In vitro study of the protective role of CCND2 gene variants against type 2 diabetes in obesity: looking at the crosstalk between adipose tissue and pancreatic b cells

• Grant number: 23/02315-0
• Support Opportunities: Scholarships abroad - Research
• Start date: March 04, 2024
• End date: March 03, 2025
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: Anna Karenina Azevedo Martins
• Grantee: Anna Karenina Azevedo Martins
• Host Investigator: Miriam Cnop
• Host Institution: Escola de Artes, Ciências e Humanidades (EACH). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Université Libre de Bruxelles (ULB), Belgium

Abstract

Type 2 diabetes (T2D) is a complex disease characterized by progressive b cell failure in a context of insulin resistance. Genome-wide association studies (GWAS) have identified >500 genetic loci, that alter T2D risk by affecting insulin secretion or sensitivity. The molecular mechanisms through which these gene variants confer T2D risk remain ill understood. Expression quantitative trait locus (eQTL) mapping allows to identify the association between gene variants and gene expression. Co-localization between GWAS and eQTL single nucleotide polymorphisms (SNPs) can then causally link a variant to an effector transcript. A human islet eQTL was recently discovered for the low-frequency CCND2 rs76895963[G] variant, which is known to reduce T2D risk by half and to increase insulin secretion. The same SNP increases body mass index, suggesting that the b cells of CCND2 rs76895963[G] variant carriers are particularly well equipped to stave off obesity-induced T2D. Here, we will study the adipose tissue-b cell axis to identify rs76895963[G]-dependent protective mechanism(s). We will generate an in vitro model by differentiating CCND2 [G]- or [T]-carrying human induced pluripotent stem cells (iPSCs) into b cells, and explore the adipose tissue-islet crosstalk in the context of the adverse metabolic environment of obesity. This study aims to evaluate the impact of the CCND2 genetic variant on in vitro b cell development, function, and survival under basal and adipose stress conditions. This project will clarify how the CCND2 genetic variant and gene-obese environment interactions lead to changes in b cell maturation, function, and survival as a result of interorgan crosstalk in T2D pathogenesis. (AU)