Tacrolimus and sirolimus have distinct effects on insulin signaling in male and female rats

Shivaswamy, Vijay; Bennett, Robert G.; Clure, Cara C.; Ottemann, Brendan M.; Davis, John S.; Larsen, Jennifer L.; Hamel, Frederick G.

doi:10.1016/j.trsl.2013.12.002

Cited by 35 publications

(27 citation statements)

References 35 publications

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“…In the TAC group, plasma insulin concentration decreased because of the reduced pancreatic β-cell mass, whereas in the SRL group, it decreased because of impaired insulin secretion. This conclusion is consistent with previous reports showing that the predominant mechanism of hyperglycemia induced by TAC is reduced β-cell mass through direct TAC-induced pancreatic β-cell injury and that hyperglycemia caused by SRL is closely associated with impaired insulin signaling [24]. …”

Section: Discussionsupporting

confidence: 93%

Effects of metformin on hyperglycemia in an experimental model of tacrolimus- and sirolimus-induced diabetic rats

Jin

Lim

Jin

et al. 2017

Korean J Intern Med

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Background/AimsMetformin (MET) is a first-line drug for type 2 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).MethodsDM 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 adenosine monophosphate-activated protein kinase (AMPK), a pharmacological target of MET, were compared between TAC- and SRL-treated islets.ResultsIPGTT showed that both TAC and SRL induced hyperglycemia and reduced plasma insulin concentration compared with vehicle. These changes were reversed by addition of MET to SRL but not to TAC. Pancreatic islet cell size was decreased by TAC but not by SRL, but addition of MET did not affect pancreatic islet cell size in either group. MET significantly increased GSIS in SRL- but not in TAC-treated rats. AMPK expression was not affected by TAC but was significantly decreased in SRL-treated islets. Addition of MET restored AMPK expression in SRL-treated islets but not in TAC-treated islets.ConclusionsMET has different effects on hyperglycemia caused by TAC and SRL. The discrepancy between these drugs is related to their different mechanisms causing DM.

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Section: Discussionsupporting

confidence: 93%

Effects of metformin on hyperglycemia in an experimental model of tacrolimus- and sirolimus-induced diabetic rats

Jin

Lim

Jin

et al. 2017

Korean J Intern Med

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“…In normal Sprague-Dawley rats, we showed that sirolimus treatment resulted in a dose-dependent increase in hyperglycemia accompanied by relative hyperinsulinemia and a dose-dependent increase in insulin secretion in response to an oral glucose challenge, both suggesting insulin resistance (56). Sirolimus suppresses insulin-stimulated Akt phosphorylation in the liver, fat, and muscle of male and female rats (54,55).…”

Section: Role Of Immunosuppression Agentsmentioning

confidence: 85%

“…We have shown that short-term tacrolimus treatment of normal male and female Sprague-Dawley rats caused hyperglycemia with mild hyperinsulinemia in response to glucose challenge in a dose-dependent manner, suggesting mild insulin resistance; with longer duration of treatment, hyperinsulinemia was no longer observed, suggesting loss of insulin secretion (37,54). Tacrolimus was also shown to reduce ␤-cell mass and increase islet apoptosis, but it had less impact on insulin signaling, suggesting that its predominant action was on insulin production (56). CNI treatment of animal models has also demonstrated decreased glucokinase activity and reduced insulin gene expression (57)(58)(59).…”

Section: Role Of Immunosuppression Agentsmentioning

confidence: 99%

“…Time on medication may also be a factor because studies done acutely have not shown an impact. Some studies have already alluded to a potential biphasic effect of time, where an increase in insulin sensitivity was observed acutely after sirolimus treatment in C2C12 myotubes (100), L6 skeletal muscle cells (101), and healthy humans (96), possibly mediated by disrupting an S6-mediated feedback loop (100), whereas chronic administration induces insulin resistance in vitro (in C2C12 myotubes) (100) and in vivo (56,93,102), most likely due to disruption of mTORC2 (93).…”

Section: Role Of Immunosuppression Agentsmentioning

confidence: 99%

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Post-Transplant Diabetes Mellitus: Causes, Treatment, and Impact on Outcomes

Shivaswamy

Boerner

Larsen³

2015

Endocrine Reviews

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239

203

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and VA Nebraska-Western Iowa Health Care System (V.S.), Omaha, Nebraska 68105Post-transplant diabetes mellitus (PTDM) is a frequent consequence of solid organ transplantation. PTDM has been associated with greater mortality and increased infections in different transplant groups using different diagnostic criteria. An international consensus panel recommended a consistent set of guidelines in 2003 based on American Diabetes Association glucose criteria but did not exclude the immediate post-transplant hospitalization when many patients receive large doses of corticosteroids. Greater glucose monitoring during all hospitalizations has revealed significant glucose intolerance in the majority of recipients immediately after transplant. As a result, the international consensus panel reviewed its earlier guidelines and recommended delaying screening and diagnosis of PTDM until the recipient is on stable doses of immunosuppression after discharge from initial transplant hospitalization. The group cautioned that whereas hemoglobin A1C has been adopted as a diagnostic criterion by many, it is not reliable as the sole diabetes screening method during the first year after transplant. Risk factors for PTDM include many of the immunosuppressant medications themselves as well as those for type 2 diabetes. The provider managing diabetes and associated dyslipidemia and hypertension after transplant must be careful of the greater risk for drug-drug interactions and infections with immunosuppressant medications. Treatment goals and therapies must consider the greater risk for fluctuating and reduced kidney function, which can cause hypoglycemia. Research is actively focused on strategies to prevent PTDM, but until strategies are found, it is imperative that immunosuppression regimens are chosen based on their evidence to prolong graft survival, not to avoid PTDM. (Endocrine Reviews 37: 37-61, 2016)

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“…ROS scavenging ability has been reported to improve beta cell health (41). It is known that the pathogenesis of SRL-induced DM involves impaired insulin signaling or direct pancreatic islet cell injury (43). Therefore, the ideal antidiabetic drugs to treat SRLinduced DM should work by improving impaired insulin signaling and protecting against islet cell injury.…”

Section: Cellsmentioning

confidence: 99%

Effects of addition of a dipeptidyl peptidase IV inhibitor to metformin on sirolimus-induced diabetes mellitus

Jin

Lim

Jin

et al. 2016

Translational Research

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Tacrolimus and sirolimus have distinct effects on insulin signaling in male and female rats

Cited by 35 publications

References 35 publications

Effects of metformin on hyperglycemia in an experimental model of tacrolimus- and sirolimus-induced diabetic rats

Effects of metformin on hyperglycemia in an experimental model of tacrolimus- and sirolimus-induced diabetic rats

Post-Transplant Diabetes Mellitus: Causes, Treatment, and Impact on Outcomes

Effects of addition of a dipeptidyl peptidase IV inhibitor to metformin on sirolimus-induced diabetes mellitus

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