Challenges in replicating the fructose-streptozotocin type 2 diabetes model in Sprague-Dawley rats: Severe hyperglycemia and lack of metformin responsiveness

The combination of 10% fructose supplementation in drinking water followed by a single low dose of streptozotocin (STZ) is widely adopted to induce type 2 diabetes mellitus (T2DM) in rodents, mimicking insulin resistance and partial pancreatic ?-cell dysfunction. However, the reproducibility of this model across laboratories remains uncertain, raising questions about its suitability for T2DM research. Hence, this study aimed to replicate the fructose-STZ model in male Sprague-Dawley rats and assess their glycemic response to metformin. Twenty male Sprague-Dawley rats were assigned to a diabetic group (n=14) and received 10% fructose solution ad libitum for 14 days, followed by a single intraperitoneal injection of STZ (40 mg/kg), or a non-diabetic control (NDC, n=6). Diabetic rats with fasting blood glucose (FBG) >11 mmol/L) were further divided into diabetic control (DC, n=7) and metformin-treated (DG+MET, n=7) groups. Metformin was administered orally at 300 mg/kg/day for 28 days. FBG, body weight, and clinical signs were monitored. The protocol induced severe hyperglycemia with 71.4% of DC and 42.9% of DG+MET rats displaying a FBG >33mmol/L at the end of the study. Affected animals showed marked polyphagia, polydipsia, weight loss, aggression, porphyrin staining, diarrhea, and irresponsiveness to metformin, suggesting model severity. Moreover, mortality reached 28.6% in DC and 14.3% in DG+MET. Overall, the fructose-STZ protocol produced outcomes more consistent with type 1 diabetes, highlighting challenges in replicating this T2DM model. These findings underscore the need for careful protocol optimization and inter-laboratory validation to ensure reliability for T2DM research. © 2025, University of Malaya. All rights reserved.