Abstract
Cyclosporine A (CsA) and tacrolimus have been associated with an increased risk for diabetes after transplantation, whereas sirolimus is deemed to be devoid of any effect on glucose metabolism. This study was performed to investigate the effect of the withdrawal of calcineurin inhibitors and the switch to sirolimus on peripheral insulin resistance and pancreatic β cell response. Twenty-six patients who received a kidney transplant and discontinued CsA and were converted to sirolimus and 15 recipients of suboptimal kidneys who were treated with tacrolimus plus sirolimus for the first 3 mo after grafting and thereafter with sirolimus alone were enrolled. All patients underwent an oral glucose tolerance test and intravenous insulin tolerance test before and 6 mo after the conversion to sirolimus-alone therapy. The withdrawal of CsA or tacrolimus was associated with a significant fall of insulin sensitivity (both P = 0.01) and with a defect in the compensatory β cell response, as measured by the disposition index (P = 0.004 and P = 0.02, respectively). The increase of insulin resistance and the decrease of disposition index significantly correlated with the change of serum triglyceride concentration after the conversion to sirolimus-based therapy (R2 = 0.30, P = 0.0002; and R2 = 0.19, P = 0.004, respectively). Clinically, the switch to sirolimus was associated with a 30% increase of incidence of impaired glucose tolerance and with four patients’ developing new-onset diabetes. In conclusion, the discontinuation of calcineurin inhibitors and their replacement by sirolimus fail to ameliorate the glycometabolic profile of kidney transplant recipients. Rather, it is associated with a worsening of insulin resistance and an inappropriately low insulin response.
Posttransplantation diabetes is increasingly recognized as a serious complication of solid organ transplantation that can adversely affect the survival of the transplant recipient, long-term survival of the graft, and the patient’s quality of life (1–4). Posttransplantation diabetes is believed to be multifactorial, probably involving β cell toxicity and increased insulin resistance (5,6). In addition to other risk factors, studies suggest that immunosuppressive regimens may account for a large degree of the increased risk for development of posttransplantation diabetes (1,3,4,7). However, currently used immunosuppressive therapies vary in the extent to which they induce diabetes; thus, the choice of immunosuppressive therapy can have a major influence on patients’ risk for developing the condition. In the analysis performed by Montori et al. (3), the type of immunosuppressive regimen used was found to explain 74% of the variability in incidence, with high-dose steroids being associated with the highest incidences. Aside from steroids (8), the calcineurin inhibitors (CNI) are associated with an increased risk for diabetes after transplantation, the risk being higher for tacrolimus than for cyclosporine A (CsA) (3,4,9).
The recent availability of potent nonnephrotoxic immunosuppressive drugs such as mycophenolate mofetil (MMF) and sirolimus has provided the impetus for protocols designed to minimize exposure to CNI or steroids (10–12). The results of large clinical trials have shown that diabetes was not increased when sirolimus was added to CsA and corticosteroids (13,14). Similarly, studies in which sirolimus was compared with CsA showed a similar incidence of posttransplantation diabetes (15,16). In the above studies, however, posttransplantation diabetes was defined only by the patient’s requirement for insulin without the use of oral glucose tolerance tests (OGTT) to determine the exact incidence of glycemic abnormalities. Thus, our study was designed to investigate the impact of the conversion from CNI to sirolimus on glucose metabolism, insulin action, and insulin release in adult kidney transplant recipients by using OGTT and intravenous insulin tolerance test (ITT).
Materials and Methods
This prospective study enrolled two different groups of kidney transplant recipients.
Group 1
Starting from January 2002 and up to June 2004, all CsA-treated patients who received the histologic diagnosis of chronic allograft nephropathy (CAN), with serum creatinine (sCr) levels <2.5 mg/dl and daily proteinuria ≤1.0 g, were asked to be converted to sirolimus, without any further modification of the remaining immunosuppressive therapy (low-dose steroids [prednisone 2.5 to 5 mg/d] and MMF [1 to 2 g/d]). Collectively, 32 patients were enrolled. During the follow-up, one patient developed posttransplantation lymphoproliferative disease, one patient had an acute rejection episode and progressed to end-stage kidney disease, three patients discontinued sirolimus because of serious side effects, and one declined consent, leaving a total of 26 patients to be included in the follow-up study.
The conversion protocol consisted of an abrupt CsA discontinuation. Sirolimus therapy was initiated 12 to 16 h after stopping the CNI. All recipients received a single oral loading dose of sirolimus (8 mg for patients who weighed <60 kg and 10 mg for those who weighed >60 kg), followed by a daily maintenance dose of 5 mg. Whole-blood sirolimus trough concentration first was measured on the fifth day after the conversion, and sirolimus daily dose was modified to achieve target trough levels of 8 to 12 ng/ml.
Group 2
In the same period, at our center, renal transplant recipients of suboptimal kidneys (17) received an immunosuppressive protocol that comprised tacrolimus (target trough 6 to 8 ng/ml), sirolimus (target trough 4 to 8 ng/ml), and low-dose steroids for the first 3 mo after grafting. Thereafter, patients underwent abrupt discontinuation of tacrolimus, whereas sirolimus daily dose was increased to achieve target trough levels of 8 to 12 ng/ml. Collectively, 15 consecutive patients were recruited.
In both groups, exclusion criteria were age <18 or >60 yr, the diagnosis of diabetes before transplantation or at the moment of CNI discontinuation (according to American Diabetes Association/World Health Organization [ADA/WHO] criteria) (18), significant coexisting severe disease (cardiac or liver), the coexistence of any disease that may affect glucose metabolism, or the absolute need for drugs that are known to interfere with glucose metabolism (e.g., β blockers, diuretics). All patients were asked to give their written informed consent to participate in the study, according to the Guidelines of the Local Ethical Committee. Control values for OGTT-derived measures and for ITT were obtained from 70 healthy subjects, matched for age (42.8 ± 10.4 versus 46.9 ± 10.6 yr), gender (24 female/46 male versus 13 female/28 male), body mas index (BMI; 24.8 ± 2.8 versus 24.25 ± 4.28 kg/m2), and positive family history (first-degree relatives: 8.5 versus 7.5%).
Study Protocol
All patients underwent extended (180 min) 75-g OGTT and short ITT, after a 12-h overnight fast, immediately before and 6 mo after the discontinuation of CNI.
OGTT.
Blood samples were taken at 0, 30, 60, 120, and 180 min after the ingestion of glucose for assays of glucose and immunoreactive insulin. According to ADA/WHO criteria, the recipients were divided into four different categories of glucose tolerance: Posttransplantation diabetes with fasting serum glucose (FSG) ≥7.0 mmol/L and/or 2-h serum glucose ≥11.1 mmol/L; impaired glucose tolerance (IGT) with 2-h glucose 7.8 to 11.0 mmol/L; impaired fasting glucose (IFG) with FSG 6.1 to 6.9 mmol/L; and normal glucose tolerance (NGT) with FSG <6.1 mmol/L and 2-h serum glucose <7.8 mmol/L (18).
ITT.
The patients rested in the supine position for at least 30 min before the test. The test then was started with an intravenous bolus dose (0.1 U/kg) of human soluble insulin. Blood samples for blood glucose determinations were taken before the start of the test and then at 3, 6, 9, 12, and 15 min. Thereafter, 250 ml of a 10% glucose solution was infused quickly to block the insulin hypoglycemic effect. Immunosuppressive drugs were ingested after completion of the tests.
All patients had anthropometric and laboratory parameters (comprising urinalysis, sCr, blood urea nitrogen, and lipid profile) checked at baseline and at the end of the study (6 mo). CsA exposure was monitored by the measurement of whole-blood CsA level obtained 2 h after the morning dose (C2); tacrolimus and sirolimus exposure was evaluated by predose (trough) monitoring.
Insulin Sensitivity Indexes
The OGTT-derived insulin sensitivity index for transplantation (ISITX; 0.208 to 0.0032 × BMI [kg/m2] − 0.0000645 × Ins120 [pmol/L] − 0.00375 × Gluc120 [mmol/L]) has been proposed and validated by Hjelmesæth et al. (19) against the gold standard method, the hyperinsulinemic-euglycemic glucose clamp, in a renal transplant population and turned out to correlate best with ISIclamp. ISI was measured also by the ITT. It was derived from linear regression of the rate of the fall of log glucose from 3 to 15 min and calculated from the equation KITT = 0.693/t1/2 × 100 (%/min). Previous studies have found coefficient of variation values for ITT between 6 and 9% and a close relationship between insulin sensitivity as measured by ITT and that measured by the euglycemic-hyperinsulinemic clamp method (20). Finally, we estimated the metabolic clearance rate (MCR) of glucose by the formula MCR (ml × kg−1 × min−1) = 19.24 to 0.281 × BMI − 0.00498 × Ins120 − 0.333 × Gluc120 validated against the hyperinsulinemic-euglycemic glucose clamp (21).
β Cell Function
Insulin release was estimated by the use of three equations documented to correlate well (r = 0.70 to 0.75) with insulin secretion as assessed by hyperglycemic clamp studies in patients with varying degrees of glucose tolerance (21). The area under curve (AUC) insulin and the AUC glucose during the OGTT were calculated using the trapezoid rule and implemented in the insulin release index: SecrAUC = AUCIns/AUCGluc (21)
The first-phase and second-phase insulin releases were estimated implementing insulin values at 0 and 60 min and glucose at 60 min (21): 
The acute insulin secretory response increases with decreasing insulin action to maintain NGT, and the relationship between insulin release and insulin sensitivity has been described as hyperbolic (22). The product of the estimates of insulin sensitivity and insulin release, known as the disposition index (DI), is a constant in normoglycemic individuals, whereas the development of glucose intolerance is associated with a decline of the DI (22). In other words, the DI describes the ability of the pancreatic β cell to compensate for various degrees of insulin resistance and therefore may represent a more appropriate measure of β cell function than the absolute insulin release (22). In this study, the DI was estimated as the product of the first-phase insulin release and the ISITX (23).
Statistical Analyses
Results of quantitative variables are expressed as mean ± SD. Differences between quantitative variables were tested by means of Wilcoxon rank test or Mann-Whitney U test, as appropriate. Correlations between nonparametric quantitative variables were evaluated by Spearman rank correlation. Differences between qualitative (categorical) variables were tested by McNemar test for paired comparisons. P < 0.05 is considered statistically significant. The Statview software package (version 5.0; SAS Inc., Chicago, IL) was used for all analyses.
Kidney graft function was evaluated using sCr levels and calculated creatinine clearance (CrCl; Cockcroft-Gault formula). Mean CsA levels represent the mean of six measures recorded during the 6 mo preceding the discontinuation of the CNI. Mean tacrolimus levels are the mean of six measures recorded every other week for the first 3 mo after engraftment, up to the discontinuation of the CNI. Whole-blood sirolimus trough levels were measured every other week in the first 3 mo after renal transplant, then at monthly intervals up to the end of the study (6 mo).
Results
Throughout the follow-up, care was taken to avoid any major modification of pharmacologic therapy. Specifically, no patient required the use of β blockers or diuretics, and the daily steroid dose was not modified in any of the patients. As for antihypertensive drugs, a few patients required the decrease of drug therapy (calcium channel blockers and/or angiotensin-converting enzyme inhibitors), whereas none required de novo prescription of antihypertensive therapy. None of the patients studied had an acute rejection episode or clinically relevant infections throughout the follow-up period. The anthropometric and laboratory features of patients at the start and end of the study are shown in Table 1.
Anthropometric and laboratory features of the patients examined at the start and end of the studya
OGTT
In group 1 patients, the withdrawal of CsA and the conversion to sirolimus failed to modify blood glucose and insulin response to oral glucose load (Figure 1). Patients of group 2 showed a significant increase of 2-h blood glucose and insulin concentration 6 mo after the discontinuation of tacrolimus and the switch to full-dose sirolimus (Figure 2).
Glucose and insulin response to 75-g oral glucose tolerance test (OGTT) in 26 renal transplant recipients who were being treated with cyclosporine A (CsA)-based immunosuppression (solid lines) and 6 mo after the discontinuation of the calcineurin inhibitor (CNI) and the conversion to sirolimus (dashed lines). Data are expressed as mean ± SD. The shaded area indicates the normal range, measured in 70 healthy control subjects who were matched for age, gender, and body mas index (BMI).
Glucose and insulin response to 75 g OGTT in 15 renal transplant recipients who were taking low-dose tacrolimus and sirolimus (solid lines) and 6 mo after the discontinuation of tacrolimus and the conversion to full-dose sirolimus (dashed lines). Data are expressed as mean ± SD. The shaded area indicates the normal range, measured in 70 healthy control subjects who were matched for age, gender, and BMI. *P = 0.03.
ISI
ISITX.
According to the OGTT-derived ISITX, which allows for 2-h glucose and insulin concentration along with patient’s BMI, CsA- but not tacrolimus-treated patients had an impaired insulin sensitivity, when compared with control healthy subjects (Figure 3, top). The discontinuation of CNI and the switch to sirolimus-based therapy was associated with a significant decrease of insulin sensitivity in both groups of patients (Figure 3, top).
Insulin sensitivity of renal transplant recipients, while taking CNI-based immunosuppression, and 6 mo after the discontinuation of CsA or tacrolimus and the conversion to sirolimus-based immunosuppression. ISITx, insulin sensitivity index, based on OGTT-derived measures; KITT, insulin sensitivity index, measured via intravenous insulin tolerance test; SRL, Sirolimus; TAC, tacrolimus (+low-dose sirolimus). *P < 0.0001 versus renal transplant recipients examined, regardless of their immunosuppressive regimen.
KITT.
Both CsA- and tacrolimus-treated patients showed an impaired insulin sensitivity at the intravenous test, when compared with control healthy subjects (Figure 3, bottom). The withdrawal of CNI caused a further significant decrease of insulin sensitivity in both groups of patients (Figure 3, bottom).
MCR.
After 6 mo of therapy with sirolimus, the MCR of glucose decreased significantly in both groups of patients (Table 2).
Evaluation of glucose metabolism, insulin resistance, and β cell function in the two groups of patients studied, while taking CNI (CsA or TAC) and 6 months after the discontinuation of CNI and the conversion to SRL-based immunosuppressiona
β Cell Function
CsA-treated patients displayed an increased insulin response, as measured by both first- and second-phase insulin release and SecrAUC, in comparison with healthy controls, whereas patients who were taking tacrolimus+sirolimus (low dose) did not show any difference with control subjects (Table 2). The withdrawal of CNI did not significantly modify any of the above measures.
DI.
The DI can be envisioned as a measure of the ability of the β cells to compensate for insulin resistance. The assertion of the foregoing is that the earliest phenotypic β cell defect that may be detected in otherwise glucose-tolerant individuals is a reduced DI.
Renal transplant recipients who were taking CNI, with or without low-dose sirolimus, had an overall normal DI (Table 2), thereby suggesting an adequate feedback loop between the insulin-sensitive tissues and the β cell response. In sharp contrast, patients who were on sirolimus-based immunosuppression showed a brisk decrease of DI (Table 2). Thus, when the effect of insulin sensitivity on β cell function is accounted for, a seemingly appropriate insulin response in fact was to be considered inappropriately low in the face of insulin resistance.
Stratification of Patients According to ADA/WHO Criteria for Classification of Disturbances of Glucose Metabolism
The combined use of FSG and OGTT allowed us to enlarge and refine the diagnosis of the defects of glucose metabolism. At baseline, 18 (43.9%) patients had IFG and 13 (31.7%) showed IGT. The conversion to sirolimus seems to have worsened glucose homeostasis: The proportion of IGT patients rose to 41.5% (17 patients) and four patients developed posttransplantation diabetes (two patients for each group), 17 recipients showing IFG (P = 0.009, by McNemar test for paired comparisons). Of note, FSG identified only two of four patients with 2-h blood glucose ≥11.1 mmol/L.
Correlations between Variables
We first sought a relationship between sirolimus exposure and glucose homeostasis. Mean sirolimus trough levels resulted to correlate weakly with the change of insulin sensitivity (Δ-KITT ρ = −0.330, P = 0.04), as well as with Δ-first phase insulin release (ρ = −0.361, P = 0.02). Then, the changes in the parameters of glucose metabolism failed to correlate with the change of either sCr or CrCl over the follow-up period (data not shown).
Finally, because abnormalities of triglyceride storage and increased free fatty acid flux have been shown to lead to impaired insulin sensitivity and impaired pancreatic β cell function (24), we wondered whether the change of serum triglyceride after the conversion to sirolimus would correlate with the change in the parameters of glucose metabolism. Increasing triglycerides correlated strongly with decreasing insulin sensitivity and explained nearly one third of the variability in KITT after sirolimus therapy (Figure 4). Similarly, a positive change in serum triglyceride was associated with a decrease of β cell response, as measured by the change of DI (Figure 4).
Relationship between the change of serum triglyceride concentration (Δ triglyceride) and the change of insulin resistance (Δ KITT; top; R2 = 0.30, P = 0.0002), as well as the change in β cell response (Δ Disposition Index; bottom; R2 = 0.19, P = 0.004).
Discussion
The mammalian target of rapomycin (mTOR) pathway is emerging as a critical player in the cause of metabolic diseases, including diabetes and obesity. The major targets of mTOR seem to be components of the translation machinery, and it has been suggested that defects in translation control may contribute to the cause of human diabetes (25). Then, the model of S6 kinase 1 (S6K1)-deficient mouse has uncovered the role of this crucial downstream target of mTOR, in the regulation of insulin sensitivity and of β cell size (26). Thus, mTOR and S6K1 have emerged as attractive new therapeutic targets in insulin resistance and type 2 diabetes (25–27).
The main finding of the study presented here is that the withdrawal of CNI and the conversion to the mTOR inhibitor sirolimus fails to ameliorate glucose homeostasis. Rather, chronic treatment with sirolimus strongly reduces insulin sensitivity, and this may be associated with a defect in the compensatory β cell response.
Posttransplantation glucose intolerance or overt diabetes results from a combination of insulin resistance and dysfunctional insulin secretion, as in the general population. However, the relative contribution of either mechanism may vary largely among patients, in relation with a series of pathogenetic factors, such as age, BMI, ethnicity, time from transplant, lipemic profile, drugs (e.g., antihypertensive medications, diuretics), and use of different immunosuppressive regimens. Among immunosuppressants, steroids have long been recognized to potently affect glucose tolerance by a prevalent increase of peripheral insulin resistance. However, daily prednisone doses as low as 5 mg, as in the patients studied here, may not influence insulin sensitivity at all (8). CNI seem to have a different diabetogenic mechanism from steroids, with dysfunctional insulin release being more prominent than insulin resistance (5,28–30).
The serine-threonine kinase mTOR plays a key role in the insulin signaling cascade. Thus, sirolimus has the potential to affect strikingly glucose metabolism. Some in vitro evidence would support the above assertion. A sirolimus-sensitive pathway, most likely acting via P70 S6K, has been implicated in the regulation of glycogen synthase kinase 3 and glycogen synthase and in the inactivation of phosphorylase by insulin (31,32). Moreover, sirolimus has been shown to abrogate the insulin-mediated increase in GLUT1 protein synthesis, thereby possibly modulating also insulin-independent glucose transport (33) mTOR and P70 S6K signal transduction pathways also have been shown to control β cell size and proliferation and insulin release; in this way, the inhibition of P70S S6K activation by sirolimus might contribute to the onset and development of “insulin resistance” in the β cell (34–36). Finally, Andoh et al. (37) reported that subtherapeutic doses of sirolimus were able to induce glucose intolerance in a rat model of CsA nephrotoxicity and that the addition of CsA strikingly worsened glucose intolerance and the degree of insulin deficiency.
Large clinical trials did not reveal any increase in the incidence of posttransplantation diabetes among patients who were treated with sirolimus (13–16), either alone or in combination with CNI, although recent investigations have challenged this conclusion (38,39). In the above studies, however, posttransplantation diabetes has been defined and recognized only by the patient’s requirement for insulin. As a matter of fact, none of these clinical trials has routinely included OGTT to determine the exact incidence of glycemic abnormalities in renal transplant recipients who are treated with the mTOR inhibitor. Like type 2 diabetes, the onset of posttransplantation diabetes can be insidious, and individuals may be asymptomatic for years before symptoms manifest clinically (1,7). Available evidence from the general population suggests that OGTT levels may be more predictive of an increased risk for cardiovascular disease than the FSG test, especially in individuals with IGT (40–42). A recent analysis has shown that not only overt diabetes but also FSG >100 mg/dl (5.6 mmol/L) were associated with higher incidence of posttransplantation cardiac and peripheral vascular disease events, thus supporting the need for aggressive detection and treatment of posttransplantation hyperglycemia (43). Finally, insulin resistance is associated with an increased risk for myocardial infarction and other clinical cardiovascular events, even in patients who do not have hyperglycemia (44).
After the conversion to sirolimus-based immunosuppression, we identified >40% of IGT patients who had a 30% increase of incidence compared with pretreatment values. Our data show that if fasting blood glucose alone had been used, then 30% of patients with isolated IGT would have received a diagnosis of having normal glucose tolerance. Four patients had 2-h blood glucose levels compatible with the diagnosis of posttransplantation diabetes, only two of them showing fasting glucose levels >7 mmol/L. Finally, 36 of 41 patients displayed an increase of insulin resistance.
Rather unexpected, we found a deterioration of glucose metabolism even among patients who discontinued tacrolimus and were converted to full-dose sirolimus. None of the patients experienced acute rejection or other acute events, such as infection, potentially responsible for the worsening of glucose metabolism; neither was there a deterioration of graft function, which slightly improved. Moreover, it has been demonstrated that long-term use of tacrolimus does not cause chronic, cumulative pancreatic toxicity (30); therefore, an adverse and cumulative effect of the CNI persisting over time, even months after its withdrawal, seems unlikely. Thus, the simplest explanation that we can raise is that full-dose sirolimus (mean trough 11.4 ng/ml) is more “diabetogenic” than a combination of low-dose tacrolimus (trough 6.1 ng/ml) plus low-dose sirolimus (trough 5.2 ng/ml). It may be of interest that a pharmacodynamic study in our laboratory has revealed that tacrolimus hampers the inhibitory effect of sirolimus on P70 S6 kinase in circulating mononuclear cells, which might help to explain the lower diabetogenic impact of low-dose tacrolimus+sirolimus, as compared with full-dose sirolimus (S.D.P. et al., unpublished data).
Previously, an in vitro study had suggested that sirolimus may partially decrease insulin resistance induced by chronic insulin exposure of 3T3-L1 adipocytes, by preventing the reduction of IRS-1 protein levels and Akt Ser-473 phosphorylation, with a partial normalization of insulin-induced glucose transport (45). Although the molecular mechanisms that cause insulin resistance in humans are largely unknown, we may suppose that in vivo several interfering factors may affect the intracellular machinery that is responsible for the response to the hormone. Sirolimus alters the insulin signaling pathway so as to increase adipose tissue lipase activity and/or decrease lipoprotein lipase activity, resulting in in vivo increased hepatic synthesis of triglyceride, increased hypertriglyceridemia, and expanded free fatty acid pool (46). Free fatty acids, in turn, deteriorate peripheral insulin sensitivity and pancreatic β cell function, leading to impaired glucose metabolism (24). Accordingly, we found that the change of insulin resistance and β cell response of renal transplant recipients who were taking sirolimus significantly correlated with the increase in serum triglyceride levels. Obviously, our study does not allow us to rule out that, conversely, increased triglycerides are the consequence, rather than the cause, of insulin resistance and inadequate insulin release.
A possible limitation of our study should be discussed, namely the use of a clinic sample with mild renal impairment, which might limit the generalizability of the conclusions to the majority of renal transplant recipients. A recent analysis of patients with varying degrees of renal function impairment demonstrated increased plasma glucose and insulin response to oral glucose load and reduced sensitivity to insulin only in patients with CrCl <50 ml/min (47), although previous research suggested that abnormal glucose metabolism may be part of the phenotype of some renal diseases, independent of renal function (48). More important, neither study was able to find any correlation between CrCl and parameters of glucose metabolism (47,48). In the cohort studied here, the conversion to sirolimus was associated with only a slight modification of renal function (Table 1), and the change of insulin resistance and β cell response failed to correlate with the change of sCr or CrCl. Thus, we infer that renal impairment likely may have affected parameters of glucose metabolism, as observed at the start of the study, whereas it would hardly explain the further derangement of glucose homeostasis after the conversion to sirolimus.
In conclusion, the results of this study suggest that the mTOR inhibitor sirolimus increases peripheral insulin resistance and impairs pancreatic β cell response and thus possibly worsens glucose homeostasis in renal transplant recipients. These findings support the need for an extensive monitoring of blood glucose levels, both fasting and postload, in all renal transplant recipients.
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
- © 2005 American Society of Nephrology
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