Reply to: “New onset diabetes after transplantation: A type 1.5 diabetes or latent autoimmune diabetes of adults?”
Authors: Qi Ling, Xiao Xu, Fengqin Dong, Shusen Zheng
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 New onset diabetes after transplantation: A type 1.5 diabetes or latent autoimmune diabetes of adults?Journal of HepatologyVol. 58Issue 5PreviewThe 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. Full-Text PDF Open Access We 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 [1Norton L. Fourcaudot M. Abdul-Ghani M.A. Winnier D. Mehta F.F. Jenkinson C.P. et al.Chromatin occupancy of transcription factor 7-like 2 (TCF7L2) and its role in hepatic glucose metabolism.Diabetologia. 2011; 54: 3132-3142Crossref PubMed Scopus (67) Google Scholar, 2Oh K.J. Park J. Kim S.S. Oh H. Choi C.S. Koo S.H. TCF7L2 modulates glucose homeostasis by regulating CREB- and FoxO1-dependent transcriptional pathway in the liver.PLoS Genet. 2012; 8: e1002986Crossref PubMed Scopus (59) Google Scholar]. TCF7L2 is important for insulin secretion and also critical for hepatic glucose production and hepatic insulin sensitivity. Therefore, in our study, both donor and recipient TCF7L2 genetic variants were associated with the onset of NODAT, possibly via the effects on donor liver glucose metabolism and recipient islets.Dr. Eshraghian presented comprehensive data on a very interesting possible link between NODAT and latent autoimmune diabetes in adults (LADA), which would help better understand the etiology of NODAT. However, there is similarity but also diversity in the etiology and pathophysiology of NODATs after different organ transplantation [[3]Dong M. Parsaik A.K. Eberhardt N.L. Basu A. Cosio F.G. Kudva Y.C. Cellular and physiological mechanisms of new-onset diabetes mellitus after solid organ transplantation.Diabet Med. 2012; 29: e1-e12Crossref PubMed Scopus (26) Google Scholar]. He pointed out that β-cell dysfunction rather than insulin resistance is the main cause of NODAT after kidney transplantation [[4]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 (145) Google Scholar], while in liver transplantation, insulin resistance, especially liver insulin resistance, is considered to make a great contribution to NODAT [[5]Gane E.J. Diabetes mellitus following liver transplantation in patients with hepatitis C virus: risks and consequences.Am J Transplant. 2012; 12: 531-538Crossref PubMed Scopus (33) Google Scholar]. Compared to other transplanted solid organs (e.g., kidney, heart, lung), the liver has the particularity that it is the principal organ for carbohydrate, protein, lipid and drug metabolism. Therefore, we hypothesized that donors’ phenotype and genotype may affect metabolic status in liver transplant recipients, and the primary purpose of our study was to investigate the role of donor liver in the development of post-liver transplantation complications. In our previous study, donor CYP3A5 gene polymorphisms were associated with the metabolism of tacrolimus in liver transplantation [[6]Yu S. Wu L. Jin J. Yan S. Jiang G. Xie H. et al.Influence of CYP3A5 gene polymorphisms of donor rather than recipient to tacrolimus individual dose requirement in liver transplantation.Transplantation. 2006; 81: 46-51Crossref PubMed Scopus (66) Google Scholar], and donor rs290487 genetic variant in TCF7L2 gene increased NODAT risk after liver transplantation [[7]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 (56) Google Scholar]. In our most recent study, we showed that donor’s genotype could even contribute to intrahepatic recurrence of hepatocellular carcinoma after liver transplantation (unpublished data). Taken together, these findings provide evidence that donor liver does have a great influence on the post-liver transplant complications, and open a door to evaluate the respective roles of donor and recipient or even their cross-talk in the outcome after liver transplantation.LADA is distinguished from type 2 diabetes by the presence of islet autoantibodies [[8]Zhou Z. Xiang Y. Ji L. Jia W. Ning G. Huang G. et al.Frequency, immunogenetics, and clinical characteristics of latent autoimmune diabetes in China (LADA China study): a Nationwide, multicenter, clinic-based cross-sectional study.Diabetes. 2013; 62: 543-550Crossref PubMed Scopus (179) Google Scholar]. With great interest, we learn the possible link between NODAT and LADA. We should admit that NODAT shares some similarities with LADA in clinical presentation. However, it is still too early to say whether NODAT could be categorized into this subgroup because the etiologies of both NODAT and LADA are unclear. According to the LADA China study [[8]Zhou Z. Xiang Y. Ji L. Jia W. Ning G. Huang G. et al.Frequency, immunogenetics, and clinical characteristics of latent autoimmune diabetes in China (LADA China study): a Nationwide, multicenter, clinic-based cross-sectional study.Diabetes. 2013; 62: 543-550Crossref PubMed Scopus (179) Google Scholar], glutamic acid decarboxylase antibody (GADA) positive phenotypic type 2 diabetes (<1 year post diagnosis, without insulin therapy for >6 months, aged ⩾30 years) was considered as LADA. Circulating islet autoantibodies are essential in the diagnosis of LADA. Up to now, the most important evidence to prove the association between NODAT and LADA is from Lohmann et al. [[9]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 Diabet. 2000; 108: 347-352Crossref PubMed Scopus (36) Google Scholar], as mentioned by Dr. Eshraghian. In a cohort of 58 patients, they found that islet cell autoantibodies-positive patients with tacrolimus treatment were more prone to have NODAT after liver transplantation [[9]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 Diabet. 2000; 108: 347-352Crossref PubMed Scopus (36) Google Scholar]. Other evidence is from genetics research indicating that both diseases were related to TCF7L2 gene polymorphisms [7Ling 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 (56) Google Scholar, 10Lukacs 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 (52) Google Scholar]. However, other important points for the diagnosis of LADA, such as time to insulin dependence, age and body mass index (BMI), are unspecific and anthropogenic in NODAT. For instance, perioperative or in-hospital hyperglycemia is routinely treated with insulin so that time for an insulin intervention is dependent on local clinicians; patient age at adult liver transplantation is usually beyond 35 years; BMI is always low in chronic consumption such as cirrhosis, but can increase in cirrhosis with massive ascites and edema. Therefore, further well-designed and large sample studies are needed to evaluate the LADA-associated characters in NODAT and to explore the possible correlation. Studying the association between TCF7L2 gene and clinical parameters (e.g., islet cell autoantibodies, insulin resistance, β-cell function, tacrolimus response, antidiabetic response) in liver transplantation can provide more valuable information.Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. We 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 [1Norton L. Fourcaudot M. Abdul-Ghani M.A. Winnier D. Mehta F.F. Jenkinson C.P. et al.Chromatin occupancy of transcription factor 7-like 2 (TCF7L2) and its role in hepatic glucose metabolism.Diabetologia. 2011; 54: 3132-3142Crossref PubMed Scopus (67) Google Scholar, 2Oh K.J. Park J. Kim S.S. Oh H. Choi C.S. Koo S.H. TCF7L2 modulates glucose homeostasis by regulating CREB- and FoxO1-dependent transcriptional pathway in the liver.PLoS Genet. 2012; 8: e1002986Crossref PubMed Scopus (59) Google Scholar]. TCF7L2 is important for insulin secretion and also critical for hepatic glucose production and hepatic insulin sensitivity. Therefore, in our study, both donor and recipient TCF7L2 genetic variants were associated with the onset of NODAT, possibly via the effects on donor liver glucose metabolism and recipient islets. Dr. Eshraghian presented comprehensive data on a very interesting possible link between NODAT and latent autoimmune diabetes in adults (LADA), which would help better understand the etiology of NODAT. However, there is similarity but also diversity in the etiology and pathophysiology of NODATs after different organ transplantation [[3]Dong M. Parsaik A.K. Eberhardt N.L. Basu A. Cosio F.G. Kudva Y.C. Cellular and physiological mechanisms of new-onset diabetes mellitus after solid organ transplantation.Diabet Med. 2012; 29: e1-e12Crossref PubMed Scopus (26) Google Scholar]. He pointed out that β-cell dysfunction rather than insulin resistance is the main cause of NODAT after kidney transplantation [[4]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 (145) Google Scholar], while in liver transplantation, insulin resistance, especially liver insulin resistance, is considered to make a great contribution to NODAT [[5]Gane E.J. Diabetes mellitus following liver transplantation in patients with hepatitis C virus: risks and consequences.Am J Transplant. 2012; 12: 531-538Crossref PubMed Scopus (33) Google Scholar]. Compared to other transplanted solid organs (e.g., kidney, heart, lung), the liver has the particularity that it is the principal organ for carbohydrate, protein, lipid and drug metabolism. Therefore, we hypothesized that donors’ phenotype and genotype may affect metabolic status in liver transplant recipients, and the primary purpose of our study was to investigate the role of donor liver in the development of post-liver transplantation complications. In our previous study, donor CYP3A5 gene polymorphisms were associated with the metabolism of tacrolimus in liver transplantation [[6]Yu S. Wu L. Jin J. Yan S. Jiang G. Xie H. et al.Influence of CYP3A5 gene polymorphisms of donor rather than recipient to tacrolimus individual dose requirement in liver transplantation.Transplantation. 2006; 81: 46-51Crossref PubMed Scopus (66) Google Scholar], and donor rs290487 genetic variant in TCF7L2 gene increased NODAT risk after liver transplantation [[7]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 (56) Google Scholar]. In our most recent study, we showed that donor’s genotype could even contribute to intrahepatic recurrence of hepatocellular carcinoma after liver transplantation (unpublished data). Taken together, these findings provide evidence that donor liver does have a great influence on the post-liver transplant complications, and open a door to evaluate the respective roles of donor and recipient or even their cross-talk in the outcome after liver transplantation. LADA is distinguished from type 2 diabetes by the presence of islet autoantibodies [[8]Zhou Z. Xiang Y. Ji L. Jia W. Ning G. Huang G. et al.Frequency, immunogenetics, and clinical characteristics of latent autoimmune diabetes in China (LADA China study): a Nationwide, multicenter, clinic-based cross-sectional study.Diabetes. 2013; 62: 543-550Crossref PubMed Scopus (179) Google Scholar]. With great interest, we learn the possible link between NODAT and LADA. We should admit that NODAT shares some similarities with LADA in clinical presentation. However, it is still too early to say whether NODAT could be categorized into this subgroup because the etiologies of both NODAT and LADA are unclear. According to the LADA China study [[8]Zhou Z. Xiang Y. Ji L. Jia W. Ning G. Huang G. et al.Frequency, immunogenetics, and clinical characteristics of latent autoimmune diabetes in China (LADA China study): a Nationwide, multicenter, clinic-based cross-sectional study.Diabetes. 2013; 62: 543-550Crossref PubMed Scopus (179) Google Scholar], glutamic acid decarboxylase antibody (GADA) positive phenotypic type 2 diabetes (<1 year post diagnosis, without insulin therapy for >6 months, aged ⩾30 years) was considered as LADA. Circulating islet autoantibodies are essential in the diagnosis of LADA. Up to now, the most important evidence to prove the association between NODAT and LADA is from Lohmann et al. [[9]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 Diabet. 2000; 108: 347-352Crossref PubMed Scopus (36) Google Scholar], as mentioned by Dr. Eshraghian. In a cohort of 58 patients, they found that islet cell autoantibodies-positive patients with tacrolimus treatment were more prone to have NODAT after liver transplantation [[9]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 Diabet. 2000; 108: 347-352Crossref PubMed Scopus (36) Google Scholar]. Other evidence is from genetics research indicating that both diseases were related to TCF7L2 gene polymorphisms [7Ling 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 (56) Google Scholar, 10Lukacs 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 (52) Google Scholar]. However, other important points for the diagnosis of LADA, such as time to insulin dependence, age and body mass index (BMI), are unspecific and anthropogenic in NODAT. For instance, perioperative or in-hospital hyperglycemia is routinely treated with insulin so that time for an insulin intervention is dependent on local clinicians; patient age at adult liver transplantation is usually beyond 35 years; BMI is always low in chronic consumption such as cirrhosis, but can increase in cirrhosis with massive ascites and edema. Therefore, further well-designed and large sample studies are needed to evaluate the LADA-associated characters in NODAT and to explore the possible correlation. Studying the association between TCF7L2 gene and clinical parameters (e.g., islet cell autoantibodies, insulin resistance, β-cell function, tacrolimus response, antidiabetic response) in liver transplantation can provide more valuable information. Conflict of interestThe authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.