Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
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An unprecedented arsenal of new xenobiotic immunosuppressive agents has been developed recently. Most of the new immunosuppressants have been tested primarily in the treatment of allograft rejection in experimental models of transplantation, and some of the new drugs have already proven their safety and efficiency in extensive clinical trials on transplant patients. Another field for their potential application is the treatment of autoimmune diseases. This review will give an overview of the therapeutic potential of the new xenobiotic drugs in different animal models of rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, multiple sclerosis, diabetes mellitus, thyroiditis and uveoretinitis. The new xenobiotics are either inhibitors of the de novo synthesis of nucleotides, for example mycophenolate mofetil, mizoribine, leflunomide, and brequinar, or are immunophilin-binding agents (cyclosporin, FK506 and rapamycin) that inhibit signal transduction and cell cycle progression in lymphocytes. A different mode of action is likely to account for the immunosuppressive effects of deoxyspergualin, which may interfere with intracellular chaperoning by the heat shock protein HSP70 and the activation of transcription factor NF-kappa B.
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PMID:Xenobiotic immunosuppressive agents: therapeutic effects in animal models of autoimmune diseases. 935 1

FK506 (tacrolimus), a potent immunosuppressant, is used for inhibiting allograft rejection in the organ transplantation field. In a preclinical toxicity study in rats, FK506 induced various toxicities, including renal and pancreatic injuries. One of these toxic findings was cataract, and we have found that cataract appeared in rats dosed orally with FK506 for 13 weeks and more. Therefore, to better elucidate the onset mechanism of FK506-induced cataract, we measured biochemical parameters, such as sorbitol, Na,K-ATPase and glutathione in the lens of rats. Rats were dosed with FK506 in oral daily doses of 0.2, 1 or 5 mg/kg for 13 weeks, the lowest dose of which approximated the expected clinical dosage. Cataract developed in the 5-mg/kg/day group, with an incidence of 25%, whereas no cataract formation was observed in the 0.2- or 1-mg/kg/day groups. Five mg/kg/day led an increase of sorbitol and a decrease of reduced type glutathione, but did not affect Na,K-ATPase activity of the lens. FK506 is known to have diabetogenicity mediated through pancreatic injury, which appears as vacuolation of islet cell in rats. Five mg/kg/day of FK506 induced an elevation of blood glucose associated with glucose intolerance, and decrease of both basal insulin level and insulin content in the pancreas, and the changes were in parallel with the cataract development in the present study. On the other hand, diabetic parameters did not change in the 0.2- or 1-mg/kg/day groups. These observation suggest that diabetes developed in the rats dosed with 5 mg/kg/day of FK506. Coadministration of a novel aldose reductase inhibitor, Zenarestat, at an oral dose of 50 mg/kg/day resulted in a reduction of incidence of the FK506-induced cataract and a decrease of sorbitol levels in the lens when compared to that in the lens of rats dosed with 5 mg/kg/day of FK506. These results suggest that FK506-induced cataract in rats is due to an accumulation of sorbitol in the lens, secondary to the diabetogenic effect of FK506. FK506 treatment at the doses of 0.2 and 1 mg/kg/day neither affected parameters indicative of diabetes nor induced cataract in rats, suggesting that the cataract would not develop with FK506 if diabetic parameters were kept under control.
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PMID:Cataract development induced by repeated oral dosing with FK506 (tacrolimus) in adult rats. 935 35

The development of atherosclerotic cardiovascular complications is a common and serious problem for the long-term survivors of organ transplantation. Cyclosporine A plus steroid-based immuno-suppression regimens in these patients are associated with the development of hypertension, hyperlipidemia, obesity, and diabetes mellitus. Whether the new immunosuppressive agent tacrolimus (FK506) confers any advantage in terms of these cardiovascular risk factors has been less well studied. We compared serial changes in blood pressure, lipids, body weight, and glucose levels during the first 12 months after liver transplantation in patients using either cyclosporine A (n = 39) or tacrolimus (n = 24)-based immunosuppression. By 12 months, the prevalence of hypertension, hypercholesterolemia, and obesity was increased in the cyclosporine A group compared to tacrolimus: 82% versus 33%, 33% versus 0%, and 46% versus 29%, respectively (all p < .05). Triglyceride and total cholesterol levels were 196 +/- 23 versus 125 +/- 13 mg/dL and 225 +/- 9 versus 159 +/- 7 mg/dL for the cyclosporine A versus tacrolimus groups, respectively (p < .05). Cumulative posttransplant steroid dose was not related to the observed lipid changes in either group, although the increase in triglycerides was positively correlated to weight gain and diuretic use in the cyclosporine A group. The incidence of diabetes mellitus was not increased from baseline in either group. These results indicate that tacrolimus, compared to cyclosporine A, is associated with a less adverse cardiovascular risk profile in the first year after liver transplantation. Whether these differences persist and become clinically relevant to a liver transplant recipient population that is increasingly older and has more preexisting cardiovascular disease remains to be determined.
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PMID:Evolution of cardiovascular risk after liver transplantation: a comparison of cyclosporine A and tacrolimus (FK506). 937 52

Pancreas transplantation for the better treatment of diabetes mellitus is becoming an important part of the service offered to diabetic patients requiring renal transplantation. Improvements in surgical technique make this a useful option. A major problem, limiting more extensive use of pancreas transplantation to other diabetic patients, remains the inadequacies of present immunosuppressive regimens. A relatively new agent, FK506 or tacrolimus, is being used increasingly because of perceived benefits over older therapeutic agents. There are concerns about the diabetogenic effect of tacrolimus. These may be dose-related, and low-dose tacrolimus regimens, by allowing reduction in dosage of other diabetogenic immunosuppressive agents, have produced encouraging results in pancreas transplantation in many centres. Further improvements in immunosuppressive regimens may widen the clinical implications for pancreas transplantation but identifying the patient group who will most benefit remains a priority.
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PMID:Update of tacrolimus in pancreas transplantation. 940 Sep 14

In order to avoid the side effects of tacrolimus (FK506), a lowdose FK506-based regimen was started from 1 June 1991. The dose was adjusted to maintain the FK506 whole blood trough level at 15-20 ng/ml for 7 days postoperatively, at 10-15 ng/ml for 2 months, and under 10 ng/ml thereafter. The graft survival rates at 3 years and 5 years were 87.8 and 82.3% (FK506) vs 86.8 and 86.8% [cyclosporine (CyA)]. The incidence of acute rejection within the first 90 days was 31.6% in the FK506 group which was lower than the 57.1% of the CyA group (P = 0.0585). Grades of acute rejection episodes over IIA in the FK506 group were 20%, which was lower than the 37% in the CyA group. The mean oral dosages of FK506 were 0.061 and 0.04 mg/kg per day at 3 and 5 years, respectively. The incidence of new onset diabetes was 27.8% in the FK506 group and 17.1% in the CyA group. However, insulin therapy was withdrawn in all patients of the FK506 group within 5 months. The percentage of patients who required an antihypertensive agent was 28.6% and 40% in the FK506 group and 73.2% and 88% in the CyA group at 1 and 3 years, respectively (P < 0.05). Nephrotoxicity was seen in 20% of the FK506 group and 14.3% of the CyA group. Hypercholesterolemia was less frequent in the FK506 group than the CyA group. The FK506-based regimen described here is a protocol with the potential to reduce its adverse effects. The Whole blood concentration of FK506 should be monitored and blood levels maintained in the range of 5-10 ng/ml after 90 postoperative days for optimal efficacy and minimal toxicity.
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PMID:Low-dose tacrolimus (FK506)-based immunosuppressive protocol in living donor renal transplantation. 966 45

The results of pancreas transplantation have improved in the ciclosporin A era. Success rates are now similar to those in other types of organ transplantation, and the number of cases has increased concomitantly. As of December 1997, 10,283 pancreas transplantation procedures had been reported to the International Pancreas Transplant Registry. Since 1995, over 1,000 have been reported annually, 75% of which have been performed in the USA. The majority (88%) of those carried out in the USA consist of simultaneous pancreas and kidney (SPK) transplantations, followed by pancreas transplantation after kidney transplantation (10%) and pancreas transplantation alone (PTA) (2%). From 1994 to 1997, the overall one-year patient survival rate was 94%. The graft survival rate for SPK was the highest, with one- and three-year graft survival rates of 82% and nearly 80%, respectively. The administration of FK506 and mycophenolate mofetil has improved the results in patients undergoing pancreas transplantation. Althought the technical failure rate has decreased, graft thrombosis remains the most frequent cause of technical failure (5.5% for SPK with exocrine bladder drainage and 11% for SPK with enteric drainage). The standard surgical procedure has included pancreas-exocrine bladder drainage, but the current trend is to perform physiological enteric drainage. It has been reported that the portal venous and enteric exocrine drainage methods are safe, with outcomes similar to those of the standard technique. It appears that these will become the standard methods in the near future. The primary objective of improved quality of life is achieved in patients with functioning pancreas grafts, and transplantation results in modest reductions in secondary diabetes mellitus complications. However, it must still be confirmed whether the long-term quality-of-life benefits outweigh the potential risks. The secondary objective of pancreas transplantation is to prevent complications of diabetes mellitus. It is necessary to develop methods for the early detection of rejection, which will lead to significant improvements in the results of PTA. Although 15 pancreas transplantation surgeries have been carried out in Japan, they ceased after 1994. Currently, social debate to determine the rules governing such procedures is ongoing.
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PMID:[Current status and future of pancreas transplantation]. 1002 97

As of November 1997, 9,891 pancreas transplantation were reported to the International Pancreas Transplant Registry. In the United States, for all 1994-97, SPK, PAK, and PTA transplants, one-year graft survival rates were 82%, 71%, and 62%, respectively. The 1994-97 pancreas survival rates in all categories were higher than in previous eras. The improvement in graft survival rates has been associated with the introduction of FK506 and MMF, but excellent results are seen with cyclosporine, so the improvement may in part be due to the increasing experience that centers now have with pancreas transplantation. Although the standard surgical procedure remains pancreas-exocrine bladder drainage, the number of enteric drainage cases is increasing. It has been reported that the portal venous and enteric drainages are safe, with outcomes similar to those of standard technique. It appears that these will become the standard methods in the near future. Although 15 pancreas transplantations have been carried out in Japan, they ceased after 1994. Currently, social debate to determine the rules governing such procedures is ongoing. As of December 1995, 306 adult islet allotransplantation were reported to the Islet Transplant Registry. One-year islet survival rates were 27% in cases for 1990-94. Islet transplantation has the potential to be the most physiological advantage for the treatment of diabetes mellitus. However, the endocrine function provided by these transplants has been far from optimal.
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PMID:[Current status and future prospect of pancreas and islet transplantation]. 1019 60

Post-transplant diabetes mellitus, a complication due to corticosteroids and the calcineurin inhibitors, cyclosporine and tacrolimus (FK506), is commonly regarded as a form of type-2 (adult-onset) diabetes mellitus. Diabetic ketoacidosis, which requires relative insulin deficiency to impair fatty acid metabolism, is a complication of type-1 diabetes mellitus. We report three patients who presented with diabetic ketoacidosis post-transplant. All three patients presented with severe hyperglycemia, significant ketosis and metabolic acidosis of variable severity. One patient was a renal transplant recipient on a cyclosporine-based regimen. The other two patients were liver transplant recipients receiving either cyclosporine or tacrolimus-based immunosuppression. Both of the liver transplant recipients were found to have moderate to high serum levels of calcineurin inhibitors on presentation. The liver recipient on cyclosporine (Neoral) had a 4 hour post-dose level of 388 ng/ml and the patient on tacrolimus was found to have a trough level of 21.2 ng/ml. Our experience suggests that post-transplant diabetes mellitus, in association with calcineurin inhibition, may result in ketoacidosis either secondary to relative beta cell dysfunction, peripheral insulin resistance, or a combination of the two effects. Post-transplant diabetes mellitus can be an atypical form of adult-onset diabetes with features of both type I and type II diabetes mellitus.
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PMID:Post-transplant diabetic ketoacidosis--a possible consequence of immunosuppression with calcineurin inhibiting agents: a case series. 1074 93

The induction of diabetes has been recognised as adverse effect of the immunsuppressive drug FK506/Tacrolimus. The aim of this study was to clarify whether insulinopenia or insulin resistance dominates and whether islet cell autoantibodies are present in patients treated by FK506. We investigated 58 patients 1-3 years after liver transplantation while under therapy with FK506 or CsA and prednisolone (0-7.5 mg) for basal blood glucose levels and islet-cell specific autoantibodies. A subgroup of 20 patients on FK506, 10 patients on cyclosporin and 15 healthy volunteers were metabolically tested by oGTT. Five patients had diabetes pre-transplantation. After transplantation, 9/28 FK506-treated patients developed newly diagnosed diabetes compared to 0/25 cyclosporin-treated patients (p<0.01). Both patient groups showed significantly higher fasting blood glucose, insulin or C-peptide levels compared to controls. Through the oGTT, FK506-treated patients without diabetes, but not cyclosporin-treated patients, had higher C-peptide levels compared to controls (p<0.05). Five/32 patients on FK506 compared to 0/26 patients on cyclosporin (p<0.05) had islet cell specific autoantibodies, mainly ICA without GAD- or IA2-Ab, a feature described for latent autoimmune diabetes in adults. ICA positivity was correlated to the diabetes associated HLA haplotype DR4/DQ*0302 (p<0.05). Although the interpretation of our metabolic data in patients with concomitant liver disease and prednisolone therapy has limitations, we suggest insulin resistance caused by treatment with FK506. However, manifestation of diabetes was associated with relative insulinopenia rather than insulin resistance in patients on FK506. Immunsuppressive therapy by FK506 was not able to suppress islet cell autoimmunity, and may even induce it in genetically predisposed patients.
Exp Clin Endocrinol Diabetes 2000
PMID:Diabetes mellitus and islet cell specific autoimmunity as adverse effects of immunsuppressive therapy by FK506/tacrolimus. 1098 53

Post-transplant diabetes mellitus (PTDM) is a common complication after orthotopic liver transplantation (oLT). In our study, we investigated the prevalence and risk factors one year after transplantation in 618 patients who underwent oLT between 1990 and 1996 in a single center. The influence of steroid medication and hepatitis B or C (HBV/HCV) was also studied. Before oLT 66 of the 618 patients were diabetic. After transplantation 37 of these 66 (56%) patients showed no further signs of DM. Of the 552 patients without DM before transplantation 39 (7.2%) developed new onset PTDM. There was no influence of steroid medication on the presence of PTDM (steroids 10.4% PTDM, no steroids 12.5% PTDM). In addition we found no influence of HBV or HCV-infection on PTDM development. Analysis for risk factors showed no significant influence of the diagnosis leading to oLT, of FK506 or Cyclosorin A medication, age, gender or Child-Pugh class. Five year patient survival was not influenced by the presence of PTDM, especially patients with a preexisting DM showed no reduced survival. However, a subgroup of patients with new onset insulin-requiring PTDM showed significantly reduced 5 year survival (p<0.05). In conclusion we found new onset PTDM in 7.2% of patients undergoing oLT one year after the operation. On the other hand in more than 50% of patients with preexisting DM, the disease was no longer present post-transplant. This could be an indication that DM is dependent on liver function in these patients. Patients with preexisting DM should not be excluded from transplantation if indicated. Development of new onset insulin-requiring PTDM could be an important prognostic factor for patient survival after oLT. Further investigations are necessary to evaluate the prognostic meaning of PTDM and the pathophysiologic mechanisms.
Exp Clin Endocrinol Diabetes 2000
PMID:Liver transplantation and diabetes mellitus. 1102 53


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