Pancreatic β-cell dysfunction and risk of new-onset diabetes after kidney transplantation

Abstract

Objective: Chronic exposure to calcineurin inhibitors and corticosteroids poses renal transplant recipients (RTR) at high risk for development of new-onset diabetes after transplantation (NODAT). Pancreatic β-cell dysfunction may be crucial to the pathophysiology of NODAT and specific markers for β-cell dysfunction may have additive value for predicting NODAT in this population. Therefore, we prospectively investigated whether proinsulin, as a marker of pancreatic β-cell dysfunction, is associated with future development of NODAT and improves prediction of it.

Research design and methods: All RTR between 2001 and 2003 with a functioning graft for ≥1 year were considered eligible for inclusion, except for subjects with diabetes at baseline who were excluded. We recorded incidence of NODAT until April 2012.

Results: A total of 487 RTR (age 50 ± 12 years, 55% men) participated at a median time of 6.0 (interquartile range [IQR], 2.6-11.5) years after transplantation. Median fasting proinsulin levels were 16.6 (IQR, 11.0-24.2) pmol/L. During median follow-up for 10.1 (IQR, 9.1-10.4) years, 42 (35%) RTR had development of NODAT in the highest quartile of the distribution of proinsulin versus 34 (9%) in the lowest three quartiles (P < 0.001). In Cox regression analyses, proinsulin (hazard ratio, 2.29; 95% CI, 1.85-2.83; P < 0.001) was strongly associated with NODAT development. This was independent of age, sex, calcineurine inhibitors, prednisolone use, components of the metabolic syndrome, or homeostasis model assessment.

Conclusions: In conclusion, fasting proinsulin is strongly associated with NODAT development in RTR. Our results highlight the role of β-cell dysfunction in the pathophysiology of NODAT and indicate the potential value of proinsulin for identification of RTR at increased risk for NODAT.

Figure 1

Kaplan-Meier curve of de novo diabetes in quartiles of proinsulin tested with log-rank test (P < 0.001). Cut-off points for quartiles of proinsulin were as follows: quartiles 1–3, 2.4–24.4 (pmol/L), and quartile 4, >24.5 (pmol/L).