Evidence of non-pancreatic beta cell-dependent roles of Tcf7l2 in the regulation of glucose metabolism in mice.
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.
Department of Human Genetics.
Kathleen A
KA
Bailey
Department of Human Genetics.
Daniel
D
Savic
Department of Medicine.
Mark
M
Zielinski
Department of Medicine.
Soo-Young
SY
Park
Department of Surgery.
Ling-Jia
LJ
Wang
Department of Surgery.
Piotr
P
Witkowski
Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, IL 60637, USA.
Matthew
M
Brady
Department of Medicine.
Manami
M
Hara
Department of Human Genetics, Department of Medicine.
Graeme I
GI
Bell
Department of Human Genetics, nobrega@uchicago.edu.
Marcelo A
MA
Nobrega
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004195:Disease Models, Animal; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics*; D015854:Up-Regulation
C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D005947:Glucose