New onset diabetes after transplantation: A type 1.5 diabetes or latent autoimmune diabetes of adults?
Authors: Ahad Eshraghian
Journal: Journal of Hepatology (2013)

Association between donor and recipient TCF7L2 gene polymorphisms and the risk of new-onset diabetes mellitus after liver transplantation in a Han Chinese populationJournal of HepatologyVol. 58Issue 2PreviewNew-onset diabetes mellitus (NODM) is a frequent and serious complication arising after liver transplantation (LT). Transcription factor 7-like 2 (TCF7L2) polymorphisms have been reported to strongly associate with type 2 diabetes. In addition, the donor liver plays a vital role in regulating blood glucose levels. In this study, we aim at evaluating the association between donor and recipient TCF7L2 gene polymorphisms with NODM after LT. Full-Text PDF Reply to: "New onset diabetes after transplantation: A type 1.5 diabetes or latent autoimmune diabetes of adults?"Journal of HepatologyVol. 58Issue 5PreviewWe would like to thank Dr. Eshraghian for his interest in and insightful comments on our article. Both of us believe that genetic factor involves in the pathogenesis of new onset diabetes after transplantation (NODAT). Dr. Eshraghian summarized the association between TCF7L2 gene and diabetes, and explained the underlying mechanism by the role of TCF7L2 gene in human pancreatic islets. Here, we would like to make an additional explanation that TCF7L2 gene also plays a crucial role in hepatic glucose metabolism by interacting with multiple gluconeogenic genes and regulating glucose intolerance in the liver [1,2]. Full-Text PDF Open Access The term "new onset diabetes after transplantation (NODAT)" refers to new incidence of diabetes mellitus after solid organ transplantation. NODAT is among the metabolic complications after liver transplantation that has been reported to be associated with negative impact on patient and graft survival. Several risk factors have been proposed but the precise pathogenesis has not been well demonstrated. It should be noted that not all patients, even with all of the risk factors, develop NODAT. This implies the role of genetic predisposition in the pathogenesis of NODAT. I read with great interest the recently published paper by Ling et al. showing the association between donor and recipient transcription factor 7-like 2 (TCF7L2) gene polymorphisms with the development of NODAT after liver transplantation [[1]Ling Q. Xie H. Lu D. Wei X. Gao F. Zhou L. et al.Association between donor and recipient TCF7L2 gene polymorphisms and the risk of new-onset diabetes mellitus after liver transplantation in a Han Chinese population.J Hepatol. 2013; 58: 271-277Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar]. In multivariate analysis, they showed that donor and recipient rs290487 single nucleotide polymorphism (SNP) (C-allele) in TCF7L2 gene was significantly associated with the incidence of NODAT after liver transplantation. Other independent risk factors for NODAT were advanced recipient age and higher blood tacrolimus levels at 1 month after liver transplantation. Their results are interesting with respect to the identification of a genetic susceptibility for NODAT in liver transplant recipients. Several previous studies have confirmed that TCF7L2 is a major susceptibility gene for type 2 diabetes in different populations [[2]Grant S.F. Thorleifsson G. Reynisdottir I. Benediktsson R. Manolescu A. Sainz J. et al.Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes.Nat Genet. 2006; 38: 320-323Crossref PubMed Scopus (1763) Google Scholar]. The product of this gene binds to beta-catenin (β-cat) and forms a bipartite transcription factor known as TCF-β-cat, which is an important effector of Wnt signaling [[3]Shu L. Sauter N.S. Schulthess F.T. Matveyenko A.V. Oberholzer J. Maedler K. Transcription factor 7-like 2 regulates beta-cell survival and function in human pancreatic islets.Diabetes. 2008; 57: 645-653Crossref PubMed Scopus (222) Google Scholar]. It has been reported that TCF7L2 depletion in human pancreatic islets resulted in a significant increase in β-cell apoptosis and decrease in insulin secretion [[3]Shu L. Sauter N.S. Schulthess F.T. Matveyenko A.V. Oberholzer J. Maedler K. Transcription factor 7-like 2 regulates beta-cell survival and function in human pancreatic islets.Diabetes. 2008; 57: 645-653Crossref PubMed Scopus (222) Google Scholar]. Expression of TCF7L2 and glucagon like peptide-1 was decreased in human islets from patients with type 2 diabetes mellitus [[4]Shu L. Matveyenko A.V. Kerr-Conte J. Cho J.H. McIntosh C.H. Maedler K. Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function.Hum Mol Genet. 2009; 18: 2388-2399Crossref PubMed Scopus (209) Google Scholar]. Therefore, TCF7L2 gene plays an important role in β-cell function and proliferation in type 2 diabetes. Recently published studies have reported TCF7L2 gene polymorphism in patients with latent autoimmune diabetes of adult (LADA) [[5]Lukacs K. Hosszufalusi N. Dinya E. Bakacs M. Madacsy L. Panczel P. The type 2 diabetes-associated variant in TCF7L2 is associated with latent autoimmune diabetes in adult Europeans and the gene effect is modified by obesity: a meta-analysis and an individual study.Diabetologia. 2012; 55: 689-693Crossref PubMed Scopus (54) Google Scholar]. LADA is classically categorized as a form of type 1 diabetes although it exhibits some clinical and laboratory features of both type 1 and 2 diabetes, resulting in the use of the term "type 1.5 diabetes" by some authors [[6]Naik R.G. Brooks-Worrell B.M. Palmer J.P. Latent autoimmune diabetes in adults.J Clin Endocrinol Metab. 2009; 94: 4635-4644Crossref PubMed Scopus (150) Google Scholar]. Patients with LADA are older than 35 years at onset of diabetes and their disease is initially controlled with diet and oral hypoglycemic agents. These clinical features are similar to patients with type 2 diabetes, but they will require insulin therapy in a shorter period of time than that of type 2 diabetes patients. On the other hand, patients with LADA are non-obese, ketosis prone patients with unstable blood glucose level and presence of islet autoantibodies in the blood [[6]Naik R.G. Brooks-Worrell B.M. Palmer J.P. Latent autoimmune diabetes in adults.J Clin Endocrinol Metab. 2009; 94: 4635-4644Crossref PubMed Scopus (150) Google Scholar]. These features are similar to those of patients with type 1 diabetes. Anti-glutamic acid decarboxylase (GAD) and anti-islet-cell cytoplasm (ICA) are more common than other types of autoantibodies in these patients [[7]Juneja R. Hirsch I.B. Naik R.G. Brooks-Worrell B.M. Greenbaum C.J. Palmer J.P. Islet cell antibodies and glutamic acid decarboxylase antibodies but not the clinical phenotype help to identify type 1 1/2 diabetes in patients presenting with type 2 diabetes.Metabolism. 2001; 50: 1008-1013Abstract Full Text PDF PubMed Scopus (74) Google Scholar]. Furthermore, insulin resistance in LADA patients is less common than type 2 diabetes and is similar to type 1 diabetes [[6]Naik R.G. Brooks-Worrell B.M. Palmer J.P. Latent autoimmune diabetes in adults.J Clin Endocrinol Metab. 2009; 94: 4635-4644Crossref PubMed Scopus (150) Google Scholar]. Several features of NODAT are comparable with LADA. Therefore, NODAT can be categorized in this subgroup of patients with diabetes. As outlined in the present study, obesity was not an independent risk factor for NODAT. In fact, body mass index (BMI) at the first and third months after liver transplantation was not different between patients with NODAT and patients without NODAT. Therefore, it seems that the effect of higher BMI in the development of NODAT, as reported in previous studies, may be delayed to the period after the 6th month of transplantation. Patients with NODAT are prone to ketosis and there are several reports of presentation of NODAT with keto-acidosis [[8]Dehghani S.M. Nikeghbalian S. Eshraghian A. Haghighat M. Imanieh M.H. Bahador A. et al.New-onset diabetes mellitus presenting with diabetic ketoacidosis after pediatric liver transplantation.Pediatr Transpl. 2009; 13: 536-539Crossref PubMed Scopus (14) Google Scholar]. Patients with NODAT can be treated initially with oral hypoglycemic agents such as patients with LADA. Although several studies have reported the role of insulin resistance and impaired insulin response in the development of NODAT, it has been reported that β-cell dysfunction rather than insulin resistance is involved in the pathogenesis of NODAT [[9]Nam J.H. Mun J.I. Kim S.I. Kang S.W. Choi K.H. Park K. et al.Beta-cell dysfunction rather than insulin resistance is the main contributing factor for the development of postrenal transplantation diabetes mellitus.Transplantation. 2001; 71: 1417-1423Crossref PubMed Scopus (150) Google Scholar]. Additional important evidence is obtained from a cross sectional study that reported ICA positivity, but not other autoantibodies, in patients after liver transplantation on tacrolimus therapy. All of these patients had post-transplant diabetes at the time of examination or developed diabetes in their follow-up [[10]Lohmann T. List C. Lamesch P. Kohlhaw K. Wenzke M. Schwarz C. et al.Diabetes mellitus and islet cell specific autoimmunity as adverse effects of immunsuppressive therapy by FK506/tacrolimus.Exp Clin Endocrinol Diabetes. 2000; 108: 347-352Crossref PubMed Scopus (36) Google Scholar]. This pattern of autoantibody positivity is also very similar to LADA patients. In this well-designed and well-performed study, TCF7L2 gene polymorphism was associated with incidence of NODAT in liver transplant recipients. TCF7L2 gene is not only a predisposing gene for type 2 diabetes but also for LADA. Investigating the association between islet autoantibodies, markers of insulin resistance and blood tacrolimus level with TCF7L2 polymorphism in patients with NODAT was some valuable information that the study did not provide. Taking this evidence into account and considering the results of the current study, NODAT should not be simply categorized as type 2 diabetes and may fall into the LADA category. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.