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New-onset Diabetes Mellitus after Renal Transplantation and its Association with Physical Activity and Proinsulin

(2012) Deinum, J. (Jolijn)

New-onset diabetes after transplantation (NODAT) is nowadays a prominent long-term problem in renal transplant recipients. Patients with NODAT are not only at higher risk to cardiovascular disease, but they also have a higher risk of development of graft failure. NODAT is also associated with reduced long-term survival in renal transplant recipients. Besides conventional risk factors for type 2 diabetes mellitus, renal transplant recipients are at high risk to develop NODAT due to the common problem of weight gain after transplantation and necessity of chronic exposure to diabetogenic immunosuppressive drugs. Both increased insulin resistance and reduced insulin production due to pancreatic beta-cell dysfunction are thought to be important in the pathogenesis of NODAT. Because physical activity possibly has an effect on insulin sensitivity, the first aim of this study was to investigate whether physical activity is associated with the development of NODAT in renal transplant recipients. Because proinsulin is an early biomarker for beta-cell dysfunction, as a second aim we investigated whether proinsulin is a predictor for the development of NODAT.

Renal transplant recipients who visited the outpatient renal transplant clinic between 2001 and 2003 and had a functioning graft ≥ year were invited to participate. Physical activity status was assessed as METS-min/day in the past 6 months from validated questionnaires (Tecumseh Occupational Activity Questionnaire (TOAQ) and Minnesota Leisure Time Physical Activity Questionnaire (MLTPAQ)) that were administered by interview. Subjects with diabetes at baseline were excluded. Incidence of NODAT and graft failure was recorded until April 2012.

A total of 501 RTR were studied (age 50.4 ± 12.2 years, 56.1% male) at a median of 6.0 [2.6-11.5] years after transplantation. Data of PA were available in 448 patients and proinsulin values in 487 patients. During median follow-up for 10.1 [9.7 – 10.4] years, 64 RTR developed NODAT. With 21 cases of NODAT (14.3%) in the first tertile of the distribution of PA, 25 (16.7%) in the second tertile and 18 (12.1%) in the third tertile, there was no significant association of PA with development of NODAT (p=0.46). With 34 (9.3%) cases of NODAT in in the first-three quartiles of the pro-insulin distribution and 42 (34.7%) in the fourth quartile, there was a significant association of pro-insulin with development of NODAT (p < 0.001). This was confirmed in a univariate Cox regression analysis, in which proinsulin was strongly associated with NODAT (HR [95% confidence interval] = 1.71 [1.53-1.91], p<0.001). In multivariate Cox regression analyses, proinsulin remained strongly associated with NODAT, independent of the potential confounders, age, gender, waist circumference, triglyceride level, glucose concentration and use of tacrolimus.

In conclusion, we found no association of PA with future development of NODAT. We, however, did find an independent association between hyperproinsulinaemia and the development of NODAT. Our results highlight the role of beta-cell dysfunction in the pathophysiology of NODAT and indicate the potential value of proinsulin for early identification of renal transplant recipients at increased risk for the development of NODAT.





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