Post-transplant diabetes mellitus (PTDM) is a common and crucial metabolic complication with increasing mortality and cardiovascular disease rates in kidney transplantation (1–3). Previously, new-onset diabetes after transplantation (NODAT) was adopted and implied only diabetes was diagnosed post-transplant. Therefore, NODAT had the shortcoming that there was a chance to exclude undiagnosed diabetes at pre-transplant screening, which is impractical for many transplant centers (4). For comprehensive management of diabetes post-transplant, the term PTDM was re-introduced on behalf of NODAT at an international consensus meeting (5). Because of the difficulty in finding undiagnosed diabetes at pre-transplant screening, it is known that the incidence of PTDM is approximately 10 to 30% (6, 7).

PTDM is caused by many factors before and after surgery, and among them, elements that can be modified and elements that cannot be modified are mixed (8–11). A typical postoperative factor is the use of immunosuppressive drugs such as tacrolimus and steroids, which are risk factors for early PTDM (12). In the case of late PTDM, metabolic causes such as obesity, prediabetes, hyperlipidemia, and insulin resistance are known to have a significant influence (13–15). As such, many studies have conducted research on PTDM. However, most studies have only addressed the risk of developing PTDM in patients without pre-transplant diabetes. Relatively, it is not well known about the natural course of pre-transplant diabetes in recipients who have already undergone a kidney transplant due to diabetic nephropathy or who were diagnosed with diabetes at the time of transplantation. After transplantation, it is thought that hyperglycemia becomes more severe or diabetes is more likely to occur because of the various factors that can cause hyperglycemia. However, on the other hand, there might be a possibility that hyperglycemia or diabetes may not worsen or improve after transplantation. Several studies previously reported how glucose and insulin levels changed in patients after kidney transplantation through the oral glucose tolerance test (OGTT) (16–18). Nevertheless, these previous studies showed meaningful results of OGTT during post-transplant PTDM, but the study populations only consisted of patients without pre-transplant diabetes. Therefore, the authors thought that it was necessary to analyze the changes in glucose metabolism in patients who already have diabetes after receiving a transplant and to understand the characteristics of patients whose glycemic status did not worsen or improve. In this study, we analyzed the results of OGTT follow-up for 1 year for kidney transplant patients who had already been diagnosed with diabetes before transplantation or pre-transplant screening. In addition, we investigated the changes in diabetes status after transplantation and the favorable factors for diabetes remission in recipients with pre-transplant diabetes.

In this multicenter prospective study, the authors evaluated a case in which recipients with pre-transplant diabetes did not worsen or improve their diabetes status 1 year after kidney transplantation despite taking immunosuppressive drugs that could worsen blood glucose levels after transplantation. As a result of the study, remission of diabetes occurred 1 year after kidney transplantation in 16 out of 74 patients (21.6%). Of the 16 kidney transplant patients whose diabetes had remitted, 15 (93.7%) were those who did not know they had diabetes until they received the transplant but were diagnosed in the pre-transplant baseline OGTT. Patients in the remission group had similar HOMA-IR values and higher IGI₃₀ values at baseline and less increased HOMA-IR and more increased IGI₃₀ values during the 1-year post-transplant period than those in the persistent diabetes group, suggesting that both insulin resistance and insulin secretory function were better in the remission group patients. In a multivariate analysis to find out the factors that did not worsen or affect the improvement of glucose metabolism, newly diagnosed patients with pre-transplant OGTT and high baseline IGI₃₀ values were analyzed as factors that contributed to the remission of diabetes after kidney transplantation.

PTDM is one of the most common metabolic complications in kidney transplant patients (23). The main issue with PTDM is not the risk of developing microvascular disease such as retinopathy, but rather the increased risk of cardiovascular disease and death (24). Furthermore, the previous cohort study reported that 5-year patient and graft survival rates in patients with pre-existing diabetes were significantly low (25). Thereafter, several studies have been conducted on newly developed diabetes after transplantation, identifying and referring to the risk factors for newly developed diabetes in patients without diabetes in advance. There have been several studies on changes in glucose metabolism after OGTT in patients without diabetes before kidney transplantation (17, 26–28). However, as in this study, it is rare to study changes in glucose metabolism and diabetes status by performing OGTT after kidney transplantation in patients with diabetes. Therefore, this study is meaningful to observe the change in diabetes status and changes in serum glucose and insulin in kidney transplant patients who have already been diagnosed with diabetes.

The previous study reported that the incidence of undiagnosed diabetes in kidney transplant candidates without known diabetes was 8.1% (4). In that study, the authors recommended pre-transplant OGTT in non-diabetic patients with high fasting blood glucose before transplantation. In our study, several patients with known diabetes were 61, and the remaining 118 patients were patients without diabetes before pre-transplant OGTT. Of 118 patients, 31 were diagnosed with diabetes by pre-transplant OGTT, and the incidence of undiagnosed diabetes was 26.3% in this study. This result suggested that a relatively large number of kidney transplant candidates could not recognize that they had diabetes. Although the results of this study cannot represent the status of all kidney transplant recipients, it can be inferred that undiagnosed diabetes exists in many kidney transplant candidates, which contributes to the prevalence of PTDM.

In the early period of post-transplantation, immunosuppression was intensively achieved using calcineurin inhibitors (CNIs) and corticosteroids, which can cause diabetes by different mechanisms. In terms of immunosuppression, changes in insulin secretion were primarily associated with CNI, whereas insulin resistance was related to corticosteroid use (29, 30). It is known that disturbance of insulin secretion rather than insulin resistance is the main mechanism for the development of PTDM in the early stages of transplantation (31). In this study, we found that impaired insulin secretion is involved not only in the development of PTDM but also in diabetes remission in patients with pre-existing diabetes. Looking at the IGI₃₀ values after transplantation, the IGI₃₀ values increased in the remission group compared to the baseline and did not increase in the persistent diabetes group. In particular, the IGI₃₀ value of the remission group increased significantly compared to baseline after transplantation. It can be inferred that, in the case of patients with well-preserved insulin secretory function, insulin secretion could be enhanced to compensate for increased insulin resistance when immunosuppressants are administered during the post-transplantation period, thereby preventing the exacerbation of glucose metabolism. It is suggested that preserving insulin secretion is important for both the development and improvement of diabetes.

In terms of OGTT, there was only one chance to perform an OGTT at pre-transplant for diagnosing diabetes in this study. The subjects of this study were patients who were scheduled to undergo kidney transplantation. In the case of deceased donor kidney transplant patients, the preoperative time for OGTT testing was only 1 to 2 days, so only one OGTT could be performed. To overcome some lack of precision, fasting glucose was measured once more before transplant surgery to confirm that they had diabetes among the newly diagnosed diabetes patients, in the case of patients whose only fasting glucose was measured as high in the OGTT result. Nevertheless, there may be limitations to diagnosing diabetes with OGTT. Especially in the remission group, the 2-hour value of seven patients was between 201 and 206 mg/dl. These subjects may have had prediabetes but not diabetes before the transplant. In these patients, it may be correct to mention that glucose metabolism or diabetes status did not deteriorate despite several factors contributing to the rise in blood glucose, such as the use of immunosuppressive drugs, rather than improving 1 year after transplantation.

The glucose metabolism in patients with end-stage renal disease (ESRD) is different from that in patients without ESRD. Dialysis in end-stage renal failure results in changes in glucose metabolism. As insulin resistance improves and insulin excretion increases, each individual’s blood sugar changes due to dynamic contributions from these two factors (32). Kidney transplantation shows similar changes to dialysis in glucose metabolism, and additional effects such as immunosuppressive drugs or kidney gluconeogenesis are added (33). Therefore, kidney transplantation generally has unfavorable effects on glucose metabolism. However, in our study, it was confirmed that the patient’s characteristics—preservation of insulin secretion at baseline and newly diagnosed diabetes—may be more important than the effect of kidney transplantation itself on glucose metabolism. In addition, lifestyle modification in diabetes remission groups like general diabetic patients is also thought to be an important factor for which glucose metabolism did not worsen or improve in kidney transplant patients, and further research is needed.

In this study, the most common cause of ESRD in pre-existing diabetic patients was diabetic nephropathy. Other causes of ESRD in newly diagnosed diabetic patients are hypertensive nephropathy, glomerular disease, and congenital renal disease, which are unknown. Depending on the cause of ESRD, there may be differences in medical care (particularly the use of immunosuppressants) after transplantation. When the cause of ESRD is diabetic kidney disease, a regimen that excludes steroids has been tried in many studies (34–38). Steroids increase the probability of metabolic complications, particularly in those patients. However, in this study, no difference in the use of steroids was observed between patients with diabetes and those without. The steroid withdrawal rate was about 30% in both groups, with no significant difference. Therefore, the effect of steroid use on glucose metabolism after transplantation may not have affected the groups differently in this study.

This study has several limitations. The first is that the number of study subjects is relatively small. It was a multicenter study, and the initial number of subjects was 179. The number of patients had to be small because of the exclusion of patients without diabetes before transplantation and patients with insufficient OGTT results. Although the study population is small, we believe that this number of study subjects can be meaningful because studies that conduct OGTT on kidney transplant patients with diabetes are uncommon. Second, this study included both groups with quite different characteristics according to our study design: a group with diabetic nephropathy and a group with newly diagnosed diabetes. This characteristic was confirmed to be an important factor in glucose metabolism after kidney transplant. That is, most of the patients with remission of diabetes were diagnosed with diabetes through the pre-transplant OGTT, and only one diabetic nephropathy patient showed remission of diabetes 1-year post-transplantation. This is consistent with the fact that remission of diabetes could be closely related to the duration of diabetes. The duration of diabetes is a factor affecting diabetes remission. Unfortunately, the exact duration of diabetes in patients with pre-existing diabetes could not be determined in this study. It was not possible to analyze the association between the duration of diabetes and diabetes remission because there was a lack of data on the duration of diabetes in subjects. However, the high rate of diabetes remission in patients with newly diagnosed diabetes suggests that a shorter diabetes duration may be related to remission. Third, the follow-up period is relatively short. This is because, in the case of a patient who already has diabetes, a period of about 1 year may not be sufficient to observe the pattern of change in blood glucose in kidney transplant patients. Therefore, a long-term follow-up study may be necessary. Lastly, there was a lack of data on recipients, such as their dietary patterns and exercise after transplantation. In addition, the incidence of diabetic retinopathy was not determined in this study. Therefore, we could not evaluate the effect of these factors on glucose metabolism after transplantation. Moreover, the initial body weight of patients may have been incorrect due to fluid retention because they were on dialysis. There could be inaccurate body weights and body mass indices in the study population; that said, most studies that have included dialysis patients probably have this limitation.

In conclusion, our prospective study revealed that in some recipients with pre-transplant diabetes, glucose metabolism did not deteriorate or diabetes status improved 1 year after kidney transplant. They had preserved insulin secretory function or newly diagnosed diabetes at pre-transplant. Considering the mechanism of PTDM that occurs after transplantation, it is reasonable that the ability to secrete insulin to compensate for increased insulin resistance after transplantation is important for glucose metabolism. Newly diagnosed diabetes as a favorable factor for diabetic remission is consistent with the factors in the non-transplant population.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Informed consent was provided to all patients and the study protocol was approved by the independent Institutional Review Board of each center (approval No. AJIRB-MED-CT4-15-422). The patients/participants provided their written informed consent to participate in this study.

Conceptualization: C-KO and SuL. Data curation: YK, SK, HY, C-DK, MJ, BS, SaL, SH, CJ, JK, and HA. Funding acquisition: C-KO. Investigation: YK, SK, HY, C-DK, MJ, BS, SaL, SH, CJ, JK, and HA. Methodology: C-KO, YK, SK, HY, C-DK, MJ, BS, SaL, SH, CJ, JK, and HA. Writing—original draft: JB. Writing—review & editing: JB, JJ, and SuL. All authors contributed to the article and approved the submitted version.