To the Editor: The article by Van Laecke et al. (1Van Laecke S Van Biesen W Verbeke F De Bacquer D Peeters P Vanholder R Post-transplantation hypomagnesemia and its relation with immunosuppression as predictors of new-onset diabetes after transplantation.Am J Transplant. 2009; 9: 2140-2149Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar) highlights the relationship between calcineurin inhibitor (CNI) induced hypomagnesemia and development of abnormal glucose metabolism posttransplantation. The authors’ analyses suggest the diabetogenicity of CNIs, primarily considered secondary to pancreatic β-cell dysfunction, is also partially related to hypomagnesemia. Insulin regulates magnesium homeostasis but magnesium itself is reciprocally implicated in both insulin and glucose metabolism (2Barbagallo M Dominguez LJ Magnesium metabolism in type 2 diabetes mellitus, metabolic syndrome and insulin resistance.Arch Biochem Biophys. 2007; 458: 40-47Crossref PubMed Scopus (263) Google Scholar). Use of magnesium replacement, dietary or pharmacological, is associated with attenuation of the risk of diabetes in the general population and therefore the authors’ paradoxical findings of magnesium supplements being associated with new-onset diabetes after transplantation, albeit on univariate analysis alone, is difficult to explicate. The explanations offered by the authors are legitimate but the answer may lie in the multitude of unappreciated confounding factors involved with glucose metabolism. CNIs are associated with numerous biochemical abnormalities, with hypomagnesemia the focus of this paper. CNIs are also well documented as causing hyperuricemia and are implicated in increased rates of gout posttransplantation. Serum uric acid has also been suggested as a risk factor for abnormal glucose metabolism in the general population; Dehghan et al. (3Dehghan A Van Hoek M Sijbrands EJ Hofman A Witteman JC High serum uric acid as a novel risk factor for type 2 diabetes.Diabetes Care. 2008; 31: 361-362Crossref PubMed Scopus (447) Google Scholar) found increasing serum uric acid to be a strong and independent risk factor for the development of diabetes in 4526 nondiabetic individuals aged 55 years and above, over a mean follow up of 10.1 years. This raises the possibility of targeting hyperuricemia posttransplantation as a strategy for attenuation of transplant-associated hyperglycemia. As with hypomagnesemia, it is difficult to extrapolate whether hyperuricemia is a precursor or consequence of abnormal glycemia but hyperuricemia could prove a confounding factor in the analysis by Van Laecke et al. The authors also report the use of active vitamin D therapy for all their patients posttransplantation and thereby add an additional confounding factor. Pittas et al. (4Pittas AG Dawson-Hughes B Li T et al.Vitamin D and calcium intake in relation to type 2 diabetes in women.Diabetes Care. 2006; 29: 650-656Crossref PubMed Scopus (619) Google Scholar) found both calcium and vitamin D intake were inversely associated with development of type 2 diabetes in a prospective study of 83 779 nondiabetic women during 20 years of follow up. Putative pathophysiological mechanisms proposed included vitamin D insufficiency induced insulin resistance and pancreatic β-cell dysfunction—the latter possibly explained by the finding of vitamin D receptors in pancreatic β-cells. Finally, there is a complicated interplay between insulin, glucose and renal graft function (5Sharif A Insulin, glucose, and glomerular filtration rate.Transplantation. 2009; 87: 1592-1593Crossref PubMed Scopus (4) Google Scholar) and the higher creatinine in the NODAT group compared to non-NODAT group (1.60 md/dL vs. 1.38 mg/dL respectively, p = 0.016) is an additional confounding factor. It is unclear whether this has been factored into the multivariate Cox proportional hazard model. In addition, the confounders highlighted above all have a ‘cause and effect’ relationship with renal function, which makes the interplay even more complicated. The work by Van Laecke et al. is a welcome addition to the NODAT literature and provides interesting ‘food for thought’. Further work is required to explore these confounding mechanisms posttransplantation to ensure findings from general population-based data translates to transplantation. Randomized controlled trials or prospectively collated observational data should be designed to address these issues, with all possible confounders acknowledged in data analysis.