Post-transplant Diabetes Mellitus Group Research Articles

Oral Glucose Tolerance Test as a Risk Marker for Developing Post-Transplant Diabetes Mellitus

IntroductionThe incidence of post-transplant diabetes mellitus (PTDM) can reach 30% during the first 6 months after kidney transplantation (KT), increasing the risk of graft failure and mortality. There is no well-established biomarker for predicting PTDM occurrence. This study evaluated the association between the abnormal 2-hour oral glucose tolerance test (OGTT) and the PTDM incidence. MethodsA retrospective single-center study, including adult kidney transplant recipients from deceased donors, was performed between March 2021 and June 2022. Exclusion criteria: age <18 years; pretransplant diabetes mellitus (DM); death with a functioning graft; loss of follow-up and/or graft failure before 6 months post-transplant. The results of pretransplant OGTT, fasting (FPG), and afternoon plasma glucose levels at hospitalization and FPG in the first, second, and third months post-transplant were evaluated. For analysis, patients were grouped according to the PTDM diagnosis: PTDM and non-PTDM. ResultsFrom 164 KT performed in the period, 50 (30%) were included, most male (n = 34, 68%), with a mean age of 48.3 ± 12.5 years. Nine patients (18%) developed PTDM, 44% between 3 and 6 months. General characteristics and immunosuppressive therapy were similar between the groups. The mean FPG in the pretransplant OGTT was significantly higher in the PTDM group compared with the non-PTDM group (85.7 ± 7.9 vs 79.1 ± 8.2, P = .03). The number of patients classified as impaired glucose tolerance (IGT) on the pre-transplant OGTT was significantly higher in the PTDM group. ConclusionIGT in the pretransplant OGTT was associated with PTDM cases in kidney transplant recipients without a previous diagnosis of DM.

Effect of post-transplant diabetes mellitus on cardiovascular events and mortality: a single-center retrospective cohort study.

This study aims to investigate the impact of post-transplant diabetes mellitus (PTDM) on cardiovascular events, graft survival, and mortality and to determine the risk factors involved in developing PTDM. A total of 703 patients who underwent kidney transplantation were included in the study. The total sample was subdivided into three groups: (i) patients with PTDM; (ii) patients who had diabetes before the transplantation (DM); and (iii) patients without diabetes (NoDM). The data on graft failure, cardiovascular events, all-cause mortality, and the potential risk factors that play a role in developing PTDM were recorded and analyzed. The patients were followed for a median of 80 (6-300) months after transplantation. Out of all patients, 41 (5.8%) had DM before transplantation, and 101 (14.4%) developed PTDM. Recipient BMI, post-transplant fasting plasma glucose, and hepatitis C seropositivity were independent risk factors for PTDM development. The incidence of cardiovascular events was 6.1% in the NoDM group, 14.9% in the PTDM group, and 29.3% in the DM group (p < 0.001). In PTDM patients, hepatitis C seropositivity and the recipient's age at transplant were independent predictors of a cardiovascular event. There were no significant differences between the groups regarding the risk of graft loss. PTDM had no significant effect on all-cause mortality. However, the survival rates of DM patients were significantly reduced compared to those with NoDM or PTDM. PTDM had no impact on patient survival. Hepatitis C seropositivity and recipient age at transplant predicted cardiovascular events in PTDM patients.

Syk/BLNK/NF-κB signaling promotes pancreatic injury induced by tacrolimus and potential protective effect from rapamycin

BackgroundThe treatment of tacrolimus-induced post-transplantation diabetes mellitus (PTDM) has become a hot topic to improve the long-term survival of organ transplant patients, however whose pathogenesis has not been fully elucidated. In pancreas, the up-regulation of NF-κB has been reported to stimulate cytokine IL-1β/TNF-α secretion, inducing pancreatic injury, meanwhile other studies have reported the inhibitory effect of rapamycin on NF-κB. PurposeThe aim of this study was to clarify the mechanism of tacrolimus-induced pancreatic injury and to explore the potential effect from small dose of sirolimus. MethodsWistar rats were randomly divided normal control (NC) group, PTDM group, sirolimus intervention (SIR) group. Transcriptomic analysis was used to screen potential mechanism of PTDM. Biochemical index detections were used to test the indicators of pancreatic injury. Pathological staining, immumohistochemical staining, immunofluorescent staining, western blot were used to verify the underlying mechanism. ResultsCompared with NC group, the level of insulin was significant reduction (P < 0.01), inversely the level of glucagon was significantly increase (P < 0.01) in PTDM group. Transcriptomic analysis indicated Syk/BLNK/NF-κB signaling was significantly up-regulated in PTDM group. Pathological staining, immumohistochemical staining, immunofluorescent staining, western blot verified Syk/BLNK/NF-κB and TNF-α/IL-1β were all significantly increased (P < 0.05 or P < 0.01), demonstrating the mechanism of tacrolimus-induced pancreatic injury via Syk/BLNK/NF-κB signaling. In addition, compared with PTDM group, the levels of weight, FPG, AMY, and GSP in SIR group were significant ameliorative (P < 0.05 or P < 0.01), and the expressions of p-NF-κB, TNF-α/IL-1β in SIR group were significantly reduction (P < 0.05 or P < 0.01), showing Syk/BLNK/NF-κB signaling promoted pancreatic injury induced by tacrolimus and potential protective effect from rapamycin reducing NF-κB. ConclusionSyk/BLNK/NF-κB signaling promotes pancreatic injury induced by tacrolimus and rapamycin has a potentially protective effect by down-regulating NF-κB. Further validation and clinical studies are needed in the future.

Tacrolimus and Diabetes in Kidney Transplantation: The Impact of Cyp3a5 Gene Polymorphism

To explore the correlation between single nucleotide polymorphisms (SNPs) of CYP3A4 rs2740574 and CYP3A5 rs776746 and post-transplant diabetes mellitus (PTDM) in Chinese renal allograft recipients treated with tacrolimus. A total of 244 patients treated with tacrolimus were included in this study, wherein DNA sequencing was detected through fluorescence in situ hybridization, and SNP genotyping was performed. Among the 244 patients, 44 (18%) developed PTDM. The PTDM group exhibited higher preoperative body mass index and fasting plasma glucose levels, with higher creatinine values one year after surgery. The CYP3A4 rs2740574 genotype was found to be unique in its homozygous AA form. For CYP3A5 rs776746, the genotypes were distributed as follows: 28 (11.5%) cases with AA, 101 (41.4%) cases with AG, and 115 (47.1%) cases with GG, respectively (P=.042). The AA genotype showed a statistically significant difference from both AG and GG genotypes. Furthermore, the A allele of CYP3A5 rs776746 was found to be associated with an increased risk for PTDM development. The occurrence of tacrolimus-related PTDM is associated with body mass index, fasting plasma glucose levels, and CYP3A5 genotype before renal transplantation. Post-transplant diabetes mellitus is correlated with unfavorable long-term renal graft function, whereas the expression of the CYP3A5 rs776746 gene is linked to an elevated risk of PTDM.

The Association between CDKAL1 Gene rs10946398 Polymorphism and Post-Transplant Diabetes in Kidney Allograft Recipients Treated with Tacrolimus.

Post-transplant diabetes mellitus (PTDM) is a common complication that occurs in kidney transplant patients, increasing the risk of infection, cardiovascular disease and loss of graft function. Currently, factors that increase the risk of this complication are being sought, among them polymorphisms in genes that regulate carbohydrate metabolism and influence pancreatic β-cell function. The aim of this study was to evaluate the association of selected polymorphisms of genes affecting carbohydrate metabolism, such as CDKAL1 rs10946398, GCK rs1799884, GCKR rs780094 and DGKB/TMEM195 rs2191349, with the development of post-transplant diabetes in kidney transplant patients. This study included 201 Caucasian patients after kidney transplantation treated with tacrolimus. An association was observed between the CDKAL1 rs10946398 gene polymorphism and PTDM. Among patients with PTDM, there was an increased prevalence of the CC genotype in the PTDM group compared to the group without PTDM. The chance of PTDM in those with the CC genotype was 2.60 times higher compared to those with the AC + AA genotypes (CC vs. AC + AA OR (95% CI): 2.60 (1.02-6.61), p = 0.040). Multivariate logistic regression analysis showed that advanced age and the CC genotype (rare homozygote) of CDKAL1 rs10946398 were risk factors for the development of PTDM at 1 year after transplantation. There was no statistically significant association between GCK rs1799884, GCKR rs780094 or DGKB/TMEM195 rs2191349 polymorphisms and the development of post-transplant diabetes mellitus in kidney transplant patients. The results of this study suggest that the CDKAL1 rs10946398 CC genotype is associated with the increased risk of PTDM development in patients after kidney graft transplantation treated with tacrolimus.

Metformin Use and Long-term Clinical Outcomes in Kidney Transplant Recipients

Metformin has been recommended for some patients with advanced chronic kidney disease. However, the value of metformin in kidney transplant recipients (KTRs) with pre-transplant diabetes mellitus (DM) or post-transplant diabetes mellitus (PTDM) is uncertain. We investigated the clinical effects of metformin in KTRs. Retrospective cohort study. A total of 1,995 KTRs with diabetes from six tertiary referral centers in the Republic of Korea. Metformin usage was defined as the use of metformin for >90 days after kidney transplantation; 1,193 KTRs were metformin users, and 802 KTRs did not use metformin. Changing usage of metformin among those exposed for >90 days was also characterized. Primary outcomes were all-cause mortality and death-censored graft failure (DCGF). Secondary outcomes were biopsy-proven acute rejection (BPAR) and lactic acidosis events. Survival analyses were conducted using multivariable Cox regression and competing risk analyses using Fine and Gray models. Changes in metformin use over time were modeled using a time-varying covariate. Metformin usage, mean daily dose, and HbA1c changes were considered in the landmark analysis to address time-varying confounding. Metformin use was associated with a lower risk of DCGF (adjusted hazard ratio [aHR] 0.47, 95% confidence interval [CI] 0.23-0.96, P = 0.038); there was no significant association with all-cause mortality (aHR 0.94, 95% CI 0.32-2.76, P = 0.915) or BPAR: (aHR 0.98, 95% CI 0.62-1.54, P = 0.942). In the subgroup analysis, metformin usage was associated with a reduced risk of all-cause mortality and a lower risk of DCGF for both the pre-transplantation DM and PTDM groups. Metformin usage was associated with a lower risk of BPAR in the PTDM group, although it was less effective in the pre-transplantation DM group. There was no confirmed case of metformin-associated lactic acidosis (MALA) in the present cohort. A higher dose of metformin was correlated with lower risks of DCGF and BPAR. Data on newer antidiabetic drugs such as SGLT2 inhibitors are limited; potential limited generalizability to other populations. Metformin usage may benefit KTRs, as evidenced by its association with a reduced risk of DCGF and the absence of MALA events. Randomized controlled trials are needed to validate these observational findings.

Impact of Post-Transplant Diabetes Mellitus on Survival and Cardiovascular Events in Kidney Transplant Recipients.

Post-transplant diabetes mellitus (PTDM) is a risk factor for poor outcomes after kidney transplantation (KT). However, the outcomes of KT have improved recently. Therefore, we investigated whether PTDM is still a risk factor for mortality, major atherosclerotic cardiovascular events (MACEs), and graft failure in KT recipients. We studied a retrospective cohort of KT recipients (between 1994 and 2017) at a single tertiary center, and compared the rates of death, MACEs, overall graft failure, and death-censored graft failure after KT between patients with and without PTDM using Kaplan-Meier analysis and a Cox proportional hazard model. Of 571 KT recipients, 153 (26.8%) were diagnosed with PTDM. The mean follow-up duration was 9.6 years. In the Kaplan- Meier analysis, the PTDM group did not have a significantly increased risk of death or four-point MACE compared with the non-diabetes mellitus group (log-rank test, P=0.957 and P=0.079, respectively). Multivariate Cox proportional hazard models showed that PTDM did not have a negative impact on death or four-point MACE (P=0.137 and P=0.181, respectively). In addition, PTDM was not significantly associated with overall or death-censored graft failure. However, patients with a long duration of PTDM had a higher incidence of four-point MACE. Patient survival and MACEs were comparable between groups with and without PTDM. However, PTDM patients with long duration diabetes were at higher risk of cardiovascular disease.

Adiponectin/Leptin Ratio as an Index to Determine Metabolic Risk in Patients after Kidney Transplantation.

Background and Objectives: It has been confirmed that adiponectin/leptin (A/L) ratio correlates better with cardiometabolic risk factors than hormone levels alone. The aim of our study was to determine the risk of developing post-transplant diabetes mellitus (PTDM) and other metabolic conditions depending on A/L ratio after kidney transplantation (KT). Material and Methods: In a prospective analysis, the studied samples were divided into three groups: control group, prediabetes and PTDM group. Pre-transplantation, at 3, 6 and 12 months after KT, we recorded basic characteristics of donor and recipient. We also monitored levels of adipocytokines and calculated A/L ratio. Results: During observed period, we recorded significant increase in A/L ratio in control group (p = 0.0013), on the contrary, a significant decrease in PTDM group (p = 0.0003). Using Cox regression Hazard model, we identified age at time of KT (HR 2.8226, p = 0.0225), triglycerides at 1 year (HR 3.5735, p = 0.0174) and A/L ratio &lt; 0.5 as independent risk factors for prediabetes and PTDM 1-year post-transplant (HR 3.1724, p = 0.0114). Conclusions: This is the first study to evaluate the relationship between A/L and risk of PTDM and associated metabolic states after KT. We found out that A/L ratio &lt;0.5 is independent risk factor for prediabetes and PTDM 1 year post-transplant.

P8.024: Evaluation of Function of Angiopoietins and ANIOPOIETIN Likes in Post-transplantation Diabetes Mellitus (PTDM) in Kuwaiti Kidney Transplanted Patients

Background: Post Transplantation Diabetes Miletus (PTDM) is a chronic metabolic disease developed in some of our kidney transplant patients. PTDM is a chronic, inflammatory disease with a direct impact on patients’ immune system. Angiopoietin and Angiopoietin-like are intrinsic mediators induced by immune cells. Objectives: To determine the relationship between circulating Angiopoietin-1 and 2 (ANG-1, 2) and Angiopoietin-like (ANGPTL 3-8) in kidney transplant patients who develop diabetes (PTDM) vs. patients who do not develop diabetes(CONTROL) after kidney transplantation. Methods: In this cross-sectional study, all patients were enrolled from Dasman Diabetes Institute Diabetes Education Department and outpatient clinics of the Hamad Al Essa Organ Transplant Centre of Kuwait between May 2015 and December 2016. The present study included 155 PTDM and 154 controls, age- and sex-matched. We collected 3 ml of venous blood from each subject. Enzyme-linked immunosorbent assay (ELISA) determined plasma ANG 1,2 and ANGPTL 3-8. We determined the correlation between plasma ANG 1 and 2 and ANGPTL3-8 levels in our PTDM and Control group. Results: In our cohorts, most of the patients (56%) were Kuwaiti. Moreover, the two groups were comparable regarding their original kidney disease, dialysis type, donor type, and the type of both induction and maintenance immunosuppression (P > 0.05). Also, pre-transplant co-morbidities were comparable in both groups, including hypertension, history of exposure to tuberculosis bacilli, ischemic heart disease, bone disease, anemia, and hyperlipidemia (P > 0.05). We found significantly higher plasma ANG-1, ANGPTNL 6, 7, 8 levels in the PTDM group compared to the control group (P < 0.001). However, we found no statistical association between our study groups concerning plasma ANG 2, ANGPTNL 3, 4 (p>0.05). Conclusion: Plasma ANG 1, ANGPTNL6, 7, 8 levels may correlate with disease severity, chronicity in transplant patients who develop diabetes post Kidney transplantation, and serve as a potential biomarker of the disease severity. Key Word: Angiopoietin; Angiopoietin Like, Kidney Transplantation, PTDM, ELISA

Insight Into the Metabolomic Characteristics of Post-Transplant Diabetes Mellitus by the Integrated LC-MS and GC-MS Approach- Preliminary Study.

Post-transplantation diabetes mellitus (PTDM) is a common metabolic complication after solid organ transplantation, which not only results in elevated microvascular morbidity, but also seriously impacts graft function and recipient survival. However, its underlying mechanism is not yet fully understood. In this study, an integrated liquid chromatography- mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) based-metabolomics approach was adopted to dissect the metabolic fluctuations and deduce potential mechanism associated with PTDM. 68 adult liver transplant recipients were recruited and classified as 32 PTDM and 36 non-PTDM subjects. PTDM group and non-PTDM group were well matched in gender, age, BMI, family history of diabetes, alcohol drinking history, ICU length of stay and hepatitis B infection. Peripheral blood samples from these recipients were collected and prepared for instrument analysis. Data acquired from LC-MS and GC-MS demonstrated significant metabolome alterations between PTDM and non-PTDM subjects. A total of 30 differential metabolites (15 from LC-MS, 15 from GC-MS) were screened out. PTDM patients, compared with non-PTDM subjects, were characterized with increased levels of L-leucine, L-phenylalanine, LysoPE (16:0), LysoPE (18:0), LysoPC (18:0), taurocholic acid, glycocholic acid, taurochenodeoxycholic acid, tauroursodeoxycholic acid, glycochenodeoxycholic acid, glycoursodeoxycholic acid, etc, and with decreased levels of LysoPC (16:1), LysoPC (18:2), LysoPE (22:6), LysoPC (20:4), etc. Taken collectively, this study demonstrated altered metabolites in patients with PTDM, which would provide support for enhancing mechanism exploration, prediction and treatment of PTDM.

Hyperleptinemia as a risk factor for post-transplant diabetes mellitus development after kidney transplantation.

Adipose tissue is involved in the synthesis of hormones that have an impact on food intake regulation, control of insulin sensitivity or regulation of inflammatory processes. The aim of this study was to determine the importance of adipocytokines and interleukins levels for the development of post-transplant diabetes mellitus (PTDM) after kidney transplantation (KT). In the prospective analysis, the studied sample (n = 104) was divided into the control group, prediabetes group and PTDM group. Prior to transplantation, and subsequently, at 3, 6 and 12 months after KT, we recorded the basic characteristics of the donor and recipient, including parameters reflecting graft function, metabolic and anthropometric parameters. At the same time, we monitored the levels of adiponectin, leptin and interleukins during the monitored period. Using multivariate logistic regression, we identified hyperleptinemia 12 months after KT as an independent risk factor for PTDM development 1 year after KT [OR 1.0320; 95% Cl 0.9785-1.0884 (p=0.0038)]. At the same time, we confirmed that age at the time of KT is also an independent risk factor for PTDM [OR 1.0903; 95% Cl 1.0149-1.1714 (p=0.0180)]. We confirmed that elevated leptin level 12 months after KT is associated with the development of PTDM (Tab. 3, Fig. 4, Ref. 22). Text in PDF www.elis.sk Keywords: adipocytokines, interleukins, post-transplant diabetes mellitus, kidney transplantation, leptin.

Insulin Secretion and Insulin Resistance Trajectories over 1 Year after Kidney Transplantation: A Multicenter Prospective Cohort Study.

BackgroundWe investigated the changing patterns of insulin secretion and resistance and risk factors contributing to the development of post-transplant diabetes mellitus (PTDM) in kidney recipients under tacrolimus-based immunosuppression regimen during 1 year after transplantation.MethodsThis was a multicenter prospective cohort study. Of the 168 subjects enrolled in this study, we analyzed a total 87 kidney transplant recipients without diabetes which was assessed by oral glucose tolerance test before transplantation. We evaluated the incidence of PTDM and followed up the index of insulin secretion (insulinogenic index [IGI]) and resistance (homeostatic model assessment for insulin resistance [HOMA-IR]) at 3, 6, 9 months, and 1 year after transplantation by oral glucose tolerance test and diabetes treatment. We also assessed the risk factors for incident PTDM.ResultsPTDM developed in 23 of 87 subjects (26.4%) during 1 year after transplantation. More than half of total PTDM (56.5%) occurred in the first 3 months after transplantation. During 1 year after transplantation, insulin resistance (HOMA-IR) was increased in both PTDM and no PTDM group. In no PTDM group, the increase in insulin secretory function to overcome insulin resistance was also observed. However, PTDM group showed no increase in insulin secretion function (IGI). Old age, status of prediabetes and episode of acute rejection were significantly associated with the development of PTDM.ConclusionIn tacrolimus-based immunosuppressive drugs regimen, impaired insulin secretory function for reduced insulin sensitivity contributed to the development of PTDM than insulin resistance during 1 year after transplantation.

1691-P: Alcohol-Related Liver Disease as Independent Risk Factor for Posttransplant Diabetes Mellitus in Liver Recipients

Background and Aims: There are few data related to identification of risk factors for post transplant diabetes mellitus (PTDM) in liver transplantation (Tx). The aim of this study was to investigate the risk factors for PTDM. Patients and methods: A retrospective study of adult patients submitted to liver Tx. Data for sex, age, BMI, pre and PTDM, Tx cause, presence of hepatocellular carcinoma (HCC), use of immunosuppressants, hepatitis B, hepatitis C (HepC) and liver biopsy were analyzed. Mann-Whitney and Chi Square tests as well as a multivariate logistic regression were performed. Results: Among 207 consecutive patients, 60.4% had no diabetes (group 1), 18.8% had pre Tx DM (group 2) and 20.8% were classified as PTDM (group 3). The major cause of transplantation was HepC (48.8%). Triglycerides (164 vs. 106mg/dL, p= 0.002) and creatinine (1.24 vs. 1.1mg/dL, p = 0.029) were higher in group 2 than in group 1, probably due to long-standing DM and metabolic syndrome in group 2. Comparisons using the Chi-Square test showed higher frequencies in group 3 than group 1 and 2, respectively, for HepC (65.1% vs. 35.1% and 37.9%, p=0.004), tacrolimus use (95.3% vs. 81.6% and 71.1%, p&amp;lt;0.001) and prednisone use (48.8% vs. 24% and 36.8%, p=0.009). HCC before Tx was more common in group 2 than in groups 1 and 3 (64.1% vs. 40.8% and 41.9%, respectively; p=0.034). Regarding biopsy data, interface activity was more severe in groups 1 and 3 compared to group 2 (62.2% and 64%% vs. 11%; p=0.040, respectively). The independent risk factors for PTDM according to the multivariate logistic model were HepC (OR 4.4; CI 95% 1.73-11.22; p=0.002), alcoholism (OR = 3.7, 95% CI, 1.2-11.5, p = 0.025), the use of tacrolimus (OR = 6.3, 95% CI 1.2-32.5, p = 0.029) and prednisone (OR = 7.2, 95% CI 2.4-21.8, p&amp;lt;0.001). Conclusion: Alcohol-related liver disease is an independent risk factor for PTDM in liver recipients. Patients with HepC and those exposed to tacrolimus and prednisone are other groups of high risk for PTDM. Disclosure M.B. Campos: None. I.D. Boin: None. A.M. Neto: None.

Post-Heart Transplant Diabetes Mellitus: Incidence, Prevalence and Outcomes

De novo diabetes mellitus (DM) is a common complication of solid organ transplantation. However, studies about post-transplant DM (PTDM) following heart transplantation (HT) are scarce. This study aims to compare baseline characteristics and clinical outcomes between patients who developed PTDM and those who did not as well as investigate the incidence and prevalence of PTDM following HT. 148 consecutive patients undergoing HT between 4/2014 and 12/2018 were enrolled to this retrospective study. PTDM diagnosis was made based on a HbA1c ≥6.5%, fasting blood glucose ≥ 126mg/dL or use of insulin or oral hypoglycemic agents. Of the 148 patients, 57 (39%) had no DM, 37 (25%) had DM prior to HT, and 54 (36%) developed PTDM. Among the patients without DM at the time of HT, cumulative incidence of PTDM was 37% at discharge, 46% at 6 months, and 48% at 1 year post-HT. The prevalence of PTDM at 6 months post-HT was 44% and decreased to 36%, 26%, and 17% at 1, 2, and 3 years, respectively (Figure 1A). PTDM patients had a significantly higher pre-HT HbA1c compared to those without DM (5.8 (5.6, 6.0) vs 5.5 (5.3, 5.9)%; p=0.017). There was no difference in the dose of immunosuppressive medications between the groups. PTDM patients had a higher rate of infection requiring hospitalization compared to patients with no DM post-HT (80% vs 61%; p=0.036). Infection free survival was significantly lower in the PTDM group at 2 years (16% vs 35%; p=0.046) (Figure 1B). Overall survival (96% vs 96% at 2 years; p=0.986), rejection-free survival (46% vs 51% at 2 years; p=0.410), rate of cardiac allograft vasculopathy (33% vs 22%; p=0.267), kidney function and number of hospitalizations were similar between the PTDM and no DM groups. The incidence of PTDM after HT was high but prevalence decreased after 6 months. Patients with PTDM had increased pre-HT HbA1c and higher post-HT rates of infection compared to patients without DM. Further studies are needed to determine the clinical impact of PTDM.

Inferior Outcomes for Patients Developing New-Onset Post-Transplant Diabetes Mellitus after Haploidentical Hematopoietic Cell Transplant

The mortality rate triples for the 50% of patients diagnosed with new-onset post-transplant diabetes mellitus (PTDM) after HLA-identical allogeneic hematopoietic cell transplant (HCT) (Griffith, BBMT 2011). Haploidentical HCT (haplo-HCT) with post-transplant cyclophosphamide (PTCY) is increasingly utilized for patients with hematological disorders but without a conventional HLA-matched donor; however, the effects of PTDM after haplo-HCT is unknown. We examined the incidence, outcomes, and risk factors for PTDM in patients undergoing haplo-HCT. Patients receiving haplo-HCT with PTCY at Vanderbilt-Ingram Cancer Center (n= 65) were retrospectively analyzed for PTDM diagnosis (defined as a random blood glucose ≥200 mg/dL). Exclusion criteria included non-haplo-HCTs, second HCT, or pre-existing diabetes mellitus. The primary outcome was the incidence of new-onset PTDM by day 100. Secondary outcomes included: cumulative incidence (CI) of grades 2-4 graft-versus-host disease (GVHD), time to systemic steroids, PTDM risk factors, overall survival (OS), disease free survival (DFS), and non-relapse mortality (NRM). PTDM was diagnosed in 14 (21.5%) patients at a median of 18 days after haplo-HCT (range, 8-72 days). Hyperglycemia preceded grade 2-4 GVHD and steroids in 12 (85.7%) patents. Clinical characteristics including ablative conditioning and GVHD did not predict PTDM development (Table 1). OS was decreased in the PTDM group (Figure 1). Among haplo-HCT recipients with cancer (n= 41) DFS was lower and the CI of relapse was increased in PTDM patients (Figure 1). Similar to HLA-identical transplants, PTDM occurs frequently, precedes alloreactivity, and leads to inferior survival following haplo-HCT. Interestingly, glucose metabolism appears to be associated with relapse risk. Prophylaxis/treatment of PTDM may improve outcomes after conventional and haplo-HCT.

Exploring the Mechanism of Skeletal Muscle in a Tacrolimus-Induced Posttransplantation Diabetes Mellitus Model on Gene Expression Profiles.

Objective Posttransplantation diabetes mellitus (PTDM) is a known complication of transplantation that affects the prognosis. Tacrolimus (Tac or FK506) is a widely used immunosuppressant that has been reported to be a risk factor for PTDM and to further induce complications in heart and skeletal muscles, but the mechanism is still largely unknown. In our preliminary experiments, we found that after Tac treatment, blood glucose increased, and the weight of skeletal muscle declined. Here, we hypothesize that tacrolimus can induce PTDM and influence the atrophy of skeletal muscle. Methods We designed preliminary experiments to establish a tacrolimus-induced PTDM model. Gene expression profiles in quadriceps muscle from this rat model were characterized by oligonucleotide microarrays. Then, differences in gene expression profiles in muscle from PTDM rats that received tacrolimus and control subjects were analyzed by using GeneSpring GX 11.0 software (Agilent). Functional annotation and enrichment analysis of differentially expressed genes (DEGs) helped us identify clues for the side effects of tacrolimus. Results Our experiments found that the quadriceps in tacrolimus-induced PTDM group were smaller than those in the control group. The study identified 275 DEGs that may be responsible for insulin resistance and the progression of PTDM, including 86 upregulated genes and 199 downregulated genes. GO and KEGG functional analysis of the DEGs showed a significant correlation between PTDM and muscle development. PPI network analysis screened eight hub genes and found that they were related to troponin and tropomyosin. Conclusions This study explored the molecular mechanism of muscle atrophy in a tacrolimus-induced PTDM model by bioinformatics analyses. We identified 275 DEGs and identified significant biomarkers for predicting the development and progression of tacrolimus-induced PTDM.

Prevalence and risk factors for posttransplant diabetes mellitus: Data from government tertiary care center

Background: Diabetes occurs in substantial number of patients following renal transplantation, contributing to mortality and morbidity in particular the cardiovascular disease and infection. The prevalence and risk factors in South Indian population is not precisely clear. Our study aimed at determining the prevalence, epidemiology, and risk factors in kidney transplant recipients with posttransplant diabetes mellitus (PTDM). Methodology: This is a single-center analytical, cross-sectional, and retrospective study of adult renal transplant recipients who underwent transplant between January 2014 and December 2016. Institutional ethics committee approval was obtained. Results: Of 149 patients transplanted, 115 were included for study. Twenty-six patients (22.6%) developed PTDM. The mean age of the PTDM group was 35.2 years and 76.92% were males. Univariate analysis revealed age (P 1 year (OR = 1.75), and induction therapy (OR = 2.0) to be independent risk factors for PTDM. Conclusions: There is high risk of developing diabetes after transplant with one quarter of this south Indian cohort developing PTDM. Older age, male sex, family history of diabetes, dialysis vintage, and use of induction therapy were independent risk factors for PTDM.

Significant Association between Toll-Like Receptor Gene Polymorphisms and Posttransplantation Diabetes Mellitus

Background: Posttransplantation diabetes mellitus (PTDM) is an important metabolic complication after renal transplantation. Activation of the innate immune system via toll-like receptors (TLRs) is implicated in the pathogenesis of insulin resistance and deficiency. Although links between diabetes, dysregulated innate immune responses, and the TLR signaling pathway have been reported, no study so far has investigated their associations with PTDM. In this study, we ascertained whether single nucleotide polymorphisms (SNPs) in TLRs are associated with PTDM in the Korea population. Methods: A total of 305 patients who received renal transplants without previously diagnosed diabetes were included. We analyzed the association between PTDM development and 6 SNPs within 2 genes of TLR2, 1 gene of TLR4, and 3 genes of TRL6. Results: Of 305 patients, PTDM developed in 51 patients (16.6%). Patients in the PTDM group were older than those in the non-PTDM group (45.56 ± 1.28 vs. 38.28 ± 0.71 years). Patients with PTDM had significantly higher allele frequency compared to those without PTDM for the TLR4 rs1927914*T, TLR6 rs3775073*A, TLR6 rs3821985*C, and TLR6 rs1039559*C alleles. Of the 6 SNPs, rs1927914 in the TLR4 gene and rs1039559 in the TLR6 gene were significantly associated with the development of PTDM after adjustment for age, gender, and tacrolimus usage. Conclusions: Our study demonstrates a significant association between SNPs rs1927914 in TLR4 and rs1039559 in TLR6 and PTDM in the renal transplantation recipient group. These data suggest that the activation of the innate immune system and inflammation via TLR activation might have an essential role in the pathogenesis of PTDM in renal transplantation.

Evaluation of Posttransplantation Diabetes Mellitus After Liver Transplantation: Assessment of Insulin Administration as a Risk Factor.

Impaired glucose regulation posttransplantation can affect allograft survival and may lead to the development of posttransplant diabetes mellitus (PTDM). The primary purpose of this study is to assess the difference in insulin burden between liver transplant patients who develop PTDM and patients who do not. This was a single-center, retrospective study. Adult liver transplant recipients transplanted between January 1, 2005, and August 1, 2013, were included. PTDM was defined as: (1) use of an oral antihyperglycemic agent for ≥30 consecutive days after transplant, (2) use of insulin ≥30 consecutive days after transplant, or (3) hemoglobin A1C≥6.5 any time after transplant. Of the 114 patients included, 48 (42%) developed PTDM. The average 24-hour insulin requirement on the medical floors was 17.2 ± 14.5 units in the PTDM group and 11.3 ± 12.2 units in the PTDM-free group;P= 0.02. The average blood glucose level on the medical floor was 184.7 ± 31.5 mg/dL in the PTDM group and 169.3 ± 31.4 mg/dL in the PTDM-free group;P= 0.013. Multivariate analysis revealed that experiencing rejection was positively associated with the development of PTDM: adjusted odds ratio (AOR) = 3.237; 95% CI = 1.214-8.633. Basiliximab was negatively associated with the development of PTDM: AOR = 0.182; 95% CI = 0.040-0.836. Univariate analyses suggest that insulin burden is a positive risk factor for the development of PTDM; this association is lost in multivariate analyses. Rejection was a positive predictor, and use of basiliximab was a negative predictor for the development of PTDM.

Validation of the association of TCF7L2 and SLC30A8 gene polymorphisms with post-transplant diabetes mellitus in Asian Indian population.

The rs7903146 and rs13266634 polymorphisms in the TCF7L2 and SLC30A8 genes, respectively, have been reported to be associated with type 2 diabetes. However, little is known about the association of these polymorphisms with post-transplant diabetes mellitus (PTDM). To study this linkage, we determined a distribution of allele and genotype frequencies in Asian Indians. 42 PTDM and 98 non-PTDM subjects were recruited. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was performed to detect for rs7903146 and rs13266634 polymorphisms. The clinical details and statistical analysis for PTDM and non-PTDM subjects were recorded. Our results observed higher frequencies of the minor alleles in rs7903146 and rs13266634 polymorphisms in the PTDM group compared to the non-PTDM subjects. The allele frequencies also found to be significantly associated with PTDM (rs7903146: T vs C: OR-2.6; (95%CI: 1.2-5.6); p = 0.01; rs13266634: T vs C: OR-2.0; (95%CI: 1.1-3.4); p = 0.01). These findings suggest that rs7903146 and rs13266634 polymorphisms are associated with PTDM in the Asian Indian population despite a relatively small study group.