Epidemiology/Health Services/Psychosocial Research ORIGINAL ARTICLE High Incidence of Tacrolimus-Associated Posttransplantation Diabetes in the Korean Renal Allograft Recipients According to American Diabetes Association Criteria 1 2 YOUNG MIN CHO, MD JONGWON HA, MD, PHD lograft rejection, posttransplantation dia- 1 2 KYONG SOO PARK, MD, PHD SANG JOON KIM, MD, PHD betes mellitus (PTDM) has become a 1 3 HYE SEUNG JUNG, MD BYOUNG DOO RHEE, MD, PHD 1 1 major drawback in its clinical application HYUN JUNG JEON, MD SEONG YEON KIM, MD, PHD 1 1 (8–12). A temporal trend of the incidence CURIE AHN, MD, PHD HONG KYU LEE, MD, PHD 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 OBJECTIVE — The incidence of posttransplantation diabetes mellitus (PTDM) has been introduction of tacrolimus in the 1990s reported to vary according to different study populations or different definitions. In this study, (5). using American Diabetes Association criteria, the incidence and clinical characteristics of PTDM Tacrolimus inhibits the transcription of in Korean renal allograft recipients undergoing tacrolimus-based immunosuppression were the insulin gene by inhibition of calcineurin examined. after binding to FK506-binding protein 12 (FKBP12) (13,14). In contrast, sirolimus, RESEARCH DESIGN AND METHODS — A total of 21 patients taking tacrolimus as which also binds to FKBP12, interacts with primary immunosuppressant were recruited and tested with a serial 75-g oral glucose tolerance test at 0, 1, 3, and 6 months after renal transplantation. mammalian target of rapamycin, so-called mTOR, instead of calcineurin and fre- RESULTS — The cumulative incidence of PTDM was 52.4% at 1 month and 57.1% at 3 and quently causes hyperlipidemia by inhibi- 6 months. The baseline characteristics of the PTDM group were old age (especially Ͼ40 years), tion of insulin action (15). Tacrolimus- a high BMI, a high fasting glucose level, a high plasma insulin level, and increased insulin induced PTDM has been proven to be resistance. Among these parameters, old age was the only independent risk factor. The insulin reversible after withdrawing tacrolimus secretory capacity in the PTDM group was maximally suppressed 3 months after transplantation. (13,14,16), and we have recently reported a Thereafter, it was gradually restored along with dose reduction of tacrolimus. case showing complete insulin indepen- dence after severe diabetic ketoacidosis as- 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 sociated with tacrolimus treatment (17). postrenal transplantation. It has been reported that PTDM is as- sociated with diabetic microvascular Diabetes Care 26:1123–1128, 2003 complications, an increased frequency of sepsis as a cause of death, and a risk of developing graft failure (18). Considering acrolimus is an effective alternative potential of tacrolimus is much higher the well-known serious clinical outcomes to cyclosporine as a primary immu- than that of cyclosporine in the early post- of hyperglycemia and the established nosuppressant after kidney trans- transplantation period (5–7). Despite its benefits of intensive glycemic control T (19,20), the chronic metabolic derange- plantation (1–4). The diabetogenic excellent prophylactic effect on renal al- ment in PTDM, even though the severity ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● of which is mild, could lead to many dia- From the 1Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; betes complications and should be cor- the 2Department of Surgery, Seoul National University College of Medicine, Seoul, Korea; and the 3Depart- rected appropriately. Therefore, in this ment of Internal Medicine, Inje University Medical College, Seoul, Korea. study, to define PTDM we used the Amer- Address correspondence and reprint requests to Kyong Soo Park, MD, PHD, Department of Internal ican Diabetes Association (ADA) criteria Medicine, Seoul National University College of Medicine, 28 Yongon-Dong Chongno-Gu, Seoul, 110-744, Korea. E-mail: [email protected]. for the diagnosis of diabetes (21), which is Received for publication 12 September 2002 and accepted in revised form 10 January 2003. more stringent than ever. Abbreviations: 2-h PG, 2-h plasma glucose during an OGTT; AUC, area under the curve; FKBP, FK506- Ethnic difference contributes to the binding protein 12; FPG, fasting plasma glucose; HCV, hepatitis C virus; HOMA-BC, homeostasis model variable susceptibility to developing assessment for ␤-cell function; HOMA-IR, HOMA for insulin resistance; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; OGTT, oral glucose tolerance test; PTDM, posttransplantation diabetes mellitus. PTDM (5,12,22,23). Interestingly, most A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion type 2 diabetic patients in Korea are char- factors for many substances. acterized by defects in insulin secretion DIABETES CARE, VOLUME 26, NUMBER 4, APRIL 2003 1123 PTDM associated with tacrolimus Table 1—Comparison of baseline clinical characteristics Measurements The 75-g oral glucose tolerance test Non-PTDM PTDM P (OGTT) was used to assess the glucose tolerance and to measure the insulin re- n 912 sponse to a glucose load on four occasions Age 27 Ϯ 241Ϯ 4 Ͻ0.05 (day –1 and months 1, 3, and 6). OGTT Sex (male:female) 2:7 9:3 Ͻ0.05 was not performed (at months 3 and 6) in BMI (kg/m2) 20.1 Ϯ 1.0 23.1 Ϯ 0.9 Ͻ0.05 the patients who developed PTDM re- Family history of diabetes* 1/9 (11.1%) 3/12 (25.0%) NS quiring insulin or oral antidiabetic ther- Systolic blood pressure (mmHg) 144 Ϯ 3 140 Ϯ 6NSapy (n ϭ 4). All tests were performed in Diastolic blood pressure (mmHg) 86 Ϯ 380Ϯ 3NSthe morning after an overnight fast, and Fasting plasma glucose (mmol/l) 4.9 Ϯ 0.3 5.6 Ϯ 0.2 Ͻ0.05 the blood pressure, height, and weight Ϯ Ϯ HbA1c (%) 5.0 0.2 4.8 0.3 NS were measured before OGTT of each visit. Ϯ Ϯ Fasting plasma C-peptide (nmol/l) 2.4 0.6 2.3 0.2 NS The HbA1c, HLA type, anti-hepatitis C vi- Fasting plasma insulin (pmol/l) 55.8 Ϯ 35.2 80.4 Ϯ 18.9 Ͻ0.05 rus (HCV) antibody, total cholesterol, tri- HOMA-IR 2.5 Ϯ 1.7 3.5 Ϯ 0.9 Ͻ0.05 glyceride, and HDL cholesterol levels HOMA-BC 95.5 Ϯ 36.3 121.5 Ϯ 27.7 NS were measured by routine assays in the Insulinogenic index 2.3 Ϯ 1.4 5.8 Ϯ 4.5 NS Department of Clinical Pathology at Seoul Total cholesterol (mmol/l) 4.1 Ϯ 0.3 4.1 Ϯ 0.1 NS National University Hospital. The LDL Triglycerides (mmol/l) 1.1 Ϯ 0.1 1.6 Ϯ 0.3 NS cholesterol level was calculated by Friede- HDL cholesterol (mmol/l) 1.1 Ϯ 0.1 1.1 Ϯ 0.1 NS wald’s equation. The fasting plasma insu- LDL cholesterol (mmol/l) 2.5 Ϯ 0.2 2.3 Ϯ 0.2 NS lin and C-peptide levels were determined Data are means Ϯ SEM unless otherwise indicated. *Family history of clinical diabetes in a first-degree by radioimmunoassay (BioSource Europe relative. NS, not significant. S.A., Nivelles, Belgium) in a single large batch. Using the plasma glucose and insulin rather than insulin resistance (24,25). ceived a renal allograft from a living- data obtained from the OGTT, the ho- Thus, tacrolimus-based immunosuppres- related donor, and 3 patients received an meostasis model assessment of insulin re- sion, which causes ␤-cell toxicity and allograft from their spouse. Patients sistance (HOMA-IR) and ␤-cell function subsequent insulin secretory defects, may undergoing cadaver-donor kidney trans- (HOMA-BC) were calculated (26). The exert more detrimental effects in the Ko- plantation were not included. The insulinogenic index, which has been rean population. primary causes of renal failure were hy- demonstrated to show an excellent corre- In this background, we examined the pertension (n ϭ 3), IgA nephropathy (n ϭ lation with acute insulin response (27), incidence and clinical characteristics of 3), glomerulonephritis (n ϭ 2), systemic was used to estimate the early insulin se- PTDM defined by ADA criteria in the Ko- lupus erythematosus (n ϭ 2; they did not cretion using OGTT data. rean patients receiving tacrolimus-based take glucocorticoids at the time of trans- immunosuppression after kidney trans- plantation, because their disease was clin- Definition plantation. ically inactive), Alport’s syndrome (n ϭ In this study, the ADA criteria were used 1), solitary kidney (n ϭ 1), and an un- to diagnose PTDM. Briefly, the symptoms RESEARCH DESIGN AND known primary pathology (n ϭ 9). No of typical diabetes plus casual plasma glu- METHODS cose concentration Ն11.1 mmol/l, fasting patient tested positive for anti-GAD anti- plasma glucose (FPG) Ն7.0 mmol/l with bodies. Subjects no calorie intake for at least 8 h, or 2-h The following criteria were used to deter- plasma glucose during an OGTT (2-h PG) mine which patients were eligible to par- Ն11.1 mmol/l was defined as PTDM. In Immunosuppression ticipate in the study: age 18 years or older, addition, impaired fasting glucose (IFG) recipients of a kidney allograft, no known The immunosuppressive regimen con- and impaired glucose tolerance (IGT) history of clinical diabetes, no current use sisted of tacrolimus and glucocorticoid in were defined as FPG Ն6.1Ͻ7.0 mmol/l of steroids or other immunosuppressive all patients. The initial tacrolimus dose and 2-h PG Ն7.8 Ͻ11.1 mmol/l, agents, and no previous history of organ was 0.075 mg/kg body wt given twice respectively.