Hyperglycemia induced by tacrolimus and sirolimus is reversible in normal sprague–dawley rats

Abstract

Post-transplant diabetes mellitus (PTDM) worsens outcomes after kidney transplantation, and immunosuppression agents contribute to PTDM. We have previously shown that tacrolimus (TAC) and sirolimus (SIR) cause hyperglycemia in normal rats. While there is little data on the mechanism for immunosuppressant-induced hyperglycemia, we hypothesized that the TAC and SIR-induced changes are reversible. To study this possibility, we compared normal rats treated for 2 weeks with either TAC, SIR, or a combination of TAC and SIR prior to evaluating their response to glucose challenge, with parallel groups also treated for 2 weeks after which treatment was stopped for 4 weeks, prior to studying their response to glucose challenge. Mean daily glucose and growth velocity was decreased in SIR, and TAC+SIR-treated animals compared to controls (P < 0.05). TAC, SIR, and TAC+SIR treatment also resulted in increased glucose response to glucose challenge, compared to controls (P < 0.05). SIR-treated animals also had elevated insulin concentrations in response to glucose challenge, compared to controls (P < 0.05). Insulin content was decreased in TAC and TAC+SIR, and islet apoptosis was also increased after TAC+SIR treatment (P < 0.05). Four weeks after treatments were stopped, all differences resolved between groups. In conclusion, TAC, SIR, and the combination of TAC+SIR-induced changes in glucose and insulin responses to glucose challenge that were accompanied by changes in islet apoptosis and insulin content. These changes were no longer present 4 weeks after cessation of therapy suggesting immunosuppressant-induced changes in glucose metabolism are likely reversible.

Exercise Increases Insulin Content and Basal Secretion in Pancreatic Islets in Type 1 Diabetic Mice

“…First, insulin immune reactivity per islet was calculated using published techniques [37]. In the islets from control animals, there was strong insulin staining in all β -cells (Figure 5(b)).…”

Strategy for clinical setting in intramuscular and subcutaneous islet transplantation

“…It is known that immunosuppressive drugs can be causes of islet damage. Intraportally transplanted islets suffer from immunosuppressive drugs including sirolimus and tacrolimus, which are toxic to islets . The blood level of the immunosuppressive drugs is higher in the portal vein than in peripheral vessels.…”

Prediabetes in Pediatric Recipients of Liver Transplant: Mechanism and Risk Factors

“…(12,25) In rats, tacrolimus treatment decreased pancreatic islet size and induced islet apoptosis, but hyperglycemia was reversed and insulin secretion normalized when tacrolimus was stopped. (26,27) Of note, these rats did have dose-dependent worsening of hyperglycemia; insulin levels increased at the highest tacrolimus doses. In humans, tacrolimus-induced reduction in insulin secretion, with dose-dependence and reversibility, has been demonstrated in adult transplant recipients, but never in a cohort with such extended post-transplant follow-up.…”