Transcriptome determination of the pancreatic islets from rats with maternal Diabetes-programmed Hyperglycemia

• Grant number: 23/04866-4
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2023
• End date: September 30, 2025
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: Débora Cristina Damasceno
• Grantee: Débora Cristina Damasceno
• Host Institution: Faculdade de Medicina (FMB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
• Associated researchers: Erick da Cruz Castelli ; Patricia Pintor dos Reis
• Associated research grant(s): 24/02138-4 - miRNAs involved in the dysfunction of pancreatic ²-cells in rats with hyperglycemia programmed by maternal diabetes, AP.R

Abstract

Diabetes mellitus (DM) is one of the most serious health problems in the world, which represents a significant threat to public health. Intrauterine exposure to diabetes can affect fetal development leading to long-term effects on the health of the offspring. The development of metabolic, structural, and functional changes in various organs, including the endocrine pancreas (pancreatic islets) are the most common outcomes. Offspring of diabetic mothers are highly predisposed to glucose intolerance, obesity, insulin resistance, and arterial hypertension in adult life. Hyperglycemia during pregnancy seems to be responsible for abnormal glucose metabolism and pancreatic cell function in the offspring. Studies based on genome sequencing have found alterations in genes essential for the development, maturation, and function of beta cells, which may be associated with the risk of developing diabetes. These mechanisms involve epigenetic control mediated by microRNAs (miRNAs). miRNAs are non-protein coding molecules with potent regulatory action on gene expression and are altered in several diseases. Studies suggest that circulating miRNAs can be considered biomarkers for the development of diseases such as diabetes. Considering that maternal diabetes impairs pancreatic function and, consequently, glucose metabolism in pups of both women and laboratory animals, and considering the need to analyze the biomarkers responsible for the passage of the diabetic phenotype between generations, this study aims to evaluate the impact of maternal hyperglycemia on coding and non-coding transcriptome expression, the latter focusing on miRNAs in pancreatic islets isolated from diabetic mother rats and their adult female offspring. Female rats will be submitted to the induction of diabetes by administration of citrate buffer (non-diabetic= control group) or streptozotocin (beta-cytotoxic drug - diabetic group) in the neonatal life. After confirmation of diabetes in adult life, these rats will be mated to obtain offspring, which will be evaluated in adulthood (120 days of life). Subsequently, diabetic mother rats and their adult female offspring will be anesthetized to be submitted to laparotomy for collection of the pancreas, which will be processed for later transcriptomic analysis (total mRNA and miRNAs) expressed in the pancreatic islets. Our hypothesis is that daughters of diabetic rats reproduce the diabetic condition of their mothers based on alterations in the coding and non-coding transcriptome, and miRNAs might be important predictors of the passage of the diabetic phenotype to the offspring. By determining changes in the transcriptome of the endocrine-pancreatic tissue of diabetic mother rats and their daughters, we will be able not only to understand the complex molecular mechanisms that drive the diabetic phenotype across generations but also to identify targets for new therapeutic opportunities. (AU)