Discrepant Effect Of Metformin On Diabetes Mellitus Caused By Tacrolimus And Sirolimus

Aim:Metformin (MET) is a first-line drug for type Ⅱ diabetes mellitus (DM); its effect on new-onset diabetes after transplantation caused by immunosuppressant therapy is unclear. We compared the effects of MET on DM caused by tacrolimus (TAC) or sirolimus (SRL).Methods:DM was induced by injection of TAC (1.5 mg/kg) or SRL (0.3 mg/kg) for 2 weeks in rats, and MET (200 mg/kg) was injected for 2 more weeks. The effects of MET on DM caused by TAC or SRL were evaluated using an intraperitoneal glucose tolerance test (IPGTT) and by measuring plasma insulin concentration, islet size, and glucose-stimulated insulin secretion (GSIS). The effects of MET on the expression of AMP-activated protein kinase (AMPK), a pharmacological target of MET, were compared between TAC- and SRL-treated islets.Results:1.The TAC and SRL groups increased blood glucose concentration and decreased plasma insulin concentration compared with the VH group. The combined treatment of MET for 2 weeks following induction of diabetes did not improve these changes in the TAC group. The AUCg was 244 ± 7 mg/dL/min in the TAC group and 270 ± 19 mg/dL/min in the TAC+MET group (p< 0.05). SRL induced hyperglycemia and reduced the plasma insulin concentration, but these effects were reversed by MET treatment. The AUCg was 216 ± 8 mg/dL/min in the SRL group and 160 ± 4 mg/dL/min in the SRL+MET group (p< 0.05).2. The islet size was significantly smaller in the TAC and TAC+MET groups compared with the VH group.The islet size did not differ significantly between the TAC and TAC+MET groups. (9.2 ± 0.9μm2 x 103 in the TAC group and 11.4 ± 0.9 μm2 × 103 in the TAC+MET group vs.20.7 ±3.2 μm2 x 103 in the VH group; p< 0.05 compared with the VH group). Consistent with the insulin-staining results, islet size did not differ significantly between the VH, SRL, and SRL+MET groups.3.Insulin concentration did not differ between the TAC+MET and TAC groups, whereas GSIS was restored in the SRL+MET group compared with the SRL group. GSIS was 20.2 ± 0.1 ng/mL in the SRL group 21.1 ± 0.2 ng/mL in the SRL+MET group (p< 0.05).4.The p-AMPK protein abundance relative to total AMPK abundance did not differ between the TAC+MET group and the TAG group compared with the VH group. p-AMPK abundance was lower in the SRL group compared with the VH group. By contrast, p-AMPK abundance was higher in the SRL+MET group compared with the SRL group (165%±9% in the SRL+MET group vs.67%±2% in the SRL group, p< 0.05).Conclusion:MET has different effects on hyperglycemia caused by TAC and SRL. The reason is that the mechanisms of diabetes induced by two kinds of immune inhibitors are different, this result can provide reference for the treatment of kidney transplant patients with NODAT.