Metformin Improves Immunosuppressant Induced Hyperglycemia and Exocrine Apoptosis in Rats

Shivaswamy, Vijay; Bennett, Robert G.; Clure, Cara C.; Larsen, Jennifer L.; Hamel, Frederick G.

doi:10.1097/tp.0b013e318275a322

Cited by 17 publications

(14 citation statements)

References 31 publications

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“…Animal studies confirmed that treatment with tacrolimus worsened glucose tolerance both in vivo and in vitro and in normal as well as insulin-resistant models, predominantly through decreasing insulin secretion (54,55). 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).…”

Section: Role Of Immunosuppression Agentsmentioning

confidence: 58%

“…However, there are few studies to demonstrate whether these medications can prevent PTDM. In animal studies, metformin can minimize immunosuppressant-induced hyperglycemia (54), and rosiglitazone prevents hyperglycemia secondary to sirolimus (210). However, the potential side effects of thiazolidinediones (eg, edema, heart failure, and bone loss) reduce enthusiasm for their use as a diabetes prevention agent in any transplant group.…”

Section: Prevention Of Ptdmmentioning

confidence: 99%

“…Animal studies suggest that metformin reduces immunosuppressant-induced exocrine (and possibly endocrine) cell apoptosis with subsequent improvement in glycemic control (54). Thus, some have suggested that metformin should be first-line therapy for PTDM after kidney transplant (174).…”

Section: B Outpatient Glucose Managementmentioning

confidence: 99%

“…Sirolimus suppresses insulin-stimulated Akt phosphorylation in the liver, fat, and muscle of male and female rats (54,55). Sirolimus also disrupts the phosphorylation of mTORC2, reducing insulin-mediated suppression of hepatic gluconeogenesis (93), and can induce Yin Yang 1 dephosphorylation, which mediates suppression of insulin signaling genes, resulting in decreased insulin signaling (94).…”

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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249

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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Section: Role Of Immunosuppression Agentsmentioning

confidence: 58%

Section: Prevention Of Ptdmmentioning

confidence: 99%

Section: B Outpatient Glucose Managementmentioning

confidence: 99%

Section: Role Of Immunosuppression Agentsmentioning

confidence: 99%

See 2 more Smart Citations

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

Shivaswamy

Boerner

Larsen³

2015

Endocrine Reviews

Self Cite

249

203

View full text Add to dashboard Cite

show abstract

“…Metformin inhibits mitochondrial respiration and activates AMP-activated protein kinase (AMPK) resulting in decreased hepatic gluconeogenesis and decreased insulin resistance resulting in lower blood glucose levels. It has already been demonstrated that metformin reduces sirolimus/tacrolimus-induced hyperglycaemia in rats, highlighting its possible efficacy in treatment-induced insulin resistance [93]. In a clinical trial in paediatric acute lymphoblastic leukaemia (ALL) patients metformin lowers steroid-induced hyperglycaemia with an acceptable side-effect profile [94].…”

Section: Diabetes Medication To Treat Therapy-induced Insulin Resistancementioning

confidence: 99%

Cancer-drug induced insulin resistance: Innocent bystander or unusual suspect

Ariaans

Jong

Gietema

et al. 2015

Cancer Treatment Reviews

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Posttransplant complications: molecular mechanisms and therapeutic interventions

Liu,

Shen,

Yan

et al. 2024

MedComm

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Posttransplantation complications pose a major challenge to the long‐term survival and quality of life of organ transplant recipients. These complications encompass immune‐mediated complications, infectious complications, metabolic complications, and malignancies, with each type influenced by various risk factors and pathological mechanisms. The molecular mechanisms underlying posttransplantation complications involve a complex interplay of immunological, metabolic, and oncogenic processes, including innate and adaptive immune activation, immunosuppressant side effects, and viral reactivation. Here, we provide a comprehensive overview of the clinical features, risk factors, and molecular mechanisms of major posttransplantation complications. We systematically summarize the current understanding of the immunological basis of allograft rejection and graft‐versus‐host disease, the metabolic dysregulation associated with immunosuppressive agents, and the role of oncogenic viruses in posttransplantation malignancies. Furthermore, we discuss potential prevention and intervention strategies based on these mechanistic insights, highlighting the importance of optimizing immunosuppressive regimens, enhancing infection prophylaxis, and implementing targeted therapies. We also emphasize the need for future research to develop individualized complication control strategies under the guidance of precision medicine, ultimately improving the prognosis and quality of life of transplant recipients.

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Metformin Improves Immunosuppressant Induced Hyperglycemia and Exocrine Apoptosis in Rats

Abstract: This is the first study to show that metformin can improve immunosuppressant-induced hyperglycemia, when administered concurrently, and reduces exocrine apoptosis (reducing the impact on potential islet progenitor cells).

Cited by 17 publications

References 31 publications

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

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

Cancer-drug induced insulin resistance: Innocent bystander or unusual suspect

Posttransplant complications: molecular mechanisms and therapeutic interventions

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