Abstract
Non-coding variation within TCF7L2 remains the strongest genetic determinant of type 2 diabetes risk in humans. A considerable effort has been placed in understanding the functional roles of TCF7L2 in pancreatic beta cells, despite evidence of TCF7L2 expression in various peripheral tissues important in glucose homeostasis. Here, we use a humanized mouse model overexpressing Tcf7l2, resulting in glucose intolerance, to infer the contribution of Tcf7l2 overexpression in beta cells and in other tissues to the metabolic phenotypes displayed by these mice. Restoring Tcf7l2 expression specifically in beta cells to endogenous levels, in face of its overexpression elsewhere, results in impaired insulin secretion, reduced beta cell number and islet area, corroborating data obtained in humans showing similar phenotypes as a result of manipulations leading to Tcf7l2 loss of function. Interestingly, the persistent overexpression of Tcf7l2 in non-pancreatic tissues results in a significant worsening in glucose tolerance in vivo, indicating that Tcf7l2 overexpression in beta cells does not account for the glucose intolerance in the Tcf7l2 overexpression mouse model. Collectively, these data posit that Tcf7l2 plays key roles in glucose metabolism through actions beyond pancreatic beta cells, and further points to functionally opposing cell-type specific effects for Tcf7l2 on the maintenance of balanced glucose metabolism, thereby urging a careful examination of its role in non-pancreatic tissues as well as its composite metabolic effects across distinct tissues. Uncovering these roles may lead to new therapeutic targets for type 2 diabetes.
Highlights
Genetic variation within introns of TCF7L2 is strongly associated with increased risk of type 2 diabetes (T2D) [1,2,3,4,5,6,7,8]
This limited focus was initially precipitated by the demonstration that reducing Tcf7l2 expression in rodent and human beta cells models can lead to impaired insulin secretion and production [17,18]
Human genetics data have added further support by demonstrating that the T2D-risk allele is associated with impaired insulin secretion in humans, even in non-diabetics [32]
Summary
Genetic variation within introns of TCF7L2 is strongly associated with increased risk of type 2 diabetes (T2D) [1,2,3,4,5,6,7,8]. This non-coding region contains cis-regulatory elements that drive expression of TCF7L2 across a variety of tissues involved in glucose homeostasis, suggesting that the risk variants likely alter the expression of TCF7L2 [9,10,11]. Mice homozygous for a Tcf7l2 null allele are born with
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