Case Report
Eurasian J Med 2015; 47: 213-5
New-Onset Diabetes Mellitus Associated with Sirolimus Use in Renal Transplant Recipients Böbrek Nakli Alıcılarında Sirolimus Kullanımı ile İlişkili Yeni Başlangıçlı Diabetes Mellitus Vural Taner Yilmaz1, Huseyin Kocak1, Ayhan Dinckan2, Ramazan Cetinkaya1 Department of Internal Medicine, Division of Nephrology, Akdeniz University School of Medicine, Antalya, Turkey Department of General Surgery, Akdeniz University School of Medicine, Antalya, Turkey
1 2
Abstract
Özet
New-onset diabetes after transplantation and impaired glucose tolerance are very common in renal transplant patients. New-onset diabetes after transplantation (NODAT) is associated with increased cardiovascular morbidity and mortality, reduced graft and patient survival. Several risk factors for NODAT have been identified: age, obesity, family history of diabetes mellitus and HCV infection. In addition, steroid and calcineurin inhibitors also contribute to the development of NODAT. Sirolimus causes immunosuppressive effects by inhibiting mammalian target of rapamycin (mTOR), and has well known side effects. The effects of sirolimus on glucose metabolism and contribution to NODAT development are not clearly known. In this report, we presented five RTX patients who developed NODAT under the treatment of sirolimus.
Renal transplant (Rtx) hastalarda transplantasyon sonrası yeni başlangıçlı diabetes mellitus (NODAT) ve bozulmuş glukoz töleransı sıklıkla gelişmektedir. NODAT artmış kardiyovasküler mortalite ve morbidite, azalmış graft ve hasta sağkalımı ile ilişkilidir. NODAT gelişiminde yaş, obezite, ailede diabetes mellitus öyküsünün olması ve hepatit-C virus (HCV) infeksiyonu önemli risk faktörleridir. Ayrıca steroid ve kalsinörin inhibitörleri de NODAT gelişimine neden olabilmektedir. Sirolimusun etki mekanizması ve yan etkileri oldukça iyi bilinmektedir. Bununla birlikte glukoz metabolizması ve NODAT gelişimi üzerine olan etkileri tam olarak bilinmemektedir. Çalışmamızda sirolimus kullanmakta iken NODAT tanısı konulan 5 vaka değerlendirilmiştir
Keywords: Renal transplantation, diabetes mellitus, sirolimus
Introduction New-onset diabetes after transplantation (NODAT) and impaired glucose tolerance are very common among RTX patients. It has been reported in different studies that NODAT rates have ranged between 20% and 50% [1]. NODAT is associated with increased cardiovascular morbidity and mortality, reduced graft and patient survival. With regard to cardiovascular risk factors, NODAT is a more serious risk factor compared to hypertension and hyperlipidaemia [2]. Several risk factors for NODAT have been identified: family history, cytomegalovirus infection, hepatitis C virus infection, age and weight [3]. In addition, steroid and calcineurin inhibitors also contribute to the development of NODAT. In the early period of transplantation, it has been reported that tacrolimus is more diabetogenic than cyclosporine, although it has been shown that both cause similar rate of NODAT development in long term follow up [4]. In the pathogenetic
Anahtar Kelimeler: Böbrek nakli, diabetes mellitus, sirolimus
process of NODAT, calcineurin inhibitors inhibit insulin secretion by causing beta cell damage [5]. Sirolimus, new immunosuppressive drugs, causes immunosuppressive effects by acting on mammalian target of rapamycin (mTOR) [6]. Although side effects of sirolimus are well described, its effects on glucose metabolism and association with NODAT are not clear. Herein, we present five renal transplant patients who developed NODAT under the treatment of sirolimus.
Case Reports Case 1 A 42 years old female end stage renal disease patient referred to our centre for renal transplantation. Past medical history revealed that the aetiology of ESRD was hypoplastic kidney and she was maintained on haemodialysis for 4 years. Her height was 150 cm (4.9 feet), her body mass index was 21
Received: May 19, 2014 / Accepted: August 12, 2014 Correspondence to: Vural Taner Yilmaz, Department of Internal Medicine, Division of Nephrology, Akdeniz University School of Medicine, Antalya, Turkey Phone: +90 242 249 6128 e-mail: [email protected] ©Copyright 2015 by the Atatürk University School of Medicine - Available online at www.eurasianjmed.com DOI:10.5152/eurasianjmed.2015.049
214
Yilmaz et al. Sirolimus and New-Onset Diabetes Mellitus
Eurasian J Med 2015; 47: 213-5
Table 1. General characteristics of patients with diagnosis of NODAT
Case Age Sex
Blood type BMI Miss-match
Preop. FBG
Family history of DM HCV Ab
Etiology of ESRD
2
42
M
B (+)
25
2
80
(+)
(-)
Nephrolithiasis
3
58
M
A (+)
29
3
83
(-)
(-)
HT
4
33
M
B (+)
21
3
88
(-)
(-)
HT
5
36
M
B (+)
24
2
78
(-)
(-)
HT
BMI: body mass index (kg/m2); HT: hypertension; HCV: Hepatitis-C virus; ESRD: end stage renal disease; DM: diabetes mellitus; FBG: fasting blood glucose; NODAT: new-onset diabetes after transplantation.
kg/m², her blood type was 0 Rh (-). Preoperative laboratory tests were: blood urea nitrogen (BUN): 38 mg/dL, serum levels of creatinine (Cr): 7.4 mg/dL, creatinine clearance (CrCL): 8mL/ minute, hepatitis-C virus antibody (HCV Ab) (-), fasting blood glucose (FBG): 78 mg/dL. In 2009, she received kidney from a 53 years old deceased donor with five HLA mismatches. Antithymocyte globulin was introduced as an induction treatment. Immunosuppressive therapy consisted of sirolimus (initial dose: 3 mg/day, target blood level: 8-10 ng/mL), mycophenolate mofetil (1.5 gr/day) and prednisolone (1. day: 1000 mg, 2. day: 500 mg, 3 day: 250 mg, 4.day: 160 mg, 5. day: 80 mg, 6. day: 40 mg, 7. day-1. month: 20 mg, 1.-2. month: 17.5 mg, 2.-3. month: 15 mg, 3.-6. month: 10 mg, 6.-12. month: 7.5 mg, >1.year: 5 mg/day). At the early post-operative periods, acute rejection attack, delayed graft function and infection were not observed. In routine biochemical examination, FBG was >90 mg/dL and creatinine level was 1.5 mg/dL. At the second month of renal transplantation operation, patient’s FBG raised (140-160 mg/dL), patient was diagnosed as diabetes mellitus according to the criteria of American Diabetes Association (ADA). We initiated nateglinide 120 mg as an antidiabetic treatment and achieved adequate blood glucose control. Her last glomerular filtration rate was 80 ml/minute, FBG was under 100 mg/dL. Cases 2-3-4-5 We also observed NODAT development in four renal transplant patients receiving sirolimus (3 mg/day , target blood level: 8-10 mg/mL), mycophenolate mofetil (1.5 gr/day ) and prednisolone (doses were same amount of firs patients) treatment. General characteristic features are presented in Table 1. All renal transplantation types were living-related. There is only family history of DM in second case. However, acute rejection attacks were not observed in any case. In our patients, at the first three months of post-transplant period, FBG started to rise. All our patients were diagnosed as diabetes mellitus according to the criteria of ADA between 5th and 6th months. Adequate blood glucose level was achieved by diet at the 2nd case, by nateglinide treatment for the 3rd and 4th cases and glyburide treatment for the 5th case. When DM was
Table 2. Serum levels of fasting blood glucose, postprandial blood glucose and hemoglobine-A1C when the patient was diagnosed as NODAT
2nd 3rd 4th 5th Parameters patient patient patient patient FBG (mg/dL)
126
130
132
146
PBG (mg/dL)
142
154
160
168
6
6.1
6.3
6.5
HbA1C (%)
PBG: postprandial blood glucose; HbA1C: hemoglobine-A1C
diagnosed, LDL, triglyceride and total cholesterol levels also increased to approximately 2-2.5 folds of preoperative values. The serum levels of fasting blood glucose, postprandial blood glucose and hemoglobine-A1C are presented in Table 2. Informed consent was obtained from all patients for this study.
Discussion In this study, we presented five renal transplant patients who developed NODAT under the treatment of sirolimus. NODAT has multifactorial aetiology. Drugs (steroids, calcineurin inhibitors, proliferation signal inhibitors), obesity, family history, male sex, positive test results for hepatitis-c virus, transplantation from deceased-donor are identified risk factors associated with NODAT. Evidence suggests that obesity and immunosuppressive drugs are major risk factors for the development of NODAT. Among the immunosuppressive drugs, cyclosporine and tacrolimus are well known drugs associated with NODAT [1]. Sirolimus causes immunosuppressive effects by acting on mammalian target of rapamycin (mTOR). mTOR inhibits interleukin-2 mediated signal transduction, resulting in cell cycle arrest in the G1-S phase. By this mechanism, sirolimus blocks the response of T- and B-cell activation by cytokines, which prevents cell-cycle progression and proliferation [6]. It is well known that sirolimus may show adverse effects on gastrointestinal, hematologic and pulmonary system. One
Eurasian J Med 2015; 47: 213-5
of the discussed subjects for sirolimus is that whether it has beneficial or adverse effect on glucose metabolism. In our cases, although we cannot exclude genetic susceptibility, family history (in one case) and prednisolone use for the NODAT risk factors, we can say that common risk factors in all cases for NODAT was the use of sirolimus. Therefore, our cases led us to think that sirolimus use in our patients might cause NODAT by clearly unknown mechanism. New-onset diabetes after transplantation is especially associated with the uses of tacrolimus, cyclosporine and high dose prednisolone due to acute rejection attack in early post-transplant period and the risk of development of NODAT much more raised in the presence of other diabetogenic factors. We almost excluded all other secondary diabetogenic factors for example obesity, the history of family and hepatitis C virus infection except for the using of the immunosuppressive drugs. Acute rejection attacks were not observed in any patients. As well as, NODAT developed in other four patients except for first case at the late post-transplant period. Due to all these causes, we think that using of sirolimus is the most important factor for the developed of NODAT in our cases. Indeed, the effects of sirolimus on glucose metabolism are not very clear. Insulin receptor substrate-1 (IRS-1) and mTOR play a role in insulin signalling. Early in-vitro studies suggest that it increases insulin responses in chronic insulin stimulation by inhibiting IRS-1 degradation [7]. Contrary to this finding, more recent in-vitro studies showed that longterm mTOR inhibition impairs activation of IRS-1 and AKT and augments insulin resistance and β- cell dysfunction [8, 9]. Other possible mechanisms, by which sirolimus may cause NODAT, include impaired insulin-mediated suppression of hepatic glucose production, insulin resistance from ectopic triglyceride deposition or direct β-cell toxicity. Recently, Johnston et al. [10] analysed the data of USRDS and reported that sirolimus may be independently associated with NODAT. Nevertheless, our cases may support this in-vitro and clinic study reporting that sirolimus may play a role in the development of NODAT and the need for further studies, which contain more patients. In conclusion, our study has suggested that sirolimus is associated with NODAT, but this is not well established and our findings should be confirmed in prospective studies or in meta-analyses of existing trials that involved sirolimus. Ethics Committee Approval: Ethics committee approval was received for this study.
Yilmaz et al. Sirolimus and New-Onset Diabetes Mellitus 215
Informed Consent: Written informed consent was obtained from patients who participated in this study. Peer-review: Externally peer-reviewed. Author Contributions: Concept - V.T.Y., R.C.; Design - V.T.Y.; Supervision - V.T.Y., H.K.; Materials - V.T.Y., H.K.; Data Collection and/ or Processing - V.T.Y., A.D.; Analysis and/or Interpretation - V.T.Y., H.K., R.C.; Literature Search - V.T.Y., H.K., A.D.; Writing Manuscript - V.T.Y., R.C., H.K. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support.
References 1. Luan FL, Zang H, Schaubel DE, Miles CD, Cibrik D, Norman S. Comparative risk of impaired glucose metabolism associated with cyclosporine versus tacrolimus in the late posttransplant period. American Journal of Transplantation 2008; 8: 1871-7. 2. Miles AM, Sumrani N, Horowitz R, et al. Diabetes mellitus after renal transplantation: as deleterious as non-transplant-associated diabetes? Transplantation 1998; 65: 380-4. 3. Roland M, Gatault P, Doute C, et al. Immunosuppressive medications, clinical and metabolic parameters in new-onset diabetes mellitus after kidney transplantation. Transpl Int 2008; 21: 52330. 4. Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and meta-analysis. Am J Transplant 2004; 4: 583-95. 5. Marchetti P, Navalesi R. The metabolic effects of cyclosporin and tacrolimus. J Endocrinol Invest 2000; 23: 482-90. 6. Morath C, Arns W, Schwenger V, et al. Sirolimus in renal transplantation. Nephrol Dial Transplant 2007; 22: 61-5. 7. Berg CE, Lavan BE, Rondinone CM. Rapamycin partially prevents insulin resistance induced by chronic insulin treatment. Biochem Biophys Res Commun 2002; 293: 1021-7. 8. Di Paolo S, Teutonico A, Leogrande D, Capobianco C, Schena PF. Chronic inhibition of mammalian target of rapamycin signaling downregulates insulin receptor substrates 1 and 2 and AKT activation: Acrossroad between cancer and diabetes? J Am Soc Nephrol 2006; 17: 2236-44. 9. Fraenkel M, Ketzinel-Gilad M, Ariav Y, et al. mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 2008; 57: 945-57. 10. Johnston O, Rose CL, Webster AC, Gill JS. Sirolimus is associated with new-onset diabetes in kidney transplant recipients. J Am Soc Nephrol 2008; 19: 1411-8.
Eurasian J Med 2015; 47: 213-5
New-Onset Diabetes Mellitus Associated with Sirolimus Use in Renal Transplant Recipients Böbrek Nakli Alıcılarında Sirolimus Kullanımı ile İlişkili Yeni Başlangıçlı Diabetes Mellitus Vural Taner Yilmaz1, Huseyin Kocak1, Ayhan Dinckan2, Ramazan Cetinkaya1 Department of Internal Medicine, Division of Nephrology, Akdeniz University School of Medicine, Antalya, Turkey Department of General Surgery, Akdeniz University School of Medicine, Antalya, Turkey
1 2
Abstract
Özet
New-onset diabetes after transplantation and impaired glucose tolerance are very common in renal transplant patients. New-onset diabetes after transplantation (NODAT) is associated with increased cardiovascular morbidity and mortality, reduced graft and patient survival. Several risk factors for NODAT have been identified: age, obesity, family history of diabetes mellitus and HCV infection. In addition, steroid and calcineurin inhibitors also contribute to the development of NODAT. Sirolimus causes immunosuppressive effects by inhibiting mammalian target of rapamycin (mTOR), and has well known side effects. The effects of sirolimus on glucose metabolism and contribution to NODAT development are not clearly known. In this report, we presented five RTX patients who developed NODAT under the treatment of sirolimus.
Renal transplant (Rtx) hastalarda transplantasyon sonrası yeni başlangıçlı diabetes mellitus (NODAT) ve bozulmuş glukoz töleransı sıklıkla gelişmektedir. NODAT artmış kardiyovasküler mortalite ve morbidite, azalmış graft ve hasta sağkalımı ile ilişkilidir. NODAT gelişiminde yaş, obezite, ailede diabetes mellitus öyküsünün olması ve hepatit-C virus (HCV) infeksiyonu önemli risk faktörleridir. Ayrıca steroid ve kalsinörin inhibitörleri de NODAT gelişimine neden olabilmektedir. Sirolimusun etki mekanizması ve yan etkileri oldukça iyi bilinmektedir. Bununla birlikte glukoz metabolizması ve NODAT gelişimi üzerine olan etkileri tam olarak bilinmemektedir. Çalışmamızda sirolimus kullanmakta iken NODAT tanısı konulan 5 vaka değerlendirilmiştir
Keywords: Renal transplantation, diabetes mellitus, sirolimus
Introduction New-onset diabetes after transplantation (NODAT) and impaired glucose tolerance are very common among RTX patients. It has been reported in different studies that NODAT rates have ranged between 20% and 50% [1]. NODAT is associated with increased cardiovascular morbidity and mortality, reduced graft and patient survival. With regard to cardiovascular risk factors, NODAT is a more serious risk factor compared to hypertension and hyperlipidaemia [2]. Several risk factors for NODAT have been identified: family history, cytomegalovirus infection, hepatitis C virus infection, age and weight [3]. In addition, steroid and calcineurin inhibitors also contribute to the development of NODAT. In the early period of transplantation, it has been reported that tacrolimus is more diabetogenic than cyclosporine, although it has been shown that both cause similar rate of NODAT development in long term follow up [4]. In the pathogenetic
Anahtar Kelimeler: Böbrek nakli, diabetes mellitus, sirolimus
process of NODAT, calcineurin inhibitors inhibit insulin secretion by causing beta cell damage [5]. Sirolimus, new immunosuppressive drugs, causes immunosuppressive effects by acting on mammalian target of rapamycin (mTOR) [6]. Although side effects of sirolimus are well described, its effects on glucose metabolism and association with NODAT are not clear. Herein, we present five renal transplant patients who developed NODAT under the treatment of sirolimus.
Case Reports Case 1 A 42 years old female end stage renal disease patient referred to our centre for renal transplantation. Past medical history revealed that the aetiology of ESRD was hypoplastic kidney and she was maintained on haemodialysis for 4 years. Her height was 150 cm (4.9 feet), her body mass index was 21
Received: May 19, 2014 / Accepted: August 12, 2014 Correspondence to: Vural Taner Yilmaz, Department of Internal Medicine, Division of Nephrology, Akdeniz University School of Medicine, Antalya, Turkey Phone: +90 242 249 6128 e-mail: [email protected] ©Copyright 2015 by the Atatürk University School of Medicine - Available online at www.eurasianjmed.com DOI:10.5152/eurasianjmed.2015.049
214
Yilmaz et al. Sirolimus and New-Onset Diabetes Mellitus
Eurasian J Med 2015; 47: 213-5
Table 1. General characteristics of patients with diagnosis of NODAT
Case Age Sex
Blood type BMI Miss-match
Preop. FBG
Family history of DM HCV Ab
Etiology of ESRD
2
42
M
B (+)
25
2
80
(+)
(-)
Nephrolithiasis
3
58
M
A (+)
29
3
83
(-)
(-)
HT
4
33
M
B (+)
21
3
88
(-)
(-)
HT
5
36
M
B (+)
24
2
78
(-)
(-)
HT
BMI: body mass index (kg/m2); HT: hypertension; HCV: Hepatitis-C virus; ESRD: end stage renal disease; DM: diabetes mellitus; FBG: fasting blood glucose; NODAT: new-onset diabetes after transplantation.
kg/m², her blood type was 0 Rh (-). Preoperative laboratory tests were: blood urea nitrogen (BUN): 38 mg/dL, serum levels of creatinine (Cr): 7.4 mg/dL, creatinine clearance (CrCL): 8mL/ minute, hepatitis-C virus antibody (HCV Ab) (-), fasting blood glucose (FBG): 78 mg/dL. In 2009, she received kidney from a 53 years old deceased donor with five HLA mismatches. Antithymocyte globulin was introduced as an induction treatment. Immunosuppressive therapy consisted of sirolimus (initial dose: 3 mg/day, target blood level: 8-10 ng/mL), mycophenolate mofetil (1.5 gr/day) and prednisolone (1. day: 1000 mg, 2. day: 500 mg, 3 day: 250 mg, 4.day: 160 mg, 5. day: 80 mg, 6. day: 40 mg, 7. day-1. month: 20 mg, 1.-2. month: 17.5 mg, 2.-3. month: 15 mg, 3.-6. month: 10 mg, 6.-12. month: 7.5 mg, >1.year: 5 mg/day). At the early post-operative periods, acute rejection attack, delayed graft function and infection were not observed. In routine biochemical examination, FBG was >90 mg/dL and creatinine level was 1.5 mg/dL. At the second month of renal transplantation operation, patient’s FBG raised (140-160 mg/dL), patient was diagnosed as diabetes mellitus according to the criteria of American Diabetes Association (ADA). We initiated nateglinide 120 mg as an antidiabetic treatment and achieved adequate blood glucose control. Her last glomerular filtration rate was 80 ml/minute, FBG was under 100 mg/dL. Cases 2-3-4-5 We also observed NODAT development in four renal transplant patients receiving sirolimus (3 mg/day , target blood level: 8-10 mg/mL), mycophenolate mofetil (1.5 gr/day ) and prednisolone (doses were same amount of firs patients) treatment. General characteristic features are presented in Table 1. All renal transplantation types were living-related. There is only family history of DM in second case. However, acute rejection attacks were not observed in any case. In our patients, at the first three months of post-transplant period, FBG started to rise. All our patients were diagnosed as diabetes mellitus according to the criteria of ADA between 5th and 6th months. Adequate blood glucose level was achieved by diet at the 2nd case, by nateglinide treatment for the 3rd and 4th cases and glyburide treatment for the 5th case. When DM was
Table 2. Serum levels of fasting blood glucose, postprandial blood glucose and hemoglobine-A1C when the patient was diagnosed as NODAT
2nd 3rd 4th 5th Parameters patient patient patient patient FBG (mg/dL)
126
130
132
146
PBG (mg/dL)
142
154
160
168
6
6.1
6.3
6.5
HbA1C (%)
PBG: postprandial blood glucose; HbA1C: hemoglobine-A1C
diagnosed, LDL, triglyceride and total cholesterol levels also increased to approximately 2-2.5 folds of preoperative values. The serum levels of fasting blood glucose, postprandial blood glucose and hemoglobine-A1C are presented in Table 2. Informed consent was obtained from all patients for this study.
Discussion In this study, we presented five renal transplant patients who developed NODAT under the treatment of sirolimus. NODAT has multifactorial aetiology. Drugs (steroids, calcineurin inhibitors, proliferation signal inhibitors), obesity, family history, male sex, positive test results for hepatitis-c virus, transplantation from deceased-donor are identified risk factors associated with NODAT. Evidence suggests that obesity and immunosuppressive drugs are major risk factors for the development of NODAT. Among the immunosuppressive drugs, cyclosporine and tacrolimus are well known drugs associated with NODAT [1]. Sirolimus causes immunosuppressive effects by acting on mammalian target of rapamycin (mTOR). mTOR inhibits interleukin-2 mediated signal transduction, resulting in cell cycle arrest in the G1-S phase. By this mechanism, sirolimus blocks the response of T- and B-cell activation by cytokines, which prevents cell-cycle progression and proliferation [6]. It is well known that sirolimus may show adverse effects on gastrointestinal, hematologic and pulmonary system. One
Eurasian J Med 2015; 47: 213-5
of the discussed subjects for sirolimus is that whether it has beneficial or adverse effect on glucose metabolism. In our cases, although we cannot exclude genetic susceptibility, family history (in one case) and prednisolone use for the NODAT risk factors, we can say that common risk factors in all cases for NODAT was the use of sirolimus. Therefore, our cases led us to think that sirolimus use in our patients might cause NODAT by clearly unknown mechanism. New-onset diabetes after transplantation is especially associated with the uses of tacrolimus, cyclosporine and high dose prednisolone due to acute rejection attack in early post-transplant period and the risk of development of NODAT much more raised in the presence of other diabetogenic factors. We almost excluded all other secondary diabetogenic factors for example obesity, the history of family and hepatitis C virus infection except for the using of the immunosuppressive drugs. Acute rejection attacks were not observed in any patients. As well as, NODAT developed in other four patients except for first case at the late post-transplant period. Due to all these causes, we think that using of sirolimus is the most important factor for the developed of NODAT in our cases. Indeed, the effects of sirolimus on glucose metabolism are not very clear. Insulin receptor substrate-1 (IRS-1) and mTOR play a role in insulin signalling. Early in-vitro studies suggest that it increases insulin responses in chronic insulin stimulation by inhibiting IRS-1 degradation [7]. Contrary to this finding, more recent in-vitro studies showed that longterm mTOR inhibition impairs activation of IRS-1 and AKT and augments insulin resistance and β- cell dysfunction [8, 9]. Other possible mechanisms, by which sirolimus may cause NODAT, include impaired insulin-mediated suppression of hepatic glucose production, insulin resistance from ectopic triglyceride deposition or direct β-cell toxicity. Recently, Johnston et al. [10] analysed the data of USRDS and reported that sirolimus may be independently associated with NODAT. Nevertheless, our cases may support this in-vitro and clinic study reporting that sirolimus may play a role in the development of NODAT and the need for further studies, which contain more patients. In conclusion, our study has suggested that sirolimus is associated with NODAT, but this is not well established and our findings should be confirmed in prospective studies or in meta-analyses of existing trials that involved sirolimus. Ethics Committee Approval: Ethics committee approval was received for this study.
Yilmaz et al. Sirolimus and New-Onset Diabetes Mellitus 215
Informed Consent: Written informed consent was obtained from patients who participated in this study. Peer-review: Externally peer-reviewed. Author Contributions: Concept - V.T.Y., R.C.; Design - V.T.Y.; Supervision - V.T.Y., H.K.; Materials - V.T.Y., H.K.; Data Collection and/ or Processing - V.T.Y., A.D.; Analysis and/or Interpretation - V.T.Y., H.K., R.C.; Literature Search - V.T.Y., H.K., A.D.; Writing Manuscript - V.T.Y., R.C., H.K. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support.
References 1. Luan FL, Zang H, Schaubel DE, Miles CD, Cibrik D, Norman S. Comparative risk of impaired glucose metabolism associated with cyclosporine versus tacrolimus in the late posttransplant period. American Journal of Transplantation 2008; 8: 1871-7. 2. Miles AM, Sumrani N, Horowitz R, et al. Diabetes mellitus after renal transplantation: as deleterious as non-transplant-associated diabetes? Transplantation 1998; 65: 380-4. 3. Roland M, Gatault P, Doute C, et al. Immunosuppressive medications, clinical and metabolic parameters in new-onset diabetes mellitus after kidney transplantation. Transpl Int 2008; 21: 52330. 4. Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and meta-analysis. Am J Transplant 2004; 4: 583-95. 5. Marchetti P, Navalesi R. The metabolic effects of cyclosporin and tacrolimus. J Endocrinol Invest 2000; 23: 482-90. 6. Morath C, Arns W, Schwenger V, et al. Sirolimus in renal transplantation. Nephrol Dial Transplant 2007; 22: 61-5. 7. Berg CE, Lavan BE, Rondinone CM. Rapamycin partially prevents insulin resistance induced by chronic insulin treatment. Biochem Biophys Res Commun 2002; 293: 1021-7. 8. Di Paolo S, Teutonico A, Leogrande D, Capobianco C, Schena PF. Chronic inhibition of mammalian target of rapamycin signaling downregulates insulin receptor substrates 1 and 2 and AKT activation: Acrossroad between cancer and diabetes? J Am Soc Nephrol 2006; 17: 2236-44. 9. Fraenkel M, Ketzinel-Gilad M, Ariav Y, et al. mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 2008; 57: 945-57. 10. Johnston O, Rose CL, Webster AC, Gill JS. Sirolimus is associated with new-onset diabetes in kidney transplant recipients. J Am Soc Nephrol 2008; 19: 1411-8.
