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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.

Evidence of non-pancreatic beta cell-dependent roles of Tcf7l2 in the regulation of glucose metabolism in mice