Commentary Impact of transcription factor 7 - like 2 ( TCF 7 L 2 ) on pancreatic islet function and morphology in mice and men

Common genetic variations in the gene encoding the Transcription factor 7-like 2 TCF7L2 reveal the strongest association with type 2-diabetes known to date. These lead to impaired insulin production and output, but the mechanisms of disease remain incompletely known. In this issue of Diabeteologia two publications provide new insights into TCF7L2-dependent diabetes. The heterogeneity of type 2 diabetes, taken together with the number of genetic risk variants involved in the pathogenesis of the disease, calls for reflection when singling out the most important diabetes gene. Even so, few would object to the transcription factor TCF7L2 being given that status. After the initial discovery of the strong association of genetic variation in TCF7L2 with type 2 diabetes in 2006 [1], the subsequent genome-wide association studies (GWASs) for type 2 diabetes identified the single-nucleotide polymorphism (SNP) rs7903146 in intron 4 as the genetic variation most strongly associated with disease in European– American populations [2-5]. The importance of genetic variation in TCF7L2 for type 2 diabetes has been replicated in numerous studies in populations of diverse ethical backgrounds, although the exact location of the genetic variation associated with the disease is different in cohorts of Asian descent [6]. The general lesson learnt from the GWASs is that the vast majority of genetic risk variants associated with type 2 diabetes reduce the capacity for insulin secretion. Likewise, the clinical phenotype of TCF7L2-related type 2 diabetes is that of insulin deficiency. As for any genetic risk variant that associates with insulin deficiency, it may result from cellular factors that reduce beta cell mass and/or lower insulin output by impairing beta cell function. At present, we lack methods to unequivocally determine the predominant mechanism of reduced insulin production at different stages of disease. Be that as it may, the genetic discoveries have prompted intense activity in the area of islet biology. Despite the collective efforts by many different groups we are still far from having a unifying view on which functions transcription factor 7-like 2 (TCF7L2) protein fulfils under normal conditions, or how these fail during the development and progression of type 2 diabetes. The report by da Silva and colleagues in this issue of Diabetologia [7] adds another important facet to the evolving understanding of this transcription factor in glucose homeostasis. The present study clarifies several of the outstanding issues concerning the fundamental actions of TCF7L2 and its products on beta