Cellular and physiological mechanisms of new-onset diabetes mellitus after solid organ transplantation


Y. C. Kudva, 200 First Street SW, Rochester, MN 55902, USA.
E-mail: kudva.yogish@mayo.edu


Diabet. Med. 29, e1–e12 (2012)


New-onset diabetes after transplantation is recognized as one of the metabolic consequences which may increase the risk of morbidity and mortality after solid organ transplantation. The pathophysiology of new-onset diabetes after transplantation has not been clearly defined and may resemble that of Type 2 diabetes, characterized by predominantly insulin resistance or defective insulin secretion, or both. This review aims to summarize the current state of knowledge regarding the prevalence, consequences, pathogenesis, and management of new-onset diabetes after transplantation, with a major focus on the possible mechanisms involved in the pathogenesis of the disorder. The aetiology of new-onset diabetes after transplantation is multifactorial, with diabetogenic immunosuppressive drugs playing a major role. Multiple cellular and physiologic mechanisms are involved in the process. Selection of an appropriate maintenance immunosuppressive regimen should involve balancing the risk of patient and graft survival vs. the potential for new-onset diabetes after transplantation.


With the extensive improvements in multiple medical technologies including the development of modern immunosuppressive agents and protocols, patient survival after solid organ transplantation continues to improve. New-onset diabetes after transplantation (NODAT) may increase the risk of morbidity and mortality after solid organ transplantation, especially with longer survival times. While previously referred to as post-transplantation diabetes mellitus, NODAT is the preferred current term. An international expert panel consisting of experts from the solid organ transplantation and diabetes fields published consensus guidelines in 2003 that the definition and diagnosis of NODAT should be based on American Diabetes Association or by the World Health Organization guidelines for diabetes mellitus and impaired glucose tolerance [1].

New-onset diabetes after transplantation is associated with several risk factors such as older age, non-white ethnicity, obesity, hepatitis C infection and immunosuppressive agents [2]. Among immunosuppressive agents, glucocorticoids and calcineurin inhibitors have the strongest association with NODAT. The pathophysiology of NODAT has not been clearly defined and may resemble that of Type 2 diabetes. It predominantly has insulin resistance, but may have defective insulin secretion, or both [2]. It is believed that NODAT has serious consequences, including reduced graft function and increased risk of cardiovascular morbidity and mortality [3]. This review aims to summarize the current state of knowledge regarding the prevalence, consequences, pathogenesis, and management of NODAT, with a major focus on the possible mechanisms involved in the pathogenesis of the disorder. We also discuss approaches that could decrease the risk of NODAT.

Incidence and outcomes of NODAT

The incidence of NODAT has continued to be a concern following solid organ transplantation. It has been reported to occur in 4–25% after kidney transplantation, 2.5–25% after liver transplantation and 2–53% after all kinds of solid organ transplantation [2]. The variation in the reported incidence may partly result from variable criteria used for the diagnosis of NODAT, before the publication of the International Expert Panel Consensus Guidelines [1]. Since then, it has been more comparable among different institutions and countries. Some studies have also reported the incidence of impaired glucose tolerance or impaired fasting glucose. Cosio et al. [3] reported NODAT prevalence of 13%, and impaired fasting glucose or impaired glucose tolerance prevalence of 33% 1 year after kidney transplantation. Figure 1 shows the most recent incidence of NODAT following kidney, liver and heart transplantation using the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) database from 2004 to 2008, with follow up of 1 year, 685 days and 713 days, respectively [4–6]. There are limited data about NODAT after lung transplantation. One recent study from Israel with 119 lung transplant recipients, reported development of NODAT in 23% patients 12 months after the procedure [1].

Figure 1.

 Incidence of new-onset diabetes after transplantation (NODAT) in kidney, liver, heart transplantation using the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) database from 2004 to 2008. Follow-up duration is different for the three different solid organ transplantation (SOT) cohorts.

New-onset diabetes after transplantation is a major independent risk factor for cardiovascular morbidity and mortality, and contributes to reduced graft and patient survival [2]. A prospective study involving 201 kidney transplantation recipients reported that compared with recipients without NODAT, the 8-year cumulative incidence of major cardiac events was significantly higher in patients with NODAT (20% vs. 7% and 63% vs. 80%, respectively) [1]. Similarly, increased morbidity and mortality has been reported in patients with NODAT after liver transplantation. It has been shown that the incidence of cardiac complications, major and minor infections, and acute rejection were significantly increased in patients with NODAT compared with a control group. Furthermore, the coexistence of NODAT and Hepatitis C virus (HCV) infection may represent a high-risk population [7]. Limited data are available regarding the impact of NODAT on outcomes after heart transplantation. Pham et al. [2] reported the significant association of coronary artery stenosis and death with hyperglycaemia in heart transplant recipients during a 5-year follow-up period. Therefore, the presence of NODAT confers an increased risk of cardiovascular disease and overall morbidity and mortality across all types of solid organ transplantation.

Risk factors and Pathogenesis of NODAT

Risk factors for the development of NODAT are summarized in Fig. 2. Whereas non modifiable risk factors are age, ethnicity and family history of type 2 diabetes, modifiable risk factors are obesity, HCV and cytomegalovirus (CMV) infections, glucocorticoid treatment and other immunosuppressive medications [2]. Furthermore, some risk factors play a role in specific solid organ transplantation. For example, high risk of NODAT was observed in renal transplant recipients with polycystic kidney disease and paediatric liver transplant recipients with cystic fibrosis [8,9]. Recent reports indicate that some gene polymorphisms may also be related to NODAT after solid organ transplantation [1]. These characteristics likely reflect inherited and acquired defects in insulin sensitivity and β-cell function that contribute to hyperglycaemia.

Figure 2.

 Risk factors for new-onset diabetes after transplantation (NODAT). CMV, Cytomegalovirus; HCV, Hepatitis C virus; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; MS, metabolic Syndrome

New-onset diabetes after transplantation shares several features with Type 2 diabetes. Insulin resistance and relative insulin deficiency are involved in the pathogenesis of both disorders. A hyperglycaemic clamp study of 24 renal transplant recipients showed that both inadequate insulin secretion and insulin resistance are necessary for the development of NODAT [7]. Multiple cellular and physiological mechanisms may be involved in the pathogenesis of NODAT (Fig. 3). In addition, the impact of insulin deficiency and insulin resistance may vary in the presence of different risk factors. We conducted a meta-analysis and concluded that that among risk factors predisposing to NODAT, the type of immunosuppressant accounted for 74% of the variability in the 12-month cumulative incidence of NODAT [10]. Therefore, we mainly address the mechanisms of causation of NODAT by glucocorticoids, calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors. We also discuss the mechanisms of NODAT caused by some potentially modifiable risk factors, such as HCV and CMV infection, and the role of genetic factors.

Figure 3.

 Brief summary of pathogenesis of immunosuppressive agents. Dotted lines indicate limited or no effect, or controversial results. Solid lines indicate significant effect. Thickness of the solid line is proportionate to severity of effect. NFAT, nuclear factor of activated T-cells; CREB, cAMP-response element-binding transcription factor; mTOR, mammalian target of rapamycin; NODAT, new-onset diabetes after transplantation.


Glucocorticoids are associated with the greatest risk of developing NODAT. An early study showed that 46% of 114 renal transplant recipients treated with high dose prednisone developed NODAT with a follow up of at least 1 year [11]. The diabetogenic effect of glucocorticoids is dose dependent, and a 0.01 mg/kg.day increase in prednisolone dose has been associated with a 5% risk of developing NODAT [12]. Some studies have attempted to determine the benefits of rapidly decreasing steroid dose after solid organ transplantation, and one of them found that prednisolone dose reduction from a mean of 16 mg daily (range 10–30 mg) to 9 mg (range 5–12.5 mg) resulted in an average increase in the insulin sensitivity index of 24% [13].

The predominant underlying mechanism is increased insulin resistance based on oral glucose tolerance testing [7]. However, the precise mechanisms of glucocorticoid-induced insulin resistance are not well understood. In vivo and in vitro animal studies have demonstrated that glucocorticoids interfere at several steps in the insulin signalling cascade in skeletal muscles, resulting in reduced glucose uptake and glycogen synthesis [14]. Skeletal muscle biopsies in renal transplant recipients exposed to long-term high-dose glucocorticoids showed reduced glycogen synthesis [2]. Increased endogenous glucose production, either directly by their impact on the genes involved in hepatic carbohydrate metabolism or indirectly by antagonizing insulin action may also be involved [14]. Moreover, glucocorticoid-induced insulin resistance is associated with its indirect adverse effects, such as weight gain, increased appetite and redistribution of body fat [7].

High-dose oral prednisolone may acutely impair insulin secretion during glucose infusion in healthy volunteers, suggesting an acute inhibitory effect on β-cells [12]. However, establishing direct effects of glucocorticoids on β-cells in vivo is challenging, as they may simultaneously cause other systemic metabolic abnormalities, such as increase in non-esterified fatty acids [14]. Several mechanisms have been reported using in vitro studies of murine or human β-cell lines. Glucocorticoids were shown to reduce the expression of GLUT 2 and glucokinase, thereby impairing glucose-stimulated insulin secretion[12]. Moreover, dexamethasone was reported to stimulate the transcription of serum and glucocorticoid-inducible kinase 1, upregulating the activity of voltage-gated K+ channels resulting in reduced Ca2+ entry through voltage-gated Ca2+ channels and decreased insulin release [15]. In isolated rat islets, dexamethasone decreases the activation of protein kinase C through inhibition of the diacylglycerol-phospholipase C pathway [16]. Glucocorticoids also increase expression of α2-adrenergic receptors leading to reduced cAMP and protein kinase A activity, and decreased insulin release [17]. Moreover, glucocorticoids may reduce islet mass as they induce apoptosis in mouse islets or INS-1 cells [14]. Figure 4 shows a schematic overview of the possible mechanisms involved.

Figure 4.

 Schematic of the mechanisms of glucocorticoid induced β-cell dysfunction. Glucocorticoids (GC) reduce the expression of GLUT2 (a) and glucokinase (GK) (b), resulting in reduced glucose uptake and phosphorylation, decreased ATP synthesis and Ca2+ influx and thus impaired insulin secretion. They may stimulate the transcription of serum and glucocorticoid inducible kinase-1 (SGK1), upregulating the activity of voltage-gated K+ channel, leading to reduced Ca2+ entry and decreased insulin release (c). Glucocorticoid decrease the activation of protein kinase C (PKC) through inhibition of the diacylglycerol–phospholipase C (DAG-PLC) pathway (d), reduce cAMP levels and protein kinase A (PKA) activity though increasing expression of α2-adrenergic receptors (e), thus impairing insulin secretion. The effect of glucocorticoids may be mediated by effects on transcription of the nuclear receptor subfamily 3, group C, member 1–glucokinase (NR3C1:GC) complex or effects of this complex on cytoplasmic proteins that regulate function of key proteins mentioned above such as GLUT-2, glucokinase, serum and glucocorticoid inducible kinase-1, phospholipase C, etc. AC, adenyl cyclase; Ach, acetylcholine; G6P, glucose-6-phosphatase; Gi, G-coupled inhibitory protein; IP3, inositol triphosphate; PIP2, phosphatidylinositol biphosphate;.

Calcineurin inhibitors

Calcineurin inhibitors, mainly cyclosporine and tacrolimus, have greatly improved the outcomes of solid organ transplantation and are the mainstay of maintenance immunosuppressive therapy. Unfortunately, both have been implicated in the development of NODAT. Several studies have shown a 15–30% striking incidence of NODAT with calcineurin inhibitor use [2]. However, the mechanisms are far from well understood. Figure 5 summarizes the possible mechanisms of tacrolimus (Fig. 5a) and cyclosporine (Fig. 5b).

Figure 5.

 Schematic of the mechanisms of calcineurin inhibitors induced β-cell dysfunction. (a) Tacrolimus (Tac). a. Calcineurin dephosphorylates nuclear factor of activated T cell (NFAT) proteins and transducer of regulated CREB (cAMP-responsive element-binding transcription factor) activity-2 (TORC2). Dephosphorylation of these proteins regulates several target genes [insulin, Glut2, (pancreatic and duodenal homeobox 1 (Pdx-1), insulin receptor substrate-2 (Irs2), cyclin D1, cyclin D2, cyclin-dependent kinase 4 (CDK4), etc.) which are critical in β-cell survival, replication and function. Tacrolimus is bound to FK506-binding protein 1B (FKBP1B) before docking in the calcineurin binding site (Cnb1) of calcineurin, thus inhibiting calcineurin and its downstream pathways and decreasing β-cell replication and survival. b. Tacrolimus may inhibit the expression of genes involved in cytoskeleton remodelling, membrane trafficking, ATP generation and mitochondrial biology to affect insulin secretion. c. Tacrolimus interferes with closing of the ATP-sensitive potassium channel thus impairing glucose-stimulated insulin secretion (GSIS). d. Tacrolimus decreases glucokinase activity thus reducing ATP production to impact glucose-stimulated insulin secretion. e. Tacrolimus has an impact on the effect of the rise of intracellular Ca2+ on insulin exocytosis. (b) Cyclosporine (CsA). a. Cyclosporine is bound to cyclophilin (Cyp) and forms a complex with calcineurin binding site, thus inhibiting calcineurin and its downstream pathways mentioned above. b. Cyclosporine may activate dual leucine-zipper-bearing kinase (DLK) to induce apoptosis through inhibiting calcineurin. c. Cyclosporine binds readily to cyclophilin D in the mitochondrial permeability transition pore and blocks the opening of this channel on the mitochondrion so as to reduce the cytoplasmic free-Ca2+ concentration thus interfering with glucose-stimulated insulin secretion. d. Cyclosporine interferes with closing of the ATP-sensitive potassium channel thus impairing glucose-stimulated insulin secretion.

Effects on β-cell survival and replication

Experiments in monkeys and mice have shown that enhanced proliferation of surviving β-cells plays a major role in spontaneous recovery from a diabetogenic injury; however, tacrolimus abolishes β-cell regeneration [18,19]. Calcineurin and its downstream signalling pathways are ubiquitous molecules with biological relevance in multiple tissues. In β-cells, the phosphatase activity of calcineurin has two well-described molecular targets: nuclear factor of activated T cell and cAMP response element-binding transcriptional co-activator, transducer of regulated cAMP response element-binding activity-2 (TORC2). Tacrolimus and cyclosporine bind to their respective cognate intracellular binding immunophilins FK506-binding protein 1B, and cyclophilin before docking with the calcineurin binding site, thus inhibiting calcineurin and its downstream pathways [20]. Experiments in transgenic mice demonstrated the importance of these two pathways in maintaining β-cell function and growth by regulating expression of several genes related to insulin synthesis and function or cell cycle regulation (Fig. 5) [20]. Administration of tacrolimus to male sprague dawley rats led to a time-dependent decrease in insulin transcription in islets which resolved upon drug cessation [7]. Experiments conducted on purified islets and insulin-producing β-cell lines have mirrored these effects. Therefore, inhibition of calcineurin may underlie NODAT caused by cyclosporine and tacrolimus by direct toxic effect through nuclear factor of activated T cell and/or CREB pathway(s). However, the underlying molecular mechanism is complicated and needs to be further elucidated. Plaumann et al. [21] demonstrated that cyclopsorine mediated inhibition of calcineurin activated the dual leucine-zipper-bearing kinase possibly through the cAMP response element-binding pathway, leading to β-cell apoptosis. Recently, tacrolimus was reported to decrease Akt phosphorylation, suggesting that calcineurin could regulate replication and survival via the PI3K/Akt pathway in both rodent and human islets. Its upstream regulator insulin receptor substrates (Irs)2 mRNA and protein were also decreased, which may be mediated by both nuclear factor of activated T cell and/or cAMP response element-binding [22].

Effects on insulin secretion and action

In vitro and in vivo studies have demonstrated that pharmacological calcineurin inhibition impairs insulin secretion and may be dose dependent [7]. A clinical study revealed that the inhibitory effect of tacrolimus on insulin secretion may be caused by high blood trough levels, and that lowering of trough level is associated with improved pancreatic β-cell function [23]. A recently published research even showed that β-cell secretory capacity was normal in pancreas-kidney and kidney transplant recipients receiving low-dose glucocorticoids (5 mg daily) and modern doses of tacrolimus (standard targets of 12-h blood trough levels were 6–10 ug/l) [24].

Whether insulin secretion is directly affected by tacrolimus inhibition is unclear. Calcineurin binding site-deficient mice have markedly impaired glucose-stimulated insulin secretion; however, it may be an effect of reduced β-cell insulin content instead of an insulin secretory pathway defect [20]. Other pathways have been implicated to explain impaired insulin secretion caused by calcineurin inhibitors. Mitochondria play a key role in insulin secretion by both providing energy (ATP) and synthesizing metabolites (anaplerosis) that can couple glucose sensing to insulin exocytosis. Cyclosporine was found to bind readily to cyclophilin D in the mitochondrial permeability transition pore and block the opening of this channel, thus diminishing insulin release from mouse islets [25]. Our group recently demonstrated that pharmacological dose of tacrolimus significantly decreases mitochondrial content and respiration in INS-1 cells, probably at the level of gene transcription and translation [26]. Moreover, both tacrolimus and Cyclosporine were reported to induce defective glucose-stimulated insulin secretion by inhibiting the closure of the ATP-sensitive potassium channel [27]. Tacrolimus may also reduce glucokinase activity and affect insulin exocytosis downstream of the rise in intracellular Ca2+, resulting in decreased glucose-stimulated insulin secretion [28,29]. Using MetaCore pathway analysis, our experiments have demonstrated that multiple pathways involved in cytoskeleton, membrane trafficking, ATP generation and mitochondrial biology may explain the complex effects of tacrolimus on impaired insulin secretion [26]. However, the underlying molecular mechanism of these effects and whether these effects on insulin secretion are mediated by calcineurin inhibition or not, requires further experiments.

Although the literature is sparse, some studies have suggested that calcineurin inhibitors impair peripheral insulin action. Wahlstrom et al. [30] demonstrated that cyclosporine may inhibit insulin release and induce Insulin resistance with clamp studies in dogs. Cyclosporine withdrawal resulted in reversal of these changes. An in vitro study showed that addition of cyclosporine to skeletal muscle cells from mice, results in a significantly lower insulin-induced glucose uptake compared with controls, and blockade of calcineurin activity promotes the transformation from type I slow-twitch skeletal muscle fibres to the less insulin sensitive type II fast-twitch skeletal muscle fibres in rat soleus muscle [7]. However, detailed pathways need to be further defined. Conversely, a clinical study reported that patients with NODAT treated with prednisolone and Calcineurin inhibitors are more likely to have defects in insulin secretion, both at baseline and at the end of 1 year, indicating that defects in insulin release at baseline are more predictive of future NODAT and impaired glucose tolerance than insulin resistance [12].

Tacrolimus vs. cyclosporine

Majority of published studies describe tacrolimus as more diabetogenic than cyclosporine [1]. In a meta-analysis, a higher incidence of NODAT was reported in patients receiving tacrolimus compared with cyclosporine (16.6% vs. 9.8%), and this trend was observed across kidney, liver, heart and lung transplant groups [12]. Similarly, a recent open-label, randomized, multicentre study (DIRECT) in kidney transplant patients showed higher NODAT or impaired fasting glucose in tacrolimus-treated patients compared than in cyclosporine-treated patients (33.6% and 26%, respectively, = 0.046) [1].

Reasons for the differences between these two medications need to be evaluated in more detail. One possible explanation could be expression of FK506-binding protein 1B preferentially in β-cells, thus leading to a strong concentration of the drug in these cells, while cytochrome P450 is mainly located in the heart, liver and kidneys [12]. Furthermore, a recent study demonstrated that tacrolimus and cyclosporine may act on different pathways except for the common effect of inhibiting calcineurin activity. In this study, only tacrolimus acutely inhibited basal insulin release from INS-1E cells, while cyclosporine decreased the transcription of several essential β-cell genes [31]. Insulin resistance induced by these two drugs may also be different. A clinical study showed that tacrolimus-based therapy led to higher peripheral Insulin resistance and hyperinsulinaemia than cyclosporine -based immunosuppression in kidney allograft recipients [12].

Mammalian target of rapamycin inhibitors

Sirolimus is a macrolide that inhibits T cell activation by linking with FK506 binding protein 1B; the complex inhibits mTOR. Sirolimus is a potent immunosuppressive agent that is associated with superior graft function, and comparable acute rejection, graft loss or mortality to calcineurin inhibitors. Mammalian target of rapamycin, a conserved Ser/Thr kinase, which exists in two complexes [mTOR Complex1 (mTORC1) and mTOR Complex2 (mTORC2)], has a key role in the regulation of cellular response to nutrients by integrating extracellular and intracellular signals originating from growth factors, hormones, and nutrients. Sustained activation of mTORC1 is a major cause for nutrient-induced obesity and insulin resistance [32]. So theoretically, sirolimus could be useful in the management of obesity or Type 2 diabetes through the deactivation of the negative-feedback loop of the mTOR pathway in adipose tissue, liver and muscle [32]. However, a growing body of evidence suggests that it may also be diabetogenic. Data from the United States Renal Data System showed the association between sirolimus use and NODAT among 20 124 renal transplant recipients [33]. Compared with patients treated with cyclosporine and either mycophenolate mofetil or azathioprine, sirolimus-treated patients were at increased risk for NODAT, whether used in combination with cyclosporine, tacrolimus or an antimetabolite (mycophenolate mofetil or azathioprine). However, Araki et al. [34] did not find the increased risk of NODAT with de novo sirolimus use and sirolimus-based immunosuppression therapy in 528 renal transplant recipients.

Conclusions about the effects of sirolimus alone on the function and survival of β-cells are also paradoxical based on animal studies, studies with cell lines or human islet investigations. Sirolimus at therapeutic concentrations was reported to significantly increase insulin secretion in both basal (50%) and stimulated (40%) states in mini pigs in vivo [28]. Sirolimus also increases insulin content in human islets [32]. However, a down-regulation of insulin secretion in human islets at supra-therapeutic concentrations of sirolimus has also been reported. One study showed that like calcineurin inhibitors, sirolimus may also impair insulin secretion by inhibiting the closure of ATP-sensitive potassium channels [27]. A recent study in rat pancreatic islets showed that SRL suppresses glucose-stimulated insulin secretion by reducing mitochondrial ATP production through suppression of carbohydrate metabolism in the Krebs cycle [35].

In summary, the effects of sirolimus on insulin secretion may depend on serum levels, experimental animal species evaluated, nutrients status and whether study is in vivo or in vitro (Table 1). However, there is convincing evidence that sirolimus may disrupt islet regeneration and proliferation. Laugharne et al. demonstrated deleterious effects of sirolimus on murine islet and MIN6 cell survival [32]. Sirolimus treatment almost completely inhibited β-cell proliferation induced by pregnancy in mice by inhibiting the mTORC1 signalling pathway, which regulates protein translation through downstream effectors such as ribosomal S6 kinase (S6K) and eukaryotic translation initiation factor 4EBP1. This pathway is critical for optimal cell growth, cell cycle progression and regulation of organ size. Further, Balcazar et al. [36] demonstrated that sirolimus treatment inhibited cyclin-dependent kinase 4 activity through mTORC1 signalling by reducing cyclin D2 and D3, which are critical regulators of β-cell cycle, proliferation and mass [32]. Further, mTORC2 is also potentially important for the regulation of β-cell mass and function, by phosphorylation/activation of Akt at Ser473, which plays a pivotal role in cell survival [37]. However, its role in the pathogenesis of sirolimus-induced β-cell toxicity is still debated. One study reported that sirolimus treatment had no effect on mTORC2 and Akt activity in a controlled activation of Akt signalling murine islet cell line [36].

Table 1.  Summary of experimental approaches that have elucidated mechanism of immunosuppressive drugs that induced new-onset diabetes after transplantation (NODAT)
DrugsMechanismIslet cell linesIsolated isletsAnimal modelsHuman studies
  1. A, some studies; B, moderate number of studies; C, many studies; 1, mild abnormality; 2, moderate abnormality; 3, severe abnormality; ND, not done; NA, not applicable.

  2. *Some studies show a decrease and some show an increase or no effect.

GlucocorticoidsInsulin secretionB2A*NDA1A1
Insulin actionNANANAC3C3
β-Cell apoptosis A1A1NDNANA
β-Cell proliferationA*A*NDNANA
Calcineurin inhibitorsInsulin secretionC3C3A3C3C3
Insulin actionNANANAB*B*
β-Cell apoptosis A1A1A1NANA
β-Cell proliferationA2A2A2NANA
SirolimusInsulin secretionB*B*A*B*B*
Insulin actionNANANAB*B*
β-Cell apoptosis A1A1A1NANA
β-Cell proliferationA2A2A2NANA

Figure 6 shows a schematic overview of the possible diabetogenic mechanisms of sirolimus. In clinical practice, diabetogenic effect of sirolimus is prominent when the drug is used in combination with calcineurin inhibitors in transplant recipients [33].

Figure 6.

 Schematic of the mechanisms of sirolimus induced β-cell dysfunction. The mammalian target of rapamycin Complex1 (mTORC1) signalling pathway regulates protein translation through downstream effectors such as S6 kinase and 4E-binding protein (4EB-P) to promote optimal cell growth and cell cycle progression. The mammalian target of rapamycin Complex2 (mTORC2) complex is potentially important for the regulation of β-cell mass and function, because it is responsible for the phosphorylation/activation of Akt on Ser473, which plays a pivotal role in cell survival. Sirolimus (SRL) disrupts β-cell regeneration and proliferation mainly through its inhibition of mTORC1 (a), perhaps through mTORC2 (b). Sirolimus reduces mitochondrial ATP production through suppression of carbohydrate metabolism in the Krebs cycle (c) or inhibition of the closure of ATP-sensitive potassium channel (d), so as to impair glucose-stimulated insulin secretion. P70S6K, ribosomal S6 kinase; FKBP1B, FK506-binding protein 1B.

Hepatitis C virus and Cytomegalovirus

Epidemiologic analyses have demonstrated strong associations between HCV infection and hyperglycemias in the general population. Pretransplant HCV infection represents a significant risk for NODAT after liver transplantation and kidney transplantation [1]. The risk of NODAT was increased fivefold in HCV(+) recipients compared to HCV(–) patients. The pathogenesis remains poorly understood. Liver biopsies in patients with NODAT revealed more severe histological activity and fibrosis compared with controls without diabetes [7]. A significantly higher insulin resistance in the HCV(+) group during the first year after liver transplantation has been attributed to a direct effect of virus on insulin resistance [2]. In this study, other factors which could affect insulin resistance such as BMI, medication usage, alcohol consumption, liver function or degree of fibrosis were similar to the HCV(–) group. This effect may be explained by downregulation of Irs1 and Irs2 by the virus [38]. Hepatitis C virus induced immune mediated or direct β-cell damage may also play a role in the development of NODAT [7].

Recurrent CMV infection is highly prevalent after SOT and dramatically affects the patient morbidity and mortality [7]. The association of CMV infection with NODAT was first seen in a kidney transplantation recipient in 1985 [2]. Up to now, available data indicate that both asymptomatic CMV infection and CMV disease may be independent risk factors for NODAT, but the mechanism is unknown. Some studies have shown that CMV disease may be associated with insulin resistance and impaired insulin secretion after kidney transplantation [7]. Cytomegalovirus-induced pro-inflammatory cytokines leading to apoptosis or functional disturbances of the β-cell have also been reported [2]. Notably, the independent link between CMV infection and NODAT is difficult to confirm in human studies, as other factors may increase the risk of CMV infection, such as the degree of therapeutic immunosuppression. Interestingly, CMV infection may change the natural history of HCV infection in renal and liver transplant recipients [7], but whether coinfection of CMV and HCV modifies the risk for NODAT needs further study.

Genetic factors

Recently, the influence of genetic polymorphisms on the development of NODAT after kidney transplantation has been described, especially Type 2 diabetes susceptibility genes (Table 2) [39–50]. Of these, some seem to increase the risk of NODAT, while others may be protective. Kang et al. [48] have reported that a specific transcription factor 7-like 2 (TCF7L2) rs7903146 SNP (single-nucleotide polymorphism) is associated with an increased risk of NODAT in Korean kidney transplantation recipients. This was confirmed by a multicenter study of 1076 Caucasian recipients [46]. A protective effect of ZnT-8 (SLC30A8) rs13266634 gene variation has been reported in renal transplant recipients from Korea [47].

Table 2.  Summary of genetic studies evaluating new-onset diabetes after transplantation (NODAT) after kidney transplantation
StudySample sizeGeneSingle-nucleotide polymorphism (SNP)CountryImmuno-suppressantsMain findings
  1. NR, not reported.


  3. ‡rs12255372 and rs7901695 (TCF7L2), rs5219 and rs5215 (KCNJ1)1, rs1801282 (PPARG), rs13266634 (SLC30A8), rs10811661 and rs564398 (CDKN2A/CDKN2B), rs4402960 and rs1470579(IGF2BP2), rs10946398, rs7756992 and rs7754840(CDKAL1), and rs1111875 and rs5015480 (HHEX).


  5. §rs1801282 (PPARG), rs10010131 (WFS1), rs757210 (HNF1B), rs4402960 (IGF2BP2), rs10811661 (CDKN2A-CDKN2B region), rs13266634 (SLC30A8), rs1111875 (HHEX-IDE region), rs5215 (KCNJ11), rs7754840 (CDKAL1), rs8050136 (FTO), rs7903146 (TCF7L2).

  6. ║CYP3A5, MDR1, VDR, UCP2, PPARG, ACE, Adiponectin.

  7. ¶A6986G(CYP3A5), C3435T and G2677(A/T)(MDR1), ApaI, BsmI and TaqI(VDR),G-866A(UCP2), Pro12Ala(PPARG), I/D(ACE), T45G, G276T, and A349G(Adiponectin ).

Chakkera et al. (2009) [49]91228 Type 2 diabetes Susceptibility genes*15 SNPs†USA84% on tacrolimusNo significant association
Ghisdal et al. (2009) [46]107611811 Type 2 diabetes Susceptibility genes‡11 SNPs§Multicentre (Caucasian)Sirolimus, GlucocorticoidsTCF7L2 rs7903146 polymorphism associated with increased NODAT
Kang et al. (2008) [48]511119Transcription factor 7-like 2 (TCF7L2)rs11196205, rs4506565, rs12243326, rs7903146, rs12255372, rs7901695KoreaGlucocorticoids and cyclosporine or tacrolimusTCF7L2 rs7903146 polymorphism associated with increased NODAT
Kang et al. (2008) [47]624174ZnT-8 (SLC30A8)rs13266634KoreaCalcineurin inhibitors and glucocorticoidsSLC30A8 rs13266634 gene variation associated with protection from NODAT
Kurzawski et al. (2010) [42]21426Calpain-10 (CAPN10)rs3792267, rs3842570, rs5030952PolandTacrolimusrs3792267 heterozygosity and 1-1-2 haplotype (rs3792267:G-rs3842570:ins-rs5030952:T) increased risk of NODAT
Jeong et al. (2010) [45]31156Chemokine (C-C Motif) ligand 5 (CCL5)rs2107538, rs2280789, rs3817655KoreaNRAll three SNPs increased risk NODAT. TCA haplotype increased risk for NODAT
Dutkiewicz et al. (2010) [40]15921Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX1)SOD1 rs2234694, SOD2 rs4880, CAT rs1001179, GPX1 rs1050450PolandTacrolimus, MMF, and GlucocorticoidsPro200Leu polymorphism of GPX1 increased risk of NODAT, and allele T significantly more frequent
Chang et al. (2010) [41]37681Plasminogen activator inhibitor 1 (PAI-1)promoter −675 4G/5GTaiwancyclosporine or tacrolimus, MMF or MA, and/or GlucocorticoidsHomozygosity for 5G allele confers protection from NODAT
Ergun et al. (2010) [44]828Enzyme endothelial nitric oxide synthase (eNOS) gene intron 4NRTurkeycyclosporine -based triple therapy4a allele of the gene intron 4 polymorphism associated with NODAT
Bamoulid et al. (2006) [39]34961Interleukin-6 (IL-6)promotor -174 (G>C)FranceTacrolimus-based regimenIL-6 gene promoter polymorphism associated with NODAT. Effect occurred mostly in overweight patients
Numakura et al. (2005) [43]7010Seven genes related to tacrolimus pharmacokinetics, insulin secretion or sensitivity║12 polymorphismsJapanTacrolimus-based regimenVitamin D receptor(VDR) TaqI t allele may be a risk factor for NODAT
Torres-Romero et al. (2006) [50]45392Human lymphocytic antigen (HLA)-A, HLA-B, and DRNRPuerto RicoNRNo significant association

Pharmacogenetics has the potential to individualize the choice and dose of immunosuppressive agent that will achieve optimal therapeutic effect while minimizing the adverse effects. Calcineurin inhibitors are metabolic substrates for cytochrome P450 3A enzymes and are transported out of cells via P-glycoprotein, which is encoded by the ATP-binding cassette B1 (ABCB1) gene, also known as multidrug resistance gene (MDR1). Studies to date are indeterminate regarding the association of cytochrome P450 3A5 6986A>G SNP with long-term survival, cyclosporine- and tacrolimus-related nephrotoxicity and development of hypertension [51]. Limited data are available about the association of these SNPs with NODAT. Barrera-Pulido et al. [52] reported that CYP3A5 G/G liver allograft recipients from MDR1 C/T donors had a higher rate of NODAT than other groups; however, no such an association was found in a Japanese cohort after kidney transplantation [43].

Although these findings need to be further defined, it is likely that these polymorphisms may exert a small effect individually, but possibly strong combined effect on the development of NODAT. Genotyping might facilitate individual tailoring of immunosuppressants before and after solid organ transplantation.

Modification of immunosuppression and long-term management of NODAT

To reduce the risk of NODAT, post-transplant management should focus on selecting an appropriate immunosuppressive regimen for each individual, and balancing the risk of rejection vs. potential for NODAT, varying efficacy and diabetogenicity of immunosuppressive agents [12]. Glucocorticoid-sparing strategies have resulted in acceptable acute rejection rates, and short-term graft and patient survival, even in the early period after solid organ transplantation [7]. However, the benefits and risks of glucocorticoid withdrawal should be undertaken cautiously particularly in high-immunological risk populations such as non-Caucasian, sensitized, previously transplanted and patients with previous acute rejection [53].

Ghisdal et al. [54] reported the remission of 42% of NODAT, 1 year after conversion from tacrolimus to cyclosporine. However, conversion from cyclosporine to tacrolimus has not shown any increase in the incidence of new-onset diabetes or new-onset hyperglycaemia [55]. Moreover conversion from cyclosporine to tacrolimus has been shown to improve the cardiovascular risk profile and renal function. cyclosporine is known to cause hyperlipidaemia and arterial hypertension, and studies of switching from cyclosporine to tacrolimus report improvement in cardiovascular risk factors such as blood pressure and lipid status and renal function in the short term without increasing the risk of NODAT in renal and liver transplant recipients. The decision to switch is difficult and should be individualized [55,56].

Notably, the usage of sirolimus may enable further dose-reduction of calcineurin inhibitors, and clinical studies of sirolimus and low-dose tacrolimus combination therapy without glucocorticoids have reported an extremely low incidence of NODAT, and so may be worth investigation in selected populations [57,58].

Management of patients who have developed NODAT should follow a stepwise approach, similar to that recommended for Type 2 diabetes [2]. Therapeutic lifestyle modifications such as weight loss, exercise and smoking cessation play a critical role both in the prevention and management of NODAT. Medical intervention is recommended when therapeutic lifestyle modification fails. To our knowledge, there are no randomized, controlled clinical trials evaluating the efficacy of oral agents or insulin in NODAT. Both oral agents and insulin can be used, and the selection depends on BMI, glycaemic control, renal and liver function, and comorbidities of patients [2]. Notably, rosiglitazone has been shown to protect β-cell death induced by cyclosporine in Sprague Dawley rats, and 4 weeks’ treatment with rosiglitazone was associated with improved glycaemic control in patients with NODAT or impaired glucose tolerance after kidney transplantation [12]. However, the side effects of glitazones present a cautionary note (e.g. weight gain, oedema, anaemia, heart failure and fracture). Glucagon like peptide 1 analogues and dipeptidyl peptidase IV inhibitors may also be useful in NODAT patients because of their protective effect on β-cells, but need further experimental and clinical evidence. Simple or complex insulin programmes continue to be mainstays in NODAT based on their safety and the experience of clinicians over several decades.


New-onset diabetes after transplantation is a serious complication that can adversely affect patient and allograft outcomes. The aetiology is multifactorial, with diabetogenic immunosuppressive drugs playing a major role. Both insulin resistance and impaired β-cell function act on the pathogenesis of NODAT, but may vary in the presence of different risk factors. Multiple cellular and physiological mechanisms may be involved in the process, and need further study. Selection of an appropriate maintenance regimen should involve balancing the risk of patient and graft survival vs. the potential for NODAT. Although the attenuation of reversible risk factors may prevent or delay the onset of NODAT, definitive evidence of such benefit is awaited.

Competing Interests

Nothing to declare.


We appreciate helpful discussions with colleagues over the years especially Drs Nassir Rostambeigi, Victor Montori, K. Sreekumaran Nair and I. Lanza. M.D.’s research has been supported by promotive research fund for excellent young and middle-aged scientists of Shandong Province (Grant number: BS2009YY014). We apologize to authors whose original publications we were unable to cite because of space considerations.