【Abstract】Objective: ?This study aimed to compare the effects of different dietary intervention regimens and the combined intervention effect of metformin after the establishment of a Type 2 Diabetes Mellitus (T2DM) model, so as to establish and maintain a T2DM rat model that is more consistent with clinical practice. Methods:Fifty male Sprague-Dawley (SD) rats were randomly divided into two groups: the blank control group (Control, n=10) and the model establishment group (n=40). Rats in the model establishment group were fed a high-sugar and high-fat (HSHF) diet. Starting from the 3rd week, they were additionally given daily intragastric administration of fat emulsion. After 4 weeks, T2DM rat models were induced by two intraperitoneal injections of streptozotocin (STZ) at a dose of 25 mg/kg. After the model was successfully established, the model establishment group was randomly divided into four subgroups with 10 rats each: the high-sugar and high-fat - model group (HSHF - M), the normal diet - model group (ND - M), the high-sugar and high-fat - metformin group (HSHF - Met), and the normal diet - metformin group (ND - Met). Rats in the drug-administered groups received dietary intervention combined with metformin, while those in the model groups received only dietary intervention. Rats in the Control group were fed a normal diet, and all interventions lasted for 12 weeks. During the dietary intervention period, the general status of the rats and their survival indicators were monitored. After 12 weeks of intervention, an oral glucose tolerance test (OGTT) was performed. The serum fasting insulin (FINS) level of the rats was detected to calculate the insulin resistance index (HOMA-IR) and the islet β-cell function index (HOMA-β). Additionally, the serum levels of blood lipids, liver function, renal function, oxidative stress indicators, and inflammatory factors were measured. Pathological changes in the pancreas, liver, and kidney tissues of the rats were observed and analyzed pathologically. Results: The experiment showed that after the successful establishment of the T2DM rat model, feeding with a normal diet maintained model stability within 12 weeks. Compared with the HSHF-M group, the ND-M group had a significantly increased body weight (P < 0.05), and significantly decreased urine output and blood glucose (P < 0.05). In the OGTT, the blood glucose levels at 0, 60, 90, and 120 minutes in the ND-M group were significantly lower than those in the HSHF-M group (P < 0.05), and the area under the curve (AUC) was significantly reduced (P < 0.05). Regarding blood glucose-related indicators, significant differences were observed in glycated serum protein (GSP), FINS, and HOMA-IR (P < 0.05). For blood lipid-related indicators, the levels of total cholesterol (TC), triglycerides (TG), free fatty acids (FFA), and low-density lipoprotein cholesterol (LDL-C) were significantly decreased (P < 0.05), while the level of high-density lipoprotein cholesterol (HDL-C) was significantly increased (P < 0.05) in the ND-M group. Liver function-related indicators [alanine transaminase (ALT), alkaline phosphatase (ALP), aspartate transaminase (AST)] and renal function-related indicators [creatinine (CRE), blood urea nitrogen (BUN)] were significantly decreased (P < 0.05), while the level of nitric oxide (NO) was significantly increased (P < 0.05) in the ND-M group. For oxidative stress indicators, the level of malondialdehyde (MDA) was significantly decreased (P < 0.05), and the level of superoxide dismutase (SOD) was significantly increased (P < 0.05) in the ND-M group. The levels of inflammatory factors [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6)] were significantly decreased (P < 0.05) in the ND-M group. Histopathological observations revealed that due to the absence of long-term intake of the HSHF diet, the ND-M group showed significantly alleviated pathological changes (such as hepatic cord disorder, islet cell reduction, and glomerular vacuolation) compared with the HSHF-M group. Compared with the HSHF-M group, both the HSHF-Met group and the ND-Met group showed significant improvements in survival indicators and biochemical indicators (P < 0.05), among which the ND-Met group had a more significant improvement effect, and the pathological damage to the pancreas and liver was less severe than that in the HSHF-Met group. Conclusions Feeding a normal diet after model establishment can effectively avoid glucose and lipid metabolism disorders, oxidative stress, inflammatory responses, and multi-organ pathological damage caused by a high-sugar and high-fat diet, thereby successfully establishing and maintaining a T2DM rat model that is more consistent with clinical pathways.