American Journal of Transplantation 2009; 9: 2858Wiley Periodicals Inc.

C© 2009 The AuthorsJournal compilation C© 2009 The American Society of

Transplantation and the American Society of Transplant Surgeons

doi: 10.1111/j.1600-6143.2009.02854.xLetter to the Editor

Predictors of New-Onset Diabetes AfterTransplantation: The Overlooked Confounders

To the Editor:

The article by Van Laecke et al. (1) highlights the rela-tionship between calcineurin inhibitor (CNI) induced hy-pomagnesemia and development of abnormal glucosemetabolism posttransplantation. The authors’ analysessuggest the diabetogenicity of CNIs, primarily consideredsecondary to pancreatic b-cell dysfunction, is also par-tially related to hypomagnesemia. Insulin regulates mag-nesium homeostasis but magnesium itself is reciprocallyimplicated in both insulin and glucose metabolism (2). Useof magnesium replacement, dietary or pharmacological, isassociated with attenuation of the risk of diabetes in thegeneral population and therefore the authors’ paradoxicalfindings of magnesium supplements being associated withnew-onset diabetes after transplantation, albeit on univari-ate analysis alone, is difficult to explicate. The explanationsoffered by the authors are legitimate but the answer maylie in the multitude of unappreciated confounding factorsinvolved with glucose metabolism.

CNIs are associated with numerous biochemical abnor-malities, with hypomagnesemia the focus of this paper.CNIs are also well documented as causing hyperuricemiaand are implicated in increased rates of gout posttrans-plantation. Serum uric acid has also been suggested as arisk factor for abnormal glucose metabolism in the gen-eral population; Dehghan et al. (3) found increasing serumuric acid to be a strong and independent risk factor forthe development of diabetes in 4526 nondiabetic individ-uals aged 55 years and above, over a mean follow up of10.1 years. This raises the possibility of targeting hyper-uricemia posttransplantation as a strategy for attenuationof transplant-associated hyperglycemia. As with hypomag-nesemia, it is difficult to extrapolate whether hyperuricemiais a precursor or consequence of abnormal glycemia buthyperuricemia could prove a confounding factor in the anal-ysis by Van Laecke et al.

The authors also report the use of active vitamin D ther-apy for all their patients posttransplantation and therebyadd an additional confounding factor. Pittas et al. (4) foundboth calcium and vitamin D intake were inversely associ-ated with development of type 2 diabetes in a prospectivestudy of 83 779 nondiabetic women during 20 years of fol-low up. Putative pathophysiological mechanisms proposed

included vitamin D insufficiency induced insulin resistanceand pancreatic b-cell dysfunction—the latter possibly ex-plained by the finding of vitamin D receptors in pancreaticb-cells.

Finally, there is a complicated interplay between insulin,glucose and renal graft function (5) and the higher creati-nine in the NODAT group compared to non-NODAT group(1.60 md/dL vs. 1.38 mg/dL respectively, p = 0.016) is anadditional confounding factor. It is unclear whether this hasbeen factored into the multivariate Cox proportional hazardmodel. In addition, the confounders highlighted above allhave 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 additionto the NODAT literature and provides interesting ‘foodfor thought’. Further work is required to explore theseconfounding mechanisms posttransplantation to ensurefindings from general population-based data translates totransplantation. Randomized controlled trials or prospec-tively collated observational data should be designed toaddress these issues, with all possible confounders ac-knowledged in data analysis.

Adnan SharifUniversity Hospital Birmingham

Edgbaston, BirminghamUnited Kingdom

References

1. Van Laecke S, Van Biesen W, Verbeke F, De Bacquer D, Peeters P,Vanholder R. Post-transplantation hypomagnesemia and its relationwith immunosuppression as predictors of new-onset diabetes aftertransplantation. Am J Transplant 2009; 9: 2140–2149.

2. Barbagallo M, Dominguez LJ. Magnesium metabolism in type 2diabetes mellitus, metabolic syndrome and insulin resistance. ArchBiochem Biophys 2007; 458: 40–47.

3. Dehghan 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: 361–362.

4. Pittas AG, Dawson-Hughes B, Li T et al. Vitamin D and calciumintake in relation to type 2 diabetes in women. Diabetes Care 2006;29: 650–656.

5. Sharif A. Insulin, glucose, and glomerular filtration rate. Transplan-tation 2009; 87: 1592–1593.

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