Functional characterization of Wnt proteins in mouse and human islets: roles in beta cell mass expansion and insulin secretion during type 2 Diabetes Mellitus

• Grant number: 23/01572-0
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2023
• End date: August 31, 2025
• Field of knowledge: Biological Sciences - Morphology - Histology
• Agreement: CNPq
• Principal Investigator: Helena Cristina de Lima Barbosa
• Grantee: Helena Cristina de Lima Barbosa
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 21/11189-3 - Role of KSRP in post-transcriptional regulation and beta cell function in INS-1E lineage and pancreatic islet, AP.R
• Associated scholarship(s): 23/11004-9 - Functional characterization of Wnt proteins in mouse and human islets: roles in beta cell mass expansion and insulin secretion during type 2 diabetes mellitus., BP.JD

Abstract

Decreased beta cell mass and secretory dysfunction are the main determinants of the pathogenesis of type 2 diabetes (T2D). Thus, improved understanding of the mechanisms regulating beta cell mass and secretory function will underpin strategies for maintaining appropriate blood glucose regulation and the development of novel therapies for T2D. In this context, the Wnt family proteins are of particular interest, we have shown that: 1) analysis of gene expression of 19 mammalian Wnt subtypes in human and mouse pancreas indicated the vast majority of Wnt proteins are expressed in the islets; 2) Wnts 3a and 5b gene expression is significantly increased in hyperplastic islets from prediabetic mice relative to non-hyperplastic islets from normal mice; 3) Wnts proteins secreted by hyperplastic or non-hyperplastic islets induce a significant increase in MIN6 beta-cell proliferation; and 4) Frizzled receptors (Fz4 e Fz9), the targets of Wnt proteins, show altered expression in human hyperplastic islets obtained from obese non-diabetic donors. These important observations support this research project proposal, which aims to establish the role of Wnts proteins and the signaling pathways used by these proteins in the islets, with the main objectives: 1) the quantification of the 19 Wnt mRNAs and key members of Wnt signaling in islets from mice and humans during T2D, compared to islets from normal mice and humans, respectively; 2) the identification of which cellular types of the islet that express/secrete Wnts; 3) characterization of the effects of Wnt proteins in the regulation of beta cell mass and insulin secretion in islets isolated from humans and mice in vitro conditions; and 4) the identification which signaling pathways are used by Wnt proteins in islet cells. The results obtained will be instrumental in defining the role of Wnts in optimizing beta cell function and which may be used in therapies for T2D. (AU)