Effect of Sirolimus/Metformin Co-Treatment on Hyperglycemia and Cellular Respiration in BALB/c Mice

Sirolimus (SRL) is widely used as an immunosuppressant to prevent graft rejection, despite the risk of impairing glucose metabolism. Metformin (MET) can reduce the detrimental effects of SRL in many patients, including diabetes and renal transplant recipients. Limited in vivo studies have reported on SRL and MET therapy, particularly in relation to cellular bioenergetics, glucose metabolism, and insulin resistance. Herein, we investigated the efficacy of SRL and MET co-treatment in BALB/c mice over 4 weeks. Balb/c mice (4-6 weeks old) were divided into four groups and injected intraperitoneally (i.p.) with water (control, CTRL), MET (200 µg/g), SRL (5 µg/g), or MET (200 µg/g) +SRL (5 µg/g) over a period of one month. We evaluated the body weight, food consumption rate, random blood glucose (BG), insulin levels, serum biochemistry parameters (ALT, Albumin, BUN, Creatinine), and histomorphology in all groups using standardized techniques and assays. All drug-treated groups showed a statistically significant decrease in weight gain compared to the CTRL group, despite normal food intake. Treatment with SRL caused elevated BG and insulin levels, which were restored with SRL + MET combination. Serum biochemical parameters were within the normal range in all the studied groups. SRL+ MET co-treatment decreased liver cellular respiration and increased cellular ATP levels in the liver. In the pancreas, co-treatment resulted in increased cellular respiration and decreased cellular ATP levels. Liver and pancreatic histology were unchanged in all groups. This study showed that co-treatment of SRL with MET alleviates hyperglycemia induced by SRL without any deleterious effects. These results provide initial insights into the potential use of SRL + MET therapy in various settings.