (DAAR) has been shown to retard the development of type 2 diabetes (T2D) in obese rodents and humans through the induction of hepatic fibroblast growth factor 21 (FGF21). However, it is unclear if DAAR possesses the capacity to reverse frank T2D and its key metabolic factors. Here we fed diabetic mice ad-libitum DAAR for 4 weeks to assess the metabolic effects of DAAR on frank T2D in mice. We assessed DAAR in different diabetic mice models: namely, the polygenic New Zealand Obese (NZO) model and the high-fat diet fed, low-dose streptozotocin (HFD-STZ) model, and found that DAAR profoundly reversed hyperglycaemia in both models. However, further biometric and metabolic effects of DAAR were conflicting between NZO and HFD-STZ mice. HFD-STZ mice experienced marked weight loss with DAAR while no change was observed in the polygenic mice. DAAR also increased blood cholesterol and decreased liver cholesterol and blood and liver triglycerides in the polygenic obese mice, while a decrease in blood and liver cholesterol and no change in blood and liver triglycerides were observed in HFD-STZ mice. Given that the metabolic benefits of DAAR were attributed to hepatic FGF21 induction in prior studies,1,2 we hypothesised that FGF21 was required for T2D reversal observed in mice. Using hepatic FGF21 conditional knockout HFD-STZ mice, we demonstrated that hepatic FGF21 was not required for weight loss and T2D remission in mice. Taken together, these data demonstrate that DAAR improves the key metabolic factors of T2D independent of hepatic FGF21.