Pancreatic Pericytes Support β-Cell Function in a Tcf7l2-Dependent Manner

Abstract

Polymorphism in , a component of the canonical Wnt signaling pathway, has a strong association with β-cell dysfunction and type 2 diabetes through a mechanism that has yet to be defined. β-Cells rely on cells in their microenvironment, including pericytes, for their proper function. Here, we show that Tcf7l2 activity in pancreatic pericytes is required for β-cell function. Transgenic mice in which Tcf7l2 was selectively inactivated in their pancreatic pericytes exhibited impaired glucose tolerance due to compromised β-cell function and glucose-stimulated insulin secretion. Inactivation of pericytic Tcf7l2 was associated with impaired expression of genes required for β-cell function and maturity in isolated islets. In addition, we identified Tcf7l2-dependent pericytic expression of secreted factors shown to promote β-cell function, including bone morphogenetic protein 4 (BMP4). Finally, we show that exogenous BMP4 is sufficient to rescue the impaired glucose-stimulated insulin secretion of transgenic mice, pointing to a potential mechanism through which pericytic Tcf7l2 activity affects β-cells. To conclude, we suggest that pancreatic pericytes produce secreted factors, including BMP4, in a Tcf7l2-dependent manner to support β-cell function. Our findings thus propose a potential cellular mechanism through which abnormal TCF7L2 activity predisposes individuals to diabetes and implicates abnormalities in the islet microenvironment in this disease.

Patterns of differential gene expression in a cellular model of human islet development, and relationship to type 2 diabetes predisposition

“…Alleles associated with risk of type 2 diabetes within the TCF7L2 and HHEX loci may influence early expression of these genes, which could affect development in multiple metabolic tissues. This view is supported by cellular and murine studies indicating that TCF7L2 regulates beta cell development and function [ 46 ], including via indirect effects in supporting tissues [ 47 ], as well as affecting hepatic function [ 48 ]. Similarly, Hhex is essential for the differentiation of the posterior foregut into the liver in mice [ 44 ], yet is also thought to regulate delta cell identity and function in islets [ 49 ].…”

Transcription Factor 7-Like 2 (TCF7L2) Gene Polymorphism and Progression From Single to Multiple Autoantibody Positivity in Individuals at Risk for Type 1 Diabetes

“…The expression of dominantnegative TCF7L2 in murine b-cells led to abnormalities of b-cell gene expression, specifically for Ccnd1, Ccnd2, Irs1, Irs2, Ins1, Ins2, and Mafa (25). In a recent study, inactivation of pancreatic pericytic TCF7L2 in transgenic mice was associated with impaired expression of genes involved in b-cell function and maturation (18). It is conceivable that these abnormalities prevent the b-cell from being recognized by the immune system and therefore the islet autoimmunity process slows down.…”

“…A potential hypothesis to explain these observations is that individuals who develop autoimmune diabetes but have only mild signs of islet autoimmunity, e.g., single autoantibody positivity, may carry a second diabetogenic factor, such as a TCF7L2 genetic variant that could impair insulin secretion and/or action. However, since TCF7L2 is also involved in the differentiation and function of b-cells (10,11,18), which are the target of the autoimmune attack that starts in the preclinical phases of type 1 diabetes, it could also modify the progression of islet autoimmunity. Here, we aimed to understand whether the TCF7L2 locus influences the conversion from single to multiple islet autoantibody positivity in individuals at risk for type 1 diabetes.…”

β-Cell–Derived Angiopoietin-1 Regulates Insulin Secretion and Glucose Homeostasis by Stabilizing the Islet Microenvironment

“…5A and B). In consideration of the known role of pericytes in tissue fibrosis, inflammation (28,41), and maintenance of vascular ultrastrucure (40,43), it appears that the depletion of pericytes would lead to impaired b-cell maturation or function (43)(44)(45)(46). Indeed, our findings in Ang1 b-cell2/2 mice demonstrated the role of pericytes in maintaining glucose homeostasis, which stresses that a healthy interaction between the endothelial cells and the pericytes is an important cornerstone for maintenance of healthy islet function.…”

“…Indeed, our findings in Ang1 b-cell2/2 mice demonstrated the role of pericytes in maintaining glucose homeostasis, which stresses that a healthy interaction between the endothelial cells and the pericytes is an important cornerstone for maintenance of healthy islet function. Mechanistically, pericyte defect may hamper GSIS because of the defect in Tcf7L2/BMP4 through the PDX-1/GLUT2 pathway (46) or may lead to insufficient production of the basement membrane protein, ultimately leading to b-cell dysfunction (47).…”