OBJECTIVE: With the prevalence of diabetes worldwide, it is urgent to find a suitable treatment. Recently, the ketogenic diet has shown beneficial effects in reducing blood glucose, but some concerns have been raised about its probable side effects, such as hyperlipidemia and hepatic steatosis. Because a low-carbohydrate diet replaces part of the fat with carbohydrates on the basis of the ketogenic diet, we would like to know whether it does better in treating type 2 diabetes. The aim of this study was to explore the possibility of a low-carbohydrate diet as a substitute for a ketogenic diet intervention in mice with type 2 diabetes. METHODS: C57 BL/6 J mice with type 2 diabetes, constructed by a high-fat diet combined with streptozotocin, were fed a standard diet, a high-fat diet, a low-carbohydrate diet, or a ketogenic diet for 14 wk, respectively. Then glucose and insulin tolerance tests were conducted. At the end of the study, blood and liver samples were collected and analyzed for serum biochemical indicators, histopathologic evaluation, hepatic lipid and glycogen content, and expression levels of mRNA and protein. RESULTS: Reduced blood glucose could be observed in both low-carbohydrate and ketogenic diets, as well as improvement in glucose tolerance and insulin sensitivity. However, the ketogenic diet decreased liver glycogen content and promoted gluconeogenesis. Mechanistically, this effect was due to inhibition of phosphorylated AMP-activated protein kinase, which could be improved by a low-carbohydrate diet. Regarding lipid metabolism, the ketogenic diet increased lipid oxidation and reduced de novo lipogenesis, but the hepatic lipid content still inevitably increased. On the contrary, the low-carbohydrate diet reduced triacylglycerols and markers of liver damage. CONCLUSIONS: Collectively, these findings suggest that both diets are effective in lowering blood glucose, improving glucose tolerance, and raising insulin sensitivity. Moreover, the low-carbohydrate diet plays a role in inhibiting hepatic gluconeogenesis and improving lipid metabolism. The results suggest that the two diets have different effects on glucose and lipid metabolism, and that the low-carbohydrate diet might have more benefits in the treatment of type 2 diabetes mellitus.