Methylprednisolone acetate (MPA) is often prescribed to cats despite being recognized eventually as diabetogenic. To assess MPA-related insulin resistance and evaluate the efficacy of metformin or an obesity and diabetes mellitus (O&D) adjuvant diet as protective factors, a randomized clinical trial was conducted with 28 owned cats undergoing glucocorticoid therapy. A single MPA dose of 20 mg intramuscularly was administered to each cat. Controls (n = 10) received only MPA. In the diet group (n = 9), replacement of their habitual diet by ad-libitum feeding of a feline commercial O&D diet (Equilíbrio O&D, Total Alimentos ADM) was made. In the metformin group (n = 9), metformin chlorhydrate 25mg/cat PO/q24h was administered for 30 days. All patients were clinically evaluated at baseline (T0), day 15 (T15), and day 30 (T30) and blood draw for complete blood count, serum biochemistry, and determination of insulin concentrations. Fasting Insulin Sensitivity Index (SI), Amended Insulin to Glucose Ratio (AIGR), Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and Homeostatic Model Assessment of beta-cell function (HOMA-B) were calculated based on fasting glycemia and insulinemia. All groups showed significantly higher levels (P < .05) of neutrophils, albumin, glucose, cholesterol, triglycerides, and serum insulin at T15. Patients in the metformin group showed also higher SI, AIGR, and HOMA-IR results at T15. Also, at T15, reduced levels (P < .05) of eosinophils, lymphocytes, and creatinine were documented in all groups. An MPA single dose induced changes in insulin sensitivity in cats; however, neither metformin nor O&D feeding used in this study was effective as protective factors against MPA-related insulin resistance.