Insulin Resistance after Renal Transplantation: The Effect of Steroid Dose Reduction and Withdrawal KARSTEN MIDTVEDT,* JØRAN HJELMESÆTH,* ANDERS HARTMANN,* KIRSTEN LUND,* DAG PAULSEN,* THORE EGELAND, † and TROND JENSSEN* *Section of Nephrology, Department of Medicine, and † Biostatistics, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway. Abstract. Cardiovascular disease is a prevalent and serious com- plication after solid organ transplantation. Treatment with glu- cocorticoids is associated with increased risk for diabetes mellitus, insulin resistance, weight gain, hypercholesterolemia, and hyper- tension, all shown to be independent risk factors for cardiovascu- lar disease. We sought to test the hypothesis that tapering of prednisolone (TAP) the first year after renal transplantation im- proves insulin sensitivity (IS), and to assess the effect of complete steroid withdrawal (SW) on IS in patients on a cyclosporine-based immunosuppressive regimen. All patients (n = 57) completed two consecutive hyperinsulinemic euglycemic glucose clamp proce- dures, a TAP group (n = 34) and a control group (n = 12) at 3 and 12 mo after transplantation, and a SW group (n = 11) before and 5 mo after SW. The IS index (ISI) was calculated as the glucose disposal rate divided by mean serum insulin the last 60 min of the clamp. In the TAP group, the mean (range) daily prednisolone was reduced from 16 (10 to 30) to 9 (5 to 12.5) mg accompanied by an average increased ISI of 24% (P = 0.008). In contrast, no significant change in ISI was observed in the control group (0%, P = 0.988). In the SW group, withdrawal of 5 mg prednisolone did not influence mean ISI significantly (-8%, P = 0.206). Lowering daily prednisolone toward 5 mg/d has beneficial effects on insulin action after renal transplantation, but withdrawal of 5 mg prednisolone may not influence IS significantly. The success of renal transplantation in extending patient and graft survival has uncovered an increased risk of cardiovascu- lar disease (CVD) in allograft recipients. At present, glucocor- ticoid drugs are included in most immunosuppressive protocols used after organ transplantation. Treatment with glucocorti- coids is associated with increased risk for diabetes mellitus, insulin resistance, weight gain, hypercholesterolemia, and hy- pertension, all independent risk factors for CVD (1–5). During the last 50 yr, the term “steroid diabetes” has been used to characterize the type of diabetes that may develop in humans treated with glucocorticoids (6,7). More specifically, corticosteroid-induced diabetes may be considered a part of the group IIIE, drug- or chemical-induced diabetes, as suggested by the American Diabetes Association Expert Committee (8). The diabetogenic effect of glucocorticoids is primarily caused by insulin resistance that has been explained by enhanced gluconeogenesis in the liver and decreased glucose uptake and glycogen synthesis in skeletal muscle cells (1,2). We have previously reported that posttransplantation diabe- tes mellitus occurs in up to 20% of renal transplant recipients receiving a cyclosporine A (CsA, Neoral) based triple immu- nosuppressive regimen, and even more patients (30%) have impaired glucose tolerance (9). Moreover, data from two pro- spective observational studies indicate that tapering of daily prednisolone is associated with improved glucose tolerance, whereas long-term improvement of glucose tolerance is asso- ciated with enhanced insulin sensitivity (IS) (10,11). Ekstrand et al. (12) have shown that even renal transplant recipients with normal glucose tolerance are insulin resistant when compared with control subjects from the general popu- lation. The mean total glucose disposal during a hyperinsuline- mic euglycemic glucose clamp (HEC) was 25% lower in normoglycemic kidney transplant recipients treated with 8.2  1.5 mg methylprednisolone/d than in age- and weight-matched healthy control subjects. Weight gain is common after renal transplantation (13–15) and may represent an important and modifiable risk factor for impaired insulin action and the development of diabetes (4). In a cross-sectional study of 167 patients, we reported that daily prednisolone dose, body mass index (BMI), and triglyceride (TG) concentrations were independent predictors of insulin resistance 3 mo after renal transplantation (16). In a 6-yr follow-up study, decreasing daily prednisolone dose from a median of 10 to 5 mg was independently associ- ated with improved IS (11). An oral glucose tolerance test– derived IS index (ISI Tx ) was used to assess IS in our previous studies (11,16). It is well known that treatment with calcineurin inhibitors, tacrolimus and CsA, increases the risk for new-onset posttrans- plantation diabetes mellitus. Recently, van Duijnhoven and coworkers (17) evaluated glucose metabolism in patients re- ceiving tacrolimus or CsA the first 3 yr after transplantation but did not address changes in prednisolone dose specifically. In Received June 10, 2004. Accepted August 24, 2004. Correspondence to Dr. Jøran Hjelmesæth, Department of Medicine, The Hos- pital in Vestfold HF, Boks 2168, 3103 Tønsberg, Norway. Phone: +47 40 21 73 49; Fax: +47 33 34 39 38; E-mail: joran@online.no 1046-6673/1512-3233 Journal of the American Society of Nephrology Copyright © 2004 by the American Society of Nephrology DOI: 10.1097/01.ASN.0000145435.80005.1E J Am Soc Nephrol 15: 3233–3239, 2004