AbstractBackgroundThe discovery ofTCF7L2as a global type 2 diabetes (T2D) gene hassparked investigations to explore the clinical utility of its variants forguiding the development of new diagnostic and therapeutic strategies.However, interpreting the resulting associations into function still remainsunclear. Canonical Wnt signaling regulates β-catenin and its bindingwith TCF7L2, which in turn is critical for the production of glucagon-likepeptide-1 (GLP-1). This study examines the role of a novel frame-shiftinsertion discovered in a conserved region ofWNT16a, and it isproposed that this mutation affects T2D susceptibility in conjunction withgene variants inTCF7L2.ResultsOur results predicted that the insertion would convert the upstream openreading frame in the Wnt16a mRNA to an alternative, in-frame translationinitiation site, resulting in the prevention of nonsense-mediated decay,leading to a consequent stabilization of the mutated WNT16a message. Toexamine the role of Wnt16a in the Wnt signaling pathway, DNA and serumsamples from 2,034 individuals (48% with T2D) from the Sikh Diabetes Studywere used in this investigation. Prevalence of Wnt16a insertion did notdiffer among T2D cases (33%) and controls (32%). However, there was a 3.2fold increase in Wnt16a mRNA levels in pancreatic tissues from the insertioncarriers and a significant increase (70%, p < 0.0001) in luciferaseactivity in the constructs carrying the insertion. The expression of TCF7L2mRNA in pancreas was also elevated (~23-fold) among the insertion carriers(p=0.003).ConclusionsOur results suggest synergistic effects ofWNT16ainsertion and theat-risk ‘T’ allele of TCF7L2 (rs7903146) for elevating theexpression ofTCF7L2in human pancreas which may affect theregulation of downstream target genes involved in the development of T2Dthrough Wnt/β-catenin/TCF7L2 signaling pathway. However, furtherstudies would be needed to mechanistically link the two definitively.