Despite strict pre- and post-transplantation screening, the incidence of new-onset diabetes after transplantation (NODAT) remains as high as 60%. This complication affects the risk of cardiovascular events and patient and graft survival rates. Thus, reducing the impact of NODAT could improve overall transplant success. The pathogenesis of NODAT is multifactorial, and both modifiable and nonmodifiable risk factors have been implicated. Monitoring and controlling the blood glucose profile, implementing multidisciplinary care, performing lifestyle modifications, using a modified immunosuppressive regimen, administering anti-metabolite agents, and taking a conventional antidiabetic approach may diminish the incidence of NODAT. In addition to these preventive strategies, inhibition of dipeptidyl peptidase-4 (DPP4) by the gliptin family of drugs has recently gained considerable interest as therapy for type 2 diabetes mellitus and NODAT. This review focuses on the role of DPP4 inhibitors and discusses recent literature regarding management of NODAT.
New-onset diabetes after transplantation (NODAT) is a serious and common complication after solid organ transplantation. This clinical dilemma increases the risk of cardiovascular disease, infection (cytomegalovirus and hepatitis C virus), and graft damage (graft rejection and loss) and decreases the patient and graft survival rates. Additionally, rejection of the graft affects the incidence of NODAT, resulting in a vicious circle [1-4]. Despite strict pre- and post-transplantation screening, the incidence of NODAT remains extremely high. NODAT reportedly occurs in 2.5% to 44.2% of liver transplant recipients [5,6], 4% to 40% of heart transplant recipients , and 30% to 47% of lung transplant recipients [8,9]. A multicenter observational study of 527 kidney transplant recipients (KTRs) reported that the incidence NODAT is 5.5% and 8.4% at 1 and 2 years post-transplantation, respectively . Another long-term study showed that 60.2% of KTRs developed maintenance NODAT and 54.7% of KTRs manifested transient post-transplantation hyperglycemia among 176 KTRs from 2001 to 2012 . The overall incidence of NODAT in patients who undergo solid organ transplantation is 2% to 60%. This wide variation is dependent on each study’s definition of NODAT, which is based on different diagnostic criteria, observation periods, presence of risk factors, and types of immunosuppressants used.
Multiple risk factors are associated with the development of NODAT and are broadly classified into two categories: (1) nonmodifiable risk factors, including old age (> 40 years) [12,13], ethnicity (African-American and Hispanic) , positive family history of diabetes mellitus (DM) , human leukocyte antigen mismatch, donor source, occurrence of an acute rejection episode, genetic factors, and autosomal dominant polycystic kidney disease [15,16]; (2) modifiable risk factors, including individualized immunosuppressants (tacrolimus, corticosteroids, and sirolimus) [17,18], obesity (body mass index ≥ 30 kg/m2) or other components of metabolic syndrome , viral infections (cytomegalovirus and hepatitis C virus) [20-22], and peritoneal dialysis . The NODAT definition appears to be important for delineating preventive strategies. In 2003, the World Health Organization and the American Diabetes Association refined the NODAT definition based on three criteria : in addition to symptoms of DM, the patient must have a casual plasma glucose concentration of ≥ 200 mg/dL (11.1 mmol/L), fasting plasma glucose concentration of ≥ 126 mg/dL (7.0 mmol/L), or a 2-hour plasma glucose (2HPG) concentration of ≥ 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test. The 2009 Kidney Disease Improving Global Outcomes clinical practice guidelines added hemoglobin A1c (HbA1c) as a screening criterion for diagnosing NODAT .
Management of NODAT requires a multifaceted approach because it affects multiple organs and the allograft itself. Pre- and post-transplantation screening based on the glucose profile or glycosylated hemoglobin is strongly recommended. Strict control to maintain normoglycemia remains the mainstay of treatment for transplant recipients who develop DM with overt micro- and macroalbuminuria. In addition, use of renin-angiotensin system blockers and switching immunosuppressants to more adequate regimens are effective for minimizing the impact of NODAT .
Dipeptidyl peptidase-4 (DPP4) inhibitors are selective inhibitors of DPP4, which is the key enzyme that regulates degradation of the two major incretins glucagon-like peptide-1 (GLP-1) and glucose inhibitory peptide (GIP). Therefore, DPP-4 inhibitors are now widely used to treat type 2 diabetes mellitus (T2DM) without weight gain or hypoglycemic risk. However, DPP4 is a serine protease that cleaves incretins and many other non-incretin peptides. Therefore, although they may be used for glucose control, DPP4 inhibitors may have pleiotropic effects, such as anti-inflammatory, antiapoptotic, and immunomodulatory actions. The protective effects of DPP4 inhibitors are mirrored in various renal injuries [27-29], DM [30,31], hepatic impairment , and cardiovascular disease models [33,34]. Using a well-known animal model, we recently demonstrated that the DPP4 inhibitor MK0626 protects against tacrolimus-induced pancreatic islet and renal injury via antiapoptotic and antioxidative actions [35,36]. In this review, we searched the literature for the pleiotropic roles of DPP4 in the prevention and management of NODAT and its comorbidities.
MOLECULAR BIOLOGY OF DPP4
DPP4 was first discovered by Hopsu-Havu and Glenner  in 1966. This protein is also called CD26 and is a ubiquitously expressed 110-kDa glycoprotein that belongs to the type 2 transmembrane protein family . As a member of the serine peptidase/prolyl oligopeptidase family, DPP4 is often subclassified based on its structure and function as follows: membrane-bound peptidase (fibroblast activation protein (FAP)/seprase), resident cytoplasmic enzyme (DPP8 and DPP9), and nonenzymatic member (DPP6 and DPP10). These proteins share a typical α/β-hydrolase fold. DPP4 comprises four domains: a short cytoplasmic domain, a transmembrane domain, a flexible stalk segment, and the extracellular domain, which is further separated by a glycosylated region, the cysteine-rich region, and the catalytic region [38,39]. DPP4 can cleave dozens of peptides, including chemokines, neuropeptides, and regulatory peptides, containing a proline or alanine residue at position 2 of the amino-terminal region . Despite the preference for proline at position 2, alternate residues at the penultimate position are also cleaved by DPP4, indicating a required stereochemistry for cleavage. This DPP4 cleavage at post-proline peptide bonds inactivates peptides and/or generates new bioactive peptides, thereby regulating diverse biological processes.
Most of the in vivo and in vitro experimental approaches used in this context have been employed to identify and characterize DPP4 substrates by incubation with plasma containing DPP4, transfected DPP4, or purified soluble DPP4. The results of these studies have shown that DPP4 substrates can be broadly classified into physiological and pharmacological substrates, the former of which include GIP and GLP-1 and the latter of which consist of a superfamily member, such as brain natriuretic peptide, erythropoietin, endomorphin-1, or glucagon [38-40]. Because of its diverse substrates, DPP4 exerts pleiotropic actions via protease activity, associations with adenosine deaminases, interactions with the extracellular matrix, cell surface co-receptor activity, and regulation of intracellular signal transduction coupled to the control of cell migration and proliferation. Thus, DPP4 triggers multiple biological activities in paracrine or endocrine manners.
PIVOTAL DPP4 SUBSTRATES
Numerous peptides that contain a cleavable amino acid sequence at their penultimate position are potential DPP4 substrates. There seems to be a size limitation, at least for cytokines, because DPP4 is more prone to cleave substrates with approximately 24 amino acids [38,39]. The incretin hormones are secreted from the gut and account for approximately 50% of the insulin secretion that occurs within minutes after a meal. These hormones stimulate insulin secretion and suppress glucagon release by binding to its distinct receptors on pancreatic β-cells. GIP and GLP-1 are the most potent glucose-lowering hormones, and both proteins belong to the same glucagon peptide superfamily and share amino acid characteristics . GIP is a 42-amino acid peptide derived from preproGIP via post-translational processing by prohormone convertase (PC) 1/3, which originates mainly from enteroendocrine K cells [41,42]. GLP-1 is secreted from L cells of the distal gut after post-translational cleavage of proglucagon by PC 1/3 in the bloodstream; DPP4 can cleave GLP-1 . Intact GLP-1 promotes glucose-stimulated insulin secretion and suppresses glucagon secretion, appetite, and gastric emptying via the GLP-1 receptor (GLP-1R) . DPP4 cleavage eliminates the classical glucoregulatory actions of GLP-1 and generates peptides with a 100-fold lower receptor affinity, illustrating that the N-terminal residues are required for engaging GLP-1R. GIP is also expressed in islet α-cells and stimulates insulin secretion . DPP4 cleaves GIP to release the dipeptide (TyrAla); however, GIP is unable to activate the GIP receptor and functions as an antagonist in vitro. Unlike GLP-1, GIP has no effect on glucagon secretion, but regulates fat metabolism in adipocytes.
The majority of DPP4 substrates are so-called incretin hormones, which are key regulators of postprandial insulin release. Inhibiting DPP4 may result in its greater bioavailability, thereby prolonging the half-life of insulin action. Thus, DPP4 inhibitors have been approved for treating T2DM, either as a monotherapy, add-on, or combined therapy with other glucose-lowering agents. In addition to the lack of an effect on satiety and gastric emptying, the benefits of DPP4 inhibitors are their indifference to body weight gain and the risk of hypoglycemia. Five gliptins have been approved for clinical use: sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin. In addition, teneligliptin, anagliptin, and trelagliptin have been approved in Japan and Korea. This article outlines the five gliptins that are commonly used in clinical practice.
Sitagliptin was the first DPP4 inhibitor approved in 2006 for clinical use to treat T2DM and is currently available as a monotherapy or fixed-dose combination with other antidiabetic agents, such as metformin . It is a competitive and fully reversible DPP4 inhibitor that has a half-maximal inhibitory concentration (IC50) of 18 nM and interacts with the S2 extensive subsite of the DPP4 active center . Its high selectivity ensures targeted action on DPP4 and avoids unwanted secondary effects or potential toxicities resulting from cross-inhibition of other DPP peptides, such as DPP8 or DPP9 . Sitagliptin (50 mg once daily) may reduce DPP4 activity by 80% within 12 hours, and 100 mg of sitagliptin maintains similar effectiveness for 24 hours . Moreover, sitagliptin has high bioavailability, and approximately 80% of the parent drug is excreted unchanged in the urine. Therefore, no dose adjustment is needed in patients with mild renal insufficiency (creatinine clearance > 50 mL/min). However, a half dose (50 mg) or a one-quarter dose (25 mg) is recommended for patients with moderate (creatinine clearance of 30 to 50 mL/min) or severe (creatinine clearance of < 30 mL/min) renal insufficiency .
In contrast to sitagliptin, vildagliptin only binds to the S1 and S2 subsites and forms a covalent bond with the nitrile group of their cyanopyrrolidine moiety and Ser630 of DPP4. Because it is a substrate-enzyme blocker, vildagliptin has lower DPP4 selectivity (IC50 = 100 nM) than does sitagliptin and cross-inhibits DPP8 . Orally administered vildagliptin is well tolerated, rapidly absorbed (within 3 hours), and mainly metabolized by the liver and partially by the kidney (27%) . Although the major route for vildagliptin excretion is the liver, no difference in excretion is observed in patients with mild, moderate, or severe hepatic impairment, suggesting that no dose adjustment is necessary for hepatically impaired patients . In contrast, the recommended dose vildagliptin is the half dose (50 mg daily) for patients with moderate or severe renal insufficiency or end-stage renal disease but not in patients with mild renal impairment.
Similar to vildagliptin, saxagliptin is a selective and reversible DPP4 inhibitor that binds to the S1 and S2 subsites. However, it differs from other gliptins because it has an active metabolite (5-hydroxy-saxagliptin, BMS-510849) that is also a selective, reversible, and competitive DPP4 inhibitor. Both the parent form (12% to 29%) and the saxagliptin metabolite (21% to 52%) can be secreted by the kidneys . As a result, the saxagliptin dose should be reduced by 50% (2.5 mg daily) in patients with moderate or severe renal impairment.
Linagliptin was approved in 2011 by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency for treating T2DM. This drug interacts with both the S1’ and S2’ subsites; thus, it has an 8-fold higher activity than other gliptins. Linagliptin binds tightly to plasma proteins after oral administration, and its pharmacokinetics are influenced by storable high-affinity binding to DPP4 in the plasma and tissues, leading to a long terminal half-life [52,53]. Linagliptin kinetics may be unaffected by food intake, as it is mainly excreted unchanged in the feces (> 84%). Recent clinical trials have shown that a multiple dose of linagliptin  or linagliptin combined with metformin  is safe and well tolerated compared with placebo, suggesting that linagliptin should be administered to patients with T2DM as either monotherapy or in combination with other antihyperglycemic agents without adjusting the dose.
Alogliptin was first approved by the Pharmaceuticals and Medical Devices Agency of Japan in 2010 and by the FDA in 2013 for treating T2DM. It is a potent and highly selective inhibitor of DPP4 with a mean IC50 of 6.9 nM and 1,000-fold increased selectivity for DPP4 compared with that of the closely related serine proteases DPP2, DPP8, DPP9, FAP/seprase, prolyl endopeptidase, and tryptase . Alogliptin exhibits favorable pharmacokinetic, pharmacodynamic, and pharmacologic safety profiles. Therefore, alogliptin as a monotherapy or addon to metformin, pioglitazone, glipizide, glibenclamide, voglibose, or insulin significantly improves glycemic control compared with placebo or active comparators in adult and elderly patients with inadequately controlled T2DM [57,58]. Because the kidney is the main excretion route for alogliptin, accounting for 60% to 71%  of excretion, the oral dose should be reduced or withdrawn in patients with renal impairment. The details of DPP4 inhibitors are summarized in Table 1 [45,50,56,58-64].
ANTIDIABETIC EFFECT OF DPP4 INHIBITORS
Transplant-associated hyperglycemia comprises NODAT, impaired fasting glucose, and impaired glucose tolerance, all of which are closely related to increased morbidity and mortality in KTRs. Although NODAT confers a high risk for premature allograft failure and increased cardiovascular events, therapeutic strategies for this condition remain underexplored. Metformin is the first-line agent of choice for treating T2DM in the general population. However, the use of metformin in KTRs is often limited because of concern about lactic acidosis. DPP4 inhibitors are a class of oral antidiabetic drugs that stabilize GLP-1 and GIP, resulting in improved glycemic control, reduced postprandial hyperglycemia, and a lower risk of weight-neutral and -lowering hypoglycemia in patients with T2DM. Overwhelming evidence shows that DPP4 inhibitors are effective for managing NODAT. Strom Halden et al.  reported that 50 to 100 mg/day of sitagliptin increased the median first- and second-phase insulin secretion rates by 56.3% and 39.3%, respectively, and significantly reduced fasting and 2HPG concentrations by 14.8 and 47.5 mg/dL, respectively, compared with those in a sitagliptin-free group of stable renal recipients with NODAT. Haidinger et al.  demonstrated that vildagliptin profoundly reduced the concentrations of HbA1c (6.1% vs. 6.5%) and 2HPG (182.7 mg/dL vs. 231.2 mg/dL) compared with placebo, which was almost achieved at the primary endpoint. Treatment with sitagliptin or vildagliptin had good efficacy and safety in both study arms, and associated adverse events were mild and appeared to be negligible. This concept is supported by studies [67-69] reporting similar efficacy and safety of DPP4 inhibitors for treating NODAT. DPP4 inhibitors are considered a novel treatment alternative for KTRs with overt NODAT.
ANTIHYPERTENSIVE EFFECT OF DPP4 INHIBITORS
Hypertension is an important cause of chronic kidney disease and a common complication of KTRs, accounting for 50% to 90% of their incidence . Ogawa et al.  reported that an alternate-day treatment with sitagliptin significantly lowered systolic blood pressure (from 130.0 to 119.7 mmHg) and HbA1c levels in Japanese hypertensive patients with T2DM. However, their body mass index remained unchanged, and no association was found between systolic blood pressure and HbA1c level. The hypotensive effect of sitagliptin has also been observed in nondiabetic patients with mild to moderate hypertension, in whom both systolic and diastolic blood pressures decreased markedly after 5 days of sitagliptin treatment . These clinical observations were further confirmed by animal studies using Zucker Diabetic Fatty rats  and spontaneously hypertensive rats , in which the antihypertensive effect of the DPP4 inhibitors in which urinary flow and sodium excretion increased due to decreased expression of the type 3 sodium-hydrogen transporter in the renal proximal tubule. The molecular mechanism underlying the antihypertensive effect of DPP4 inhibitors is multifactorial and may involve neuropeptide Y (NPY) and peptide YY (PYY). Because NPY and PYY are agonists of the endogenous Y (1) receptor, which mediates vasoconstriction, these peptides are cleaved by DPP4 to NPY (3–36) and PYY (3–36) [74,75]. This additional antihypertensive effect can extend the clinical use of DPP4 inhibitors to KTRs and patients with NODAT.
ANTI-INFLAMMATORY EFFECT OF DPP4 INHIBITORS
DM is a low-grade systemic inflammatory disease. Suppressing inflammation slows the progression of DM. In addition to preserving glucose homeostasis, DPP4 inhibitors exert pleiotropic actions, such as anti-inflammatory effects. Alogliptin inhibits Toll-like receptor-4-mediated extracellular matrix signal-regulated kinase (ERK) activation and ERK-dependent matrix metalloproteinase expression in U937 histiocytes . Des-fluoro-sitagliptin (sitagliptin analog) markedly enhances GLP-1-induced cytosolic levels of cyclic adenosine monophosphate (cAMP) compared with GLP-1 alone in cultured human macrophages and endothelial cells, resulting in inhibition of nuclear factor-κB p65 nuclear translocation via the cAMP/protein kinase A pathway; it also suppresses production of the proinflammatory cytokines interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 in response to lipopolysaccharide (LPS) . DPP4 inhibitors reduce cyclooxygenase-2, IL-1β, macrophage inflammatory protein-2, and TLR-4-mediated IL-6 expression in Zucker Diabetic Fatty rat , diabetic apolipoprotein E-deficient mice , and C57BL/6J-obese/obese mice , which parallels recovery from disease. Matsubara et al.  reported that sitagliptin significantly decreases high sensitivity C-reactive protein levels and improves endothelial function in human patients with uncontrolled DM. It is speculated that the anti-inflammatory properties of DPP4 inhibitors may be largely beneficial for KTRs with DM.
ANTIAPOPTOTIC EFFECT OF DPP4 INHIBITORS
Apoptosis is an active cell clearance mechanism that plays an important role in regulating cell numbers during homeostasis, development, and under disease conditions . Although apoptosis is beneficial, it can also be deleterious if a critical number of resident cells are lost. In fact, the pathogenic role of apoptosis has been well described for a wide range of diseases, including DM and DM-associated micro- and macrovascular complications [82-84]. DM induces pancreatic β-cell apoptosis in vivo  and in vitro , and these cells are regulated by oxidative stress toward apoptotic cell death. Shimizu et al.  showed that vildagliptin increases pancreatic β-cell mass, improves aggravated endoplasmic reticulum stress, and restores pancreatic and duodenal homeobox 1 expression in diabetic pancreatic β-cell specific C/EBPB transgenic mice. The antiapoptotic effect of DPP4 inhibitors was also observed in studies of cardioprotection  and renoprotection  via modulation of the Bax to Bcl-2 ratio and caspase-3 activity. We recently reported that the DPP4 inhibitor MK-0626 attenuates both pancreatic and renal cell apoptosis in tacrolimus-induced diabetic rats and that this is associated with the regulation of 8-hydroxy-2’-deoxyguanosine, heme oxygenase-1, and manganese superoxide dismutase by preserving GLP-1 (Figs. 1 and 2) [35,36]. Our findings are consistent with those of a study performed by Chang et al. , which showed a role for sitagliptin in apoptosis and oxidative stress (glutathione peroxidase and malondialdehyde), favoring cell survival in a rat model of cardiac ischemia-reperfusion. Based on our findings and those of others, we speculate that DPP4 inhibitors trigger an antiapoptotic effect, partially by inhibiting oxidative stress injury.
IMMUNOMODULATORY EFFECT OF DPP4 INHIBITORS
Regardless of the above-mentioned effects, DM (particularly type 1 DM, autoimmune disease) is closely associated with immunological injury in which pancreatic β-cells are selectively destroyed by the immune system. Therefore, the inhibition provided by DPP4 may exert an immunomodulatory effect against DM because DPP4 is ubiquitously expressed in numerous cell types. In this context, whether DPP4 inhibitors possess immunomodulatory properties remains controversial. Sitagliptin (100 mg/day) administered to healthy volunteers  and patients with T2DM  for 28 days and 6 months showed that neither the systemic immune function (chemokine/cytokine release by stimulation with either LPS or anti-CD3) nor CD4+ T-cell activation are affected. Anz et al.  reported that sitagliptin, vildagliptin, and saxagliptin have no effect on the innate immune response in terms of cytokine secretion, immune cell activation, or lymphocyte trafficking after toll-like receptor ligand stimulation. In contrast, treatment of nonobese diabetic mice with MK0431 before and after islet transplantation reduces the effect of autoimmunity on graft survival by decreasing homing of CD4+ T-cells via cAMP/PKA/Rac1 activation . Furthermore, linagliptin and DA-1229 reduce the onset of DM and the total mass of lymphocyte insulitis and protect the β-cell mass and neogenesis in nonobese diabetic and streptozotocin-induced mice [94,95]. The reasons for this discrepancy are unknown but may be related to the study setting and type of DM. Further studies are needed to resolve this issue.
DPP4 inhibitors were developed initially and approved for treating T2DM, based on inhibiting degradation of GLP-1 and GIP. Increasing evidence demonstrates that DPP4 inhibitors exert potential pleiotropic effects including anti-inflammation, antihypertension, antiapoptosis, and immunomodulation on the heart, vessels, and kidney, independent of their hypoglycemic effect (Fig. 3). Preclinical and clinical studies have shown that DPP4 inhibitors are well tolerated, safe, and efficacious and lower the risk of hypoglycemia in stable KTRs with NODAT. This is of great clinical relevance because of the huge proportion of transplant recipients with DM. The cardioprotective and renoprotective effects of DPP4 inhibitors offer an additional therapeutic avenue for this new drug class.
This study was supported by the National Natural Science Foundation of China (No. 81160092).
1. Einollahi B, Motalebi M, Salesi M, Ebrahimi M, Taghipour M. The impact of cytomegalovirus infection on new-onset diabetes mellitus after kidney transplantation: a review on current findings. J Nephropathol 2014;3:139–148.
2. Palepu S, Prasad GV. New-onset diabetes mellitus after kidney transplantation: current status and future directions. World J Diabetes 2015;6:445–455.
3. Pham PT, Pham PM, Pham SV, Pham PA, Pham PC. New onset diabetes after transplantation (NODAT): an overview. Diabetes Metab Syndr Obes 2011;4:175–186.
4. Park CW. Does nondiabetic renal disease exacerbate diabetic nephropathy in patients with type 2 diabetes? Korean J Intern Med 2013;28:544–546.
5. Baid S, Cosimi AB, Farrell ML, et al. Posttransplant diabetes mellitus in liver transplant recipients: risk factors, temporal relationship with hepatitis C virus allograft hepatitis, and impact on mortality. Transplantation 2001;72:1066–1072.
6. Bigam DL, Pennington JJ, Carpentier A, et al. Hepatitis C-related cirrhosis: a predictor of diabetes after liver transplantation. Hepatology 2000;32:87–90.
7. Davidson J, Wilkinson A, Dantal J, et al. New-onset diabetes after transplantation: 2003 International consensus guidelines. Proceedings of an International Expert Panel Meeting. Barcelona, Spain, 19 February 2003. Transplantation 2003;75(10 Suppl):SS3–SS24.
8. Hackman KL, Snell GI, Bach LA. Prevalence and predictors of diabetes after lung transplantation: a prospective, longitudinal study. Diabetes Care 2014;37:2919–2925.
9. Ye X, Kuo HT, Sampaio MS, Jiang Y, Bunnapradist S. Risk factors for development of new-onset diabetes mellitus after transplant in adult lung transplant recipients. Clin Transplant 2011;25:885–891.
10. Kamar N, Mariat C, Delahousse M, et al. Diabetes mellitus after kidney transplantation: a French multicentre observational study. Nephrol Dial Transplant 2007;22:1986–1993.
11. Park SC, Yoon YD, Jung HY, et al. Effect of transient post-transplantation hyperglycemia on the development of diabetes mellitus and transplantation outcomes in kidney transplant recipients. Transplant Proc 2015;47:666–671.
12. Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003;3:178–185.
13. Rodrigo E, Fernandez-Fresnedo G, Valero R, et al. New-onset diabetes after kidney transplantation: risk factors. J Am Soc Nephrol 2006;17(12 Suppl 3):S291–S295.
14. Chakkera HA, Weil EJ, Swanson CM, et al. Pretransplant risk score for new-onset diabetes after kidney transplantation. Diabetes Care 2011;34:2141–2145.
15. de Mattos AM, Olyaei AJ, Prather JC, Golconda MS, Barry JM, Norman DJ. Autosomal-dominant polycystic kidney disease as a risk factor for diabetes mellitus following renal transplantation. Kidney Int 2005;67:714–720.
16. Hamer RA, Chow CL, Ong AC, McKane WS. Polycystic kidney disease is a risk factor for new-onset diabetes after transplantation. Transplantation 2007;83:36–40.
17. Johnston O, Rose CL, Webster AC, Gill JS. Sirolimus is associated with new-onset diabetes in kidney transplant recipients. J Am Soc Nephrol 2008;19:1411–1418.
18. Radu RG, Fujimoto S, Mukai E, et al. Tacrolimus suppresses glucose-induced insulin release from pancreatic islets by reducing glucokinase activity. Am J Physiol Endocrinol Metab 2005;288:E365–E371.
19. Israni AK, Snyder JJ, Skeans MA, Kasiske BL, PORT Investigators. Clinical diagnosis of metabolic syndrome: predicting new-onset diabetes, coronary heart disease, and allograft failure late after kidney transplant. Transpl Int 2012;25:748–757.
20. Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med 2000;133:592–599.
21. Fabrizi F, Martin P, Dixit V, Bunnapradist S, Kanwal F, Dulai G. Post-transplant diabetes mellitus and HCV seropositive status after renal transplantation: meta-analysis of clinical studies. Am J Transplant 2005;5:2433–2440.
22. Hjelmesaeth J, Sagedal S, Hartmann A, et al. Asymptomatic cytomegalovirus infection is associated with increased risk of new-onset diabetes mellitus and impaired insulin release after renal transplantation. Diabetologia 2004;47:1550–1556.
23. Madziarska K, Weyde W, Krajewska M, et al. The increased risk of post-transplant diabetes mellitus in peritoneal dialysis-treated kidney allograft recipients. Nephrol Dial Transplant 2011;26:1396–1401.
24. Davidson JA, Wilkinson A, International Expert Panel on New-Onset Diabetes after Transplantation. New-Onset Diabetes after Transplantation 2003 International Consensus Guidelines: an endocrinologist’s view. Diabetes Care 2004;27:805–812.
25. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9 Suppl 3:S1–S155.
26. Lipshutz GS, Wilkinson AH. Pancreas-kidney and pancreas transplantation for the treatment of diabetes mellitus. Endocrinol Metab Clin North Am 2007;36:1015–1038.
27. Glorie LL, Verhulst A, Matheeussen V, et al. DPP4 inhibition improves functional outcome after renal ischemia-reperfusion injury. Am J Physiol Renal Physiol 2012;303:F681–F688.
28. Joo KW, Kim S, Ahn SY, et al. Dipeptidyl peptidase IV inhibitor attenuates kidney injury in rat remnant kidney. BMC Nephrol 2013;14:98.
29. Katagiri D, Hamasaki Y, Doi K, et al. Protection of glucagon-like peptide-1 in cisplatin-induced renal injury elucidates gut-kidney connection. J Am Soc Nephrol 2013;24:2034–2043.
30. Park CW, Kim HW, Ko SH, et al. Long-term treatment of glucagon-like peptide-1 analog exendin-4 ameliorates diabetic nephropathy through improving metabolic anomalies in db/db mice. J Am Soc Nephrol 2007;18:1227–1238.
31. Mu J, Petrov A, Eiermann GJ, et al. Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes. Eur J Pharmacol 2009;623:148–154.
32. Shirakawa J, Fujii H, Ohnuma K, et al. Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice. Diabetes 2011;60:1246–1257.
33. Shah Z, Kampfrath T, Deiuliis JA, et al. Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation 2011;124:2338–2349.
34. Ta NN, Schuyler CA, Li Y, Lopes-Virella MF, Huang Y. DPP-4 (CD26) inhibitor alogliptin inhibits atherosclerosis in diabetic apolipoprotein E-deficient mice. J Cardiovasc Pharmacol 2011;58:157–166.
35. Jin L, Lim SW, Doh KC, et al. Dipeptidyl peptidase IV inhibitor MK-0626 attenuates pancreatic islet injury in tacrolimus-induced diabetic rats. PLoS One 2014;9:e100798.
36. Lim SW, Jin L, Piao SG, Chung BH, Yang CW. Inhibition of dipeptidyl peptidase IV protects tacrolimus-induced kidney injury. Lab Invest 2015;95:1174–1185.
37. Hopsu-Havu VK, Glenner GG. A new dipeptide naphthylamidase hydrolyzing glycyl-prolyl-beta-naphthylamide. Histochemie 1966;7:197–201.
38. Lambeir AM, Durinx C, Scharpe S, De Meester I. Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci 2003;40:209–294.
40. Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev 2014;35:992–1019.
41. Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 2013;17:819–837.
42. Zhong J, Rao X, Rajagopalan S. An emerging role of dipeptidyl peptidase 4 (DPP4) beyond glucose control: potential implications in cardiovascular disease. Atherosclerosis 2013;226:305–314.
43. Yu DM, Slaitini L, Gysbers V, et al. Soluble CD26 / dipeptidyl peptidase IV enhances human lymphocyte proliferation in vitro independent of dipeptidyl peptidase enzyme activity and adenosine deaminase binding. Scand J Immunol 2011;73:102–111.
44. Knudsen LB, Pridal L. Glucagon-like peptide-1-(9-36) amide is a major metabolite of glucagon-like peptide-1-(7-36) amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor. Eur J Pharmacol 1996;318:429–435.
45. Herman GA, Stevens C, Van Dyck K, et al. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther 2005;78:675–688.
46. Kim D, Wang L, Beconi M, et al. (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 2005;48:141–151.
47. Lankas GR, Leiting B, Roy RS, et al. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes 2005;54:2988–2994.
48. Bergman AJ, Cote J, Yi B, et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care 2007;30:1862–1864.
49. Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care 2007;30:890–895.
50. He YL, Sabo R, Campestrini J, et al. The influence of hepatic impairment on the pharmacokinetics of the dipeptidyl peptidase IV (DPP-4) inhibitor vildagliptin. Eur J Clin Pharmacol 2007;63:677–686.
51. Boulton DW, Li L, Frevert EU, et al. Influence of renal or hepatic impairment on the pharmacokinetics of saxagliptin. Clin Pharmacokinet 2011;50:253–265.
52. Retlich S, Withopf B, Greischel A, Staab A, Jaehde U, Fuchs H. Binding to dipeptidyl peptidase-4 determines the disposition of linagliptin (BI 1356): investigations in DPP-4 deficient and wildtype rats. Biopharm Drug Dispos 2009;30:422–436.
53. Fuchs H, Tillement JP, Urien S, Greischel A, Roth W. Concentration-dependent plasma protein binding of the novel dipeptidyl peptidase 4 inhibitor BI 1356 due to saturable binding to its target in plasma of mice, rats and humans. J Pharm Pharmacol 2009;61:55–62.
54. Heise T, Graefe-Mody EU, Huttner S, Ring A, Trommeshauser D, Dugi KA. Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients. Diabetes Obes Metab 2009;11:786–794.
55. Graefe-Mody EU, Padula S, Ring A, Withopf B, Dugi KA. Evaluation of the potential for steady-state pharmacokinetic and pharmacodynamic interactions between the DPP-4 inhibitor linagliptin and metformin in healthy subjects. Curr Med Res Opin 2009;25:1963–1972.
56. Lee B, Shi L, Kassel DB, Asakawa T, Takeuchi K, Christopher RJ. Pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel inhibitor of dipeptidyl peptidase-4, in rats, dogs, and monkeys. Eur J Pharmacol 2008;589:306–314.
57. Christopher R, Covington P, Davenport M, et al. Pharmacokinetics, pharmacodynamics, and tolerability of single increasing doses of the dipeptidyl peptidase-4 inhibitor alogliptin in healthy male subjects. Clin Ther 2008;30:513–527.
58. Covington P, Christopher R, Davenport M, et al. Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: a randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes. Clin Ther 2008;30:499–512.
59. Ommen ES, Xu L, O'Neill EA, Goldstein BJ, Kaufman KD, Engel SS. Comparison of treatment with sitagliptin or sulfonylurea in patients with type 2 diabetes mellitus and mild renal impairment: a post hoc analysis of clinical trials. Diabetes Ther 2015;6:29–40.
60. Avogaro A, Fadini GP. The effects of dipeptidyl peptidase-4 inhibition on microvascular diabetes complications. Diabetes Care 2014;37:2884–2894.
61. Nabeno M, Akahoshi F, Kishida H, et al. A comparative study of the binding modes of recently launched dipeptidyl peptidase IV inhibitors in the active site. Biochem Biophys Res Commun 2013;434:191–196.
62. Fura A, Khanna A, Vyas V, et al. Pharmacokinetics of the dipeptidyl peptidase 4 inhibitor saxagliptin in rats, dogs, and monkeys and clinical projections. Drug Metab Dispos 2009;37:1164–1171.
63. Huttner S, Graefe-Mody EU, Withopf B, Ring A, Dugi KA. Safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of BI 1356, an inhibitor of dipeptidyl peptidase 4, in healthy male volunteers. J Clin Pharmacol 2008;48:1171–1178.
64. Thomas L, Eckhardt M, Langkopf E, Tadayyon M, Himmelsbach F, Mark M. (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylm ethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. J Pharmacol Exp Ther 2008;325:175–182.
65. Strom Halden TA, Asberg A, Vik K, Hartmann A, Jenssen T. Short-term efficacy and safety of sitagliptin treatment in long-term stable renal recipients with new-onset diabetes after transplantation. Nephrol Dial Transplant 2014;29:926–933.
66. Haidinger M, Werzowa J, Hecking M, et al. Efficacy and safety of vildagliptin in new-onset diabetes after kidney transplantation: a randomized, double-blind, placebo-controlled trial. Am J Transplant 2014;14:115–123.
67. Boerner BP, Miles CD, Shivaswamy V. Efficacy and safety of sitagliptin for the treatment of new-onset diabetes after renal transplantation. Int J Endocrinol 2014;2014:617638.
68. Werzowa J, Hecking M, Haidinger M, et al. Vildagliptin and pioglitazone in patients with impaired glucose tolerance after kidney transplantation: a randomized, placebo-controlled clinical trial. Transplantation 2013;95:456–462.
69. Haidinger M, Werzowa J, Voigt HC, et al. A randomized, placebo-controlled, double-blind, prospective trial to evaluate the effect of vildagliptin in new-onset diabetes mellitus after kidney transplantation. Trials 2010;11:91.
70. Ogawa S, Ishiki M, Nako K, et al. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, decreases systolic blood pressure in Japanese hypertensive patients with type 2 diabetes. Tohoku J Exp Med 2011;223:133–135.
71. Mistry GC, Maes AL, Lasseter KC, et al. Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertension. J Clin Pharmacol 2008;48:592–598.
72. Ferreira L, Teixeira-de-Lemos E, Pinto F, et al. Effects of sitagliptin treatment on dysmetabolism, inflammation, and oxidative stress in an animal model of type 2 diabetes (ZDF rat). Mediators Inflamm 2010;2010:592760.
73. Pacheco BP, Crajoinas RO, Couto GK, et al. Dipeptidyl peptidase IV inhibition attenuates blood pressure rising in young spontaneously hypertensive rats. J Hypertens 2011;29:520–528.
74. Berglund MM, Hipskind PA, Gehlert DR. Recent developments in our understanding of the physiological role of PP-fold peptide receptor subtypes. Exp Biol Med (Maywood) 2003;228:217–244.
75. Mentlein R, Dahms P, Grandt D, Kruger R. Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV. Regul Pept 1993;49:133–144.
76. Ta NN, Li Y, Schuyler CA, Lopes-Virella MF, Huang Y. DPP-4 (CD26) inhibitor alogliptin inhibits TLR4-mediated ERK activation and ERK-dependent MMP-1 expression by U937 histiocytes. Atherosclerosis 2010;213:429–435.
77. Matsubara J, Sugiyama S, Sugamura K, et al. A dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin, improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice. J Am Coll Cardiol 2012;59:265–276.
78. Wang Y, Landheer S, van Gilst WH, et al. Attenuation of renovascular damage in Zucker diabetic fatty rat by NWT-03, an egg protein hydrolysate with ACE- and DPP4-inhibitory Activity. PLoS One 2012;7:e46781.
79. Schurmann C, Linke A, Engelmann-Pilger K, et al. The dipeptidyl peptidase-4 inhibitor linagliptin attenuates inflammation and accelerates epithelialization in wounds of diabetic ob/ob mice. J Pharmacol Exp Ther 2012;342:71–80.
80. Matsubara J, Sugiyama S, Akiyama E, et al. Dipeptidyl peptidase-4 inhibitor, sitagliptin, improves endothelial dysfunction in association with its anti-inflammatory effects in patients with coronary artery disease and uncontrolled diabetes. Circ J 2013;77:1337–1344.
81. Ortiz A, Lorz C, Catalan MP, Justo P, Egido J. Role and regulation of apoptotic cell death in the kidney: Y2K update. Front Biosci 2000;5:D735–D749.
82. Arya A, Jamil Al-Obaidi MM, Binti Karim R, et al. Extract of Woodfordia fruticosa flowers ameliorates hyperglycaemia and oxidative stress, and improves beta-cell function in streptozotocin-nicotinamide induced diabetic rat. J Ethnopharmacol 2015;175:229–240.
83. Xiang Y, Piao SG, Zou HB, et al. L-carnitine protects against cyclosporine-induced pancreatic and renal injury in rats. Transplant Proc 2013;45:3127–3134.
84. Han SW, Li C, Ahn KO, et al. Prolonged endoplasmic reticulum stress induces apoptotic cell death in an experimental model of chronic cyclosporine nephropathy. Am J Nephrol 2008;28:707–714.
85. Lopez-Acosta JF, Villa-Perez P, Fernandez-Diaz CM, et al. Protective effects of epoxypukalide on pancreatic beta-cells and glucose metabolism in STZ-induced diabetic mice. Islets 2015;Sep. 25. [Epub]. http://dx.doi.org/10.1080/19382014.2015.1078053.
86. Shao C, Gu J, Meng X, Zheng H, Wang D. Systematic investigation into the role of intermittent high glucose in pancreatic beta-cells. Int J Clin Exp Med 2015;8:5462–5469.
87. Shimizu S, Hosooka T, Matsuda T, et al. DPP4 inhibitor vildagliptin preserves beta-cell mass through amelioration of endoplasmic reticulum stress in C/EBPB transgenic mice. J Mol Endocrinol 2012;49:125–135.
88. Ihara M, Asanuma H, Yamazaki S, et al. An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2015;308:H1287–H1297.
89. Chang G, Zhang P, Ye L, et al. Protective effects of sitagliptin on myocardial injury and cardiac function in an ischemia/reperfusion rat model. Eur J Pharmacol 2013;718:105–113.
90. Price JD, Linder G, Li WP, et al. Effects of short-term sitagliptin treatment on immune parameters in healthy individuals, a randomized placebo-controlled study. Clin Exp Immunol 2013;174:120–128.
91. White PC, Chamberlain-Shea H, de la Morena MT. Sitagliptin treatment of patients with type 2 diabetes does not affect CD4+ T-cell activation. J Diabetes Complications 2010;24:209–213.
92. Anz D, Kruger S, Haubner S, Rapp M, Bourquin C, Endres S. The dipeptidylpeptidase-IV inhibitors sitagliptin, vildagliptin and saxagliptin do not impair innate and adaptive immune responses. Diabetes Obes Metab 2014;16:569–572.
93. Kim SJ, Nian C, Doudet DJ, McIntosh CH. Dipeptidyl peptidase IV inhibition with MK0431 improves islet graft survival in diabetic NOD mice partially via T-cell modulation. Diabetes 2009;58:641–651.
94. Jelsing J, Vrang N, van Witteloostuijn SB, Mark M, Klein T. The DPP4 inhibitor linagliptin delays the onset of diabetes and preserves beta-cell mass in non-obese diabetic mice. J Endocrinol 2012;214:381–387.