Morphological and Functional Changes of Islets of Langerhans in Fk506-Treated Rats

Hirano, Yuri; Fujihira, Shiro; Ohara, Kaname; Katsuki, Shoji; Noguchi, Hideyo

doi:10.1097/00007890-199204000-00033

Cited by 98 publications

(48 citation statements)

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“…secretion has been observed in rat and human islet cells, while dogs treated with CSA show decreased insulin secretion following glucagon stimulation (53)(54)(55). A similar dose-dependent TAC-induced decrease in insulin secretion has also been observed in a variety of models, including mice with human pancreatic islet transplants, and in rats and dogs (56)(57)(58). Decreased insulin secretion may result from compromised insulin production either via direct Bcell toxicity or via inhibition of DNA synthesis.…”

Section: Nodm After Heart Transplantationmentioning

confidence: 72%

“…Decreased insulin secretion may result from compromised insulin production either via direct Bcell toxicity or via inhibition of DNA synthesis. Morphological changes indicating B-cell toxicity after exposure to CSA or TAC include vacuolization and degranulation (58,59). Inhibition of DNA synthesis by either immunosuppressant may result from the blockade of calcineurin signaling required to activate the NFAT transcription factor that mediates insulin gene transcription.…”

Section: Nodm After Heart Transplantationmentioning

confidence: 99%

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New Onset Diabetes Mellitus in Patients Receiving Calcineurin Inhibitors: A Systematic Review and Meta-Analysis

Heisel¹,

Heisel²,

Balshaw³

et al. 2004

American Journal of Transplantation

449

286

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New onset diabetes mellitus (NODM) is a serious complication of transplantation. This meta-analysis evaluates the reported incidence of NODM after solid organ transplantation in patients receiving CNI treatment.Databases from January 1992 to April 2002 were searched. Fifty-six publications providing NODM incidence data were reviewed. Sixteen prospective, randomized comparative studies providing information on incidence of insulin-dependent diabetes mellitus (IDDM) were subjected to meta-analysis.New onset diabetes mellitus was reported in 13.4% of patients after solid organ transplantation, with a higher incidence in patients receiving tacrolimus than cyclosporine (16.6% vs. 9.8%). This trend was observed across renal, liver, heart and lung transplant groups. Meta-analysis of 16 studies included patients receiving either tacrolimus (n = = 1636) or cyclosporine (n = = 1407). The incidence of IDDM was significantly higher among tacrolimus-treated patients (10.4% vs. 4.5%, p < 0.00001), an effect observed in renal (9.8% vs. 2.7% p < 0.00001) and nonrenal (11.1% vs. 6.2%; p < 0.003) groups, and among patients receiving equal doses of concomitant medication in both treatment arms (12.0% vs. 3.0%; p < 0.00001).The reported incidence of NODM during the past decade was significantly higher among patients receiving tacrolimus than cyclosporine. These data provide a quantitative foundation for studies designed to reduce the rates of NODM following solid organ transplantation.

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Section: Nodm After Heart Transplantationmentioning

confidence: 72%

Section: Nodm After Heart Transplantationmentioning

confidence: 99%

New Onset Diabetes Mellitus in Patients Receiving Calcineurin Inhibitors: A Systematic Review and Meta-Analysis

Heisel¹,

Heisel²,

Balshaw³

et al. 2004

American Journal of Transplantation

449

286

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“…Hricik et al (23) recently reported that African-Americans were more susceptible to PTDM than Caucasians, despite similar doses of corticosteroids and lower trough levels of tacrolimus. Because the main mechanism of tacrolimus-associated PTDM is the decrease in insulin secretory capacity (13,14,16), and most type 2 diabetic patients in Korea are characterized by insulin secretory defect (24,25), the Korean population may be more susceptible to the tacrolimus-associated PTDM. Second, the ADA criteria revised in 1997 are even stricter than other definitions previously used and have the power to detect mild asymptomatic diabetes.…”

Section: Immunosuppressive Treatmentmentioning

confidence: 99%

“…In contrast, sirolimus, which also binds to FKBP12, interacts with mammalian target of rapamycin, so-called mTOR, instead of calcineurin and frequently causes hyperlipidemia by inhibition of insulin action (15). Tacrolimusinduced PTDM has been proven to be reversible after withdrawing tacrolimus (13,14,16), and we have recently reported a case showing complete insulin independence after severe diabetic ketoacidosis associated with tacrolimus treatment (17).…”

mentioning

confidence: 99%

High Incidence of Tacrolimus-Associated Posttransplantation Diabetes in the Korean Renal Allograft Recipients According to American Diabetes Association Criteria

et al. 2003

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OBJECTIVE -The incidence of posttransplantation diabetes mellitus (PTDM) has been reported to vary according to different study populations or different definitions. In this study, using American Diabetes Association criteria, the incidence and clinical characteristics of PTDM in Korean renal allograft recipients undergoing tacrolimus-based immunosuppression were examined. RESEARCH DESIGN AND METHODS -A total of 21 patients taking tacrolimus asprimary immunosuppressant were recruited and tested with a serial 75-g oral glucose tolerance test at 0, 1, 3, and 6 months after renal transplantation.RESULTS -The cumulative incidence of PTDM was 52.4% at 1 month and 57.1% at 3 and 6 months. The baseline characteristics of the PTDM group were old age (especially Ͼ40 years), a high BMI, a high fasting glucose level, a high plasma insulin level, and increased insulin resistance. Among these parameters, old age was the only independent risk factor. The insulin secretory capacity in the PTDM group was maximally suppressed 3 months after transplantation. Thereafter, it was gradually restored along with dose reduction of tacrolimus.CONCLUSIONS -Routine screening for PTDM is necessary in patients over 40 years of age who are undergoing a relatively higher dose tacrolimus therapy during the early course of postrenal transplantation. Diabetes Care 26:1123-1128, 2003T acrolimus is an effective alternative to cyclosporine as a primary immunosuppressant after kidney transplantation (1-4). The diabetogenic potential of tacrolimus is much higher than that of cyclosporine in the early posttransplantation period (5-7). Despite its excellent prophylactic effect on renal allograft rejection, posttransplantation diabetes mellitus (PTDM) has become a major drawback in its clinical application (8 -12). A temporal trend of the incidence of PTDM has been demonstrated to show a bimodal pattern corresponding to the early kidney transplantation era using high-dose steroids in the 1960s and to the introduction of tacrolimus in the 1990s (5).Tacrolimus inhibits the transcription of the insulin gene by inhibition of calcineurin after binding to FK506-binding protein 12 (FKBP12) (13,14). In contrast, sirolimus, which also binds to FKBP12, interacts with mammalian target of rapamycin, so-called mTOR, instead of calcineurin and frequently causes hyperlipidemia by inhibition of insulin action (15). Tacrolimusinduced PTDM has been proven to be reversible after withdrawing tacrolimus (13,14,16), and we have recently reported a case showing complete insulin independence after severe diabetic ketoacidosis associated with tacrolimus treatment (17).It has been reported that PTDM is associated with diabetic microvascular complications, an increased frequency of sepsis as a cause of death, and a risk of developing graft failure (18). Considering the well-known serious clinical outcomes of hyperglycemia and the established benefits of intensive glycemic control (19,20), the chronic metabolic derangement in PTDM, even though the severity of which is mild, could l...

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“…Research that examined whether these relationships are dosagedependent has yielded inconsistent results. Limited animal data and one trial suggested a dosage-dependent relationship (18,19), but in a meta-analysis of 35 trials, Heisel et al (7) failed to find any evidence of dosage dependence between Tac and NOD. Newer research suggested that once a patient develops NOD, it can often be reversed or its severity decreased by reducing the dosage of Tac and steroids (20,21), but these studies were unable to separate the effect of steroids and CNI.…”

mentioning

confidence: 99%

Influence of Early Posttransplantation Prednisone and Calcineurin Inhibitor Dosages on the Incidence of New-Onset Diabetes

Burroughs¹,

Lentine²,

Takemoto³

et al. 2007

Clinical Journal of the American Society of Nephrology

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Morphological and Functional Changes of Islets of Langerhans in Fk506-Treated Rats

Cited by 98 publications

References 0 publications

New Onset Diabetes Mellitus in Patients Receiving Calcineurin Inhibitors: A Systematic Review and Meta-Analysis

New Onset Diabetes Mellitus in Patients Receiving Calcineurin Inhibitors: A Systematic Review and Meta-Analysis

High Incidence of Tacrolimus-Associated Posttransplantation Diabetes in the Korean Renal Allograft Recipients According to American Diabetes Association Criteria

Influence of Early Posttransplantation Prednisone and Calcineurin Inhibitor Dosages on the Incidence of New-Onset Diabetes

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