Novel views on new-onset diabetes after transplantation: development, prevention and treatment

Abstract

New-onset diabetes after transplantation (NODAT) is associated with increased risk of allograft failure, cardiovascular disease and mortality, and therefore, jeopardizes the success of renal transplantation. Increased awareness of NODAT and the prediabetic states (impaired fasting glucose and impaired glucose tolerance, IGT) has fostered previous and present recommendations, based on the management of type 2 diabetes mellitus (T2DM). Unfortunately, the idea that NODAT merely resembles T2DM is potentially misleading, because the opportunity to initiate adequate anti-hyperglycaemic treatment early after transplantation might be given away for 'tailored' immunosuppression in patients who have developed NODAT or carry personal risk factors. Risk factor-independent mechanisms, however, seem to render postoperative hyperglycaemia with subsequent development of overt or 'full-blown' NODAT, the unavoidable consequence of the transplant and immunosuppressive process itself, at least in many cases. A proof of the concept that timely preventive intervention with exogenous insulin against post-transplant hyperglycaemia may decrease NODAT was recently provided by a small clinical trial, which is awaiting confirmation from a multicentre study. However, because early insulin therapy aimed at beta-cell protection seems to contrast the currently recommended, stepwise approach of 'watchful waiting' prior to pancreatic decompensation, we here aim at reviewing recent concepts regarding the development, prevention and treatment of NODAT, some of which seem to challenge the traditional view on T2DM and NODAT. In summary, we suggest a novel, risk factor-independent management approach to NODAT, which includes glycaemic monitoring and anti-hyperglycaemic treatment in virtually everybody after transplantation. This approach has widespread implications for future research and is intended to tackle NODAT and also ultimately cardiovascular disease.

FIGURE 1:

A prototypic blood glucose profile after transplantation. A 67-year-old female with body mass index 27 kg/m², without diabetes, without family history of diabetes and without hepatitis C infection, had been on haemodialysis for 18 months (lithium-induced nephropathy) before undergoing transplantation with a deceased donor kidney. The patient agreed to participate in the treat-to-target TIP-study [37] and was randomized to the conventional treatment (control) group. HbA1c was 5.0% at baseline. The very early post-transplant glucose profile and the glucose profile in post-transplant Week 3 are displayed. In post-transplant Week 2, the patient received short acting insulin on two consecutive days, but no more insulin corrections were administered and the patient was discharged on post-transplant Day 20. Non-fasting blood glucose ≥200 mg/dL had occurred only during three independent days before discharge. At the first TIP-study control visit on post-transplant Day 87, HbA1c had increased to 7.3%, 2 h glucose value during OGTT was 238 mg/dL, OGTT-derived beta-cell function was poor [insulinogenic index (IGI) = 0.016 nmol insulin/mmol glucose], while insulin sensitivity was not clearly impaired [oral glucose insulin sensitivity (OGIS) index = 300 mL/min/m²]. This patient's decompensation of glucose metabolism had not previously been noticed by measurements of fasting glucose during any of the patient's visits in the outpatient clinic. The patient received an oral antidiabetic agent (sulphonylurea) throughout the end of the study's follow-up as well as 2 years thereafter, when she was additionally contacted. Two consecutive high-dose corticosteroid treatments for acute transplant rejection had been given during post-transplant Weeks 3 and 5, which might have contributed to her rapid impairment of glucose metabolism. As discussed in the text, self-measurements of evening glucose along with early insulin therapy might have uncovered and simultaneously prevented the rapid decline in beta-cell function. Corticosteroid-treated rejections have been shown to associate with NODAT development [45, 53] and may therefore be considered transplant-specific risk factors rather than confounders, as discussed in the text. Fasting: ∼7:30 am, pre-lunch: ∼12:00 am, pre-supper: ∼5:30 pm, post-supper: ∼9:00 pm.

FIGURE 2:

General mechanisms of NODAT development, (A) early postoperative prevention and (B) late postoperative treatment. Beta cell mass inside the pancreas leading to insulin secretion is depicted by the clouds. The idea that beta cells can become stressed is symbolized by the warning flashes. Insulin resistance is depicted by the circle, and contributors to insulin resistance are also symbolized by flashes. When describing early post-transplant status (upper part of the figure = development), the figure explicitly contains only general mechanistic details, but no patient-specific risk factors of NODAT development, such as age, obesity, family history, ethnic background and viral infection, which may further influence insulin secretion and insulin resistance in a patient-specific manner. Asterisk denotes that these factors are listed in the text as contributors to hyperglycaemia (a, b and c). (A) Early basal insulin and lifestyle intervention (diet and exercise) act against evening hyperglycaemia and are helping beta cells to overcome the burden imposed after renal transplantation, as symbolized by green flashes. Insulin secretion may consequently increase. (B) Long-term anti-hyperglycaemic treatment may become necessary in stable KTRs if NODAT prevention has not been established or has failed. Note that the circle symbolizing insulin resistance is neither augmented nor diminished after renal transplantation, because the progression of insulin resistance is currently still a matter of debate. However, as indicated in the text, convincing evidence indicates that insulin resistance may even increase.

FIGURE 3:

A case of NODAT prevention after renal transplantation. A 47-year-old male with body mass index 21 kg/m², without diabetes, with family history of diabetes and without hepatitis C infection, underwent transplantation with a deceased donor kidney. Manifestation of end-stage renal disease (glomerulonephritis) had been 25 years ago (one previous graft, functioning for 18 years). The patient agreed to participate in the Treat-to-target TIP-study [37] and was randomized to the long-acting insulin treatment group. Although not required for the study protocol, this patient measured glucose at least twice daily throughout the course of one whole year, and his mean daily glucose values are displayed in the figure. In contrast to all other treatment patients, and not explicitly foreseen for the study protocol, this patient went back to injecting long-acting insulin three times after having been weaned off (which was not initially revealed to the study investigators), because he noted a rise in glucose levels upon high-dose corticosteroid treatment for rejection. As shown in the figure, HbA1c increased from baseline to the 3-month follow-up OGTT, despite insulin therapy and continuously decreased thereafter. The 2 h glucose level during the OGTT was excellent at 12 months, but higher before (data in the figure). OGTT-derived beta-cell function (IGI, displayed in the figure) was excellent at 12 months only. Insulin sensitivity (OGIS index, displayed in the figure) increased slightly towards the 12-month follow-up visit, but not nearly as strongly as insulin secretion: Specifically, from 6 to 12 months, OGIS increased by 7%, while IGI increased by 600%. At 2 years after the end of study follow-up, when that patient was additionally contacted, he reported excellent glycaemic control revealed during sporadic self-measurements of glucose, his most recent HbA1c had been 5.3%. Asterisk denotes that the y-axis units are in mg/dL for glucose, mg for prednisone, IU for insulin. Double asterisks denote during 3 days, the patient received 1000 mg of methylprednisolone, equivalent to 1250 mg of prednisone, outside the range of the axis.

FIGURE 4:

Hyperglycaemia and NODAT incidence after transplantation and possible consequences of early intervention. Plus denotes that the cumulative incidence of hyperglycaemia post-transplantation was adopted from original results reported in the TIP-study [37], e.g. 21 of 25 patients (84%) had blood glucose ≥200 mg/dL by postoperative Day 10 and 23 of 25 patients (92%) by postoperative Day 18. Double plus denotes that the cumulative incidence of overt NODAT post-transplantation was adopted from original results reported by Woodward et al. in tacrolimus-treated KTRs [31], using the USRDS's February 2001 data release. As discussed by the authors, by using the second International Coding of Diseases-9 coding for a diagnosis of diabetes after transplantation to define NODAT, they obtained ‘conservative estimates’ of the disease incidence. Because NODAT coding in this data set obtained prior to 2001 was very likely based on anti-hyperglycaemic treatment (not on hyperglycaemia itself), we applied the term overt NODAT in the figure legend. Today's incidence of NODAT is much higher, namely 40% by the third year post-transplantation, as reported by the USRDS [20]. Although the figure legend describes a 'hypothesized’ effect of early intervention, this is not fully hypothetical, as no patient in the TIP-study required anti-hyperglycaemic treatment, clinically, at the 1-year post-transplant follow-up visit [37]. NODAT , new-onset diabetes after transplantation.