Wnt signaling in pancreatic islets.

The Wnt signaling pathway is critically important not only for stem cell amplification, differentiation, and migration, but also is important for organogenesis and the development of the body plan. Beta-catenin/TCF7L2-dependent Wnt signaling (the canonical pathway) is involved in pancreas development, islet function, and insulin production and secretion. The glucoincretin hormone glucagon-like peptide-1 and the chemokine stromal cell-derived factor-1 modulate canonical Wnt signaling in beta-cells which is obligatory for their mitogenic and cytoprotective actions. Genome-wide association studies have uncovered 19 gene loci that confer susceptibility for the development of type 2 diabetes. At least 14 of these diabetes risk alleles encode proteins that are implicated in islet growth and functioning. Seven of them are either components of, or known target genes for, Wnt signaling. The transcription factor TCF7L2 is particularly strongly associated with risk for diabetes and appears to be fundamentally important in both canonical Wnt signaling and beta-cell functioning. Experimental loss of TCF7L2 function in islets and polymorphisms in TCF7L2 alleles in humans impair glucose-stimulated insulin secretion, suggesting that perturbations in the Wnt signaling pathway may contribute substantially to the susceptibility for, and pathogenesis of, type 2 diabetes. This review focuses on considerations of the hormonal regulation of Wnt signaling in islets and implications for mutations in components of the Wnt signaling pathway as a source for risk-associated alleles for type 2 diabetes.