TRANSCRIPTIONAL INHIBITION OF INSULIN BY FK506 AND POSSIBLE INVOLVEMENT OF FK506 BINDING PROTEIN-12 IN PANCREATIC Β-Cell

TAMUKA, KOUCHIT; Fujimura, Takao; Tsutsumi, Takeshi; Nakamura, Keiko; Ogawa, Toshikazu; ATLIMARU, CHIZURU; Hirano, Yuri; Ohara, Kaname; Ohtsuka, Kazuyuki; Shimomura, Kyoichi; Kobayashi, Masakazu

doi:10.1097/00007890-199506000-00018

Cited by 167 publications

(93 citation statements)

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“…FK binding protein (FKBP) is present in islet cells, and decreased insulin transcription and secretion have been demonstrated experimentally. 16,17 This decrease in secretion is reversible when tacrolimus is discontinued. The direct islet toxicity can explain both the clinical phenomenon of PTDM and its reversibility with dose reduction.…”

Section: Discussionmentioning

confidence: 99%

Reversibility of tacrolimus-induced posttransplant diabetes: an illustrative case and review of the literature

Shapiro

Scantlebury

Jordan

et al. 1997

Transplantation Proceedings

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Tacrolimus is a potent immunosuppressive agent. It has been reported to have superior immunosuppressive efficacy when compared with the standard formulation of cyclosporine (CyA), 1 based on its ability to rescue patients with failing allografts under CyA-based therapy, 2,3 lower rejection rates when used as a primary immunosuppressive agent, 4,5 and longer projected half-life. 6 However, there have been reports of an increased incidence of posttransplant diabetes (PTDM) under tacrolimus-based therapy. 4,5 We have reported on the reversibility of tacrolimus-induced PTDM in our own renal transplant patients. 7,8 In this article, we present an illustrative case demonstrating the reversibility of PTDM and review both the published and unpublished literature. The data suggest that the initial incidence of PTDM in the renal transplant population may be higher under tacrolimus than under CyA-based therapy, but the final incidence is comparable. 9-11 ILLUSTRATIVE CASEThe patient was a 64-year old black female with end-stage renal disease secondary to hypertension, who received a kidney from her son. The allograft functioned immediately, and she never experienced rejection. Her serum creatinine, tacrolimus dosages and levels, prednisone dosages, fasting blood glucose levels, and insulin requirements are shown in Table 1. Basically, she was normoglycemic until 13 weeks after transplantation, when her fasting blood glucose level was 280 mg/dL. One week later, it was 555 mg/dL, and she was admitted to the hospital and started on insulin. As her tacrolimus and steroid dosages were tapered, her blood sugars normalized, and her insulin was tapered off by 26 weeks after transplantation. She continues to have normal renal function 1.5 years after transplantation, with a serum creatinine of 1.0 mg/dL, on tacrolimus 1 mg orally twice per day and no prednisone. Her tacrolimus level is 8.7 ng/mL, and her fasting blood glucose is 140 mg/dL. Review of the LiteratureThe initial and final incidences of PTDM in various studies of tacrolimus in renal transplantation are summarized in Table 2. The initial incidence ranged from 6% to 28.3%. and the final incidence ranged from 1.4% to 12.6%, with a reversibility of 37% to 83%. 1,4,5,[12][13][14][15] Subgroup analysis was performed in only one study, the American Phase III Multicenter Trial. It showed a higher incidence of PTDM in African American than in Caucasian recipients, and an association in all patients with higher tacrolimus levels and steroid doses. 4,5 Address reprint requests to Ron Shapiro, MD, 4th Floor Falk,

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Section: Discussionmentioning

confidence: 99%

Reversibility of tacrolimus-induced posttransplant diabetes: an illustrative case and review of the literature

Shapiro

Scantlebury

Jordan

et al. 1997

Transplantation Proceedings

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“…11 Aside from differences in the definitions and timing used among the different studies, the explanation for the discrepant data on the prevalence of long-term posttransplant diabetes probably lies in the balance between the following: (1) the extent to which insulin resistance is reversed by removing the cirrhotic liver 11 ; (2) the degree of continuing pancreatic insulin secretory failure 11 ; and (3) the magnitude of the anti-insulin (diabetogenic) effects of obesity and the principal immunosuppressive medications, namely corticosteroids and the calcineurin inhibitors. [26][27][28][29] Corticosteroids induce insulin resistance in a dose-dependent manner, whereas cyclosporine and tacrolimus decrease insulin synthesis and secretion and/or induce insulin resistance and hyperinsulinemia. The other immunosuppressives (azathioprine, mycophenolate mofetil, and sirolimus) are not diabetogenic.…”

Section: Prevalence Of Diabetes In Liver Transplant Recipientsmentioning

confidence: 99%

Long-term management of the liver transplant patient: Diabetes, hyperlipidemia, and obesity

Reuben

2001

Liver Transplantation

115

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Key Points 1. As long-term survival improves after liver transplantation, cardiovascular complications are emerging as a major cause of late morbidity and mortality. It seems reasonable to correct the potentially reversible cardiovascular risk factors of diabetes, hyperlipidemia, and obesity, in addition to hypertension. 2. The results of liver transplantation in diabetics are acceptable in terms of morbidity, mortality, and prevalence of posttransplant diabetes, but the poor outcomes described in some series suggest that more extensive testing for macro-and microvascular disease may become necessary. T he main aim of liver transplantation, besides the immediate goal of saving life, is to return the patient to productive community living with good quality of life. It is ironic, therefore, that many of the health problems that afflict successful liver transplant recipients long term are those of community living in the developed world, including diabetes mellitus, hyperlipidemia, and obesity. These three metabolic derangements, together with hypertension, constitute adverse cardiovascular risk factors for transplant recipients. The management of diabetes in liver transplant recipients is not substantially different from its management in

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“…100 In one animal model, administration of tacrolimus at 10 mg/kg/day orally for 2 weeks caused a time-dependent suppression of insulin gene transcription in pancreatic beta cells due to inhibition of calcineurin. 101 Insulin mRNA transcription and insulin production returned to normal when the drug was discontinued, indicating that the adverse effect of tacrolimus on the pancreas is reversible. 101 Clinically, it is unclear whether the hyperglycemia associated with tacrolimus is dose-dependent.…”

Section: Hyperglycemiamentioning

confidence: 99%

“…101 Insulin mRNA transcription and insulin production returned to normal when the drug was discontinued, indicating that the adverse effect of tacrolimus on the pancreas is reversible. 101 Clinically, it is unclear whether the hyperglycemia associated with tacrolimus is dose-dependent. 72,88 In a study using tacrolimus alone for GVHD prophylaxis, the incidence of hyperglycemia requiring treatment during the first 6 months was 41%.…”

Section: Hyperglycemiamentioning

confidence: 99%

Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation

Jacobson

Uberti

Davis

et al. 1998

Bone Marrow Transplant

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Summary:Tacrolimus (FK506) is a macrolide lactone with potent immunosuppressive activity 100 times that of cyclosporine by weight. The molecular mechanism of action is mediated via an inhibition of the phosphorylase activity of calcineurin by drug-immunophilin complex, resulting in the inhibition of IL-2 gene expression. There are emerging studies now showing significant efficacy of tacrolimus in GVHD prevention in both related and unrelated donor transplantation. Three multicenter randomized studies comparing tacrolimus to cyclosporine have been completed, one each in related and unrelated donor transplantation; the remaining study involved both related and unrelated donor transplantation. All three studies showed a significantly lower incidence of grade II-IV acute GVHD in patients who received tacrolimus. One study in sibling donor transplantation showed that patients with advanced disease who received tacrolimus had a poorer survival than patients who received cyclosporine, but the survival was similar in patients with non-advanced disease. The remaining two studies, one in unrelated donors and the other combining both related and unrelated donors did not show any survival difference between the tacrolimus and cyclosporine groups. In addition, this review also highlights some of the critical questions regarding the role of this agent in allogeneic stem cell transplantation: (1) the contribution of methotrexate in combination with tacrolimus; (2) the starting i.v. dose of tacrolimus; (3) the suggested whole blood level of tacrolimus and its effect on nephrotoxicity; and (4) whether tacrolimus should be used in patients with advanced malignancy. Future studies using tacrolimus in combination with other immunosuppressants, and its use in patients with advanced malignancy will be warranted.

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TRANSCRIPTIONAL INHIBITION OF INSULIN BY FK506 AND POSSIBLE INVOLVEMENT OF FK506 BINDING PROTEIN-12 IN PANCREATIC Β-Cell

Cited by 167 publications

References 0 publications

Reversibility of tacrolimus-induced posttransplant diabetes: an illustrative case and review of the literature

Reversibility of tacrolimus-induced posttransplant diabetes: an illustrative case and review of the literature

Long-term management of the liver transplant patient: Diabetes, hyperlipidemia, and obesity

Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation

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