High glucose alters fetal rat islet transcriptome and induces progeny islet dysfunction

Area of Science:

• Endocrinology
• Developmental Biology
• Metabolic Disease Research

Background:

• Offspring of diabetic mothers have an increased risk of developing type 2 diabetes.
• The molecular mechanisms underlying this increased susceptibility are not fully understood.
• Pancreatic islet dysfunction is a key factor in the development of type 2 diabetes.

Purpose of the Study:

• To investigate the impact of maternal hyperglycemia on the fetal pancreatic islet transcriptome.
• To determine if prenatal hyperglycemia exposure leads to long-term islet dysfunction in offspring.
• To identify molecular pathways affected by hyperglycemia in fetal pancreatic islets.

Main Methods:

• A localized uterine horn infusion model was used to induce hyperglycemia in specific fetal rats.
• RNA sequencing was performed on fetal pancreatic islets to analyze gene expression changes.
• In vivo and ex vivo studies assessed islet cell viability and insulin secretion in offspring at different ages.

Main Results:

• Maternal hyperglycemia altered the fetal pancreatic islet transcriptome, enriching for diabetes mellitus and inflammation/cell death pathways.
• Offspring exposed to prenatal hyperglycemia exhibited decreased islet cell viability and impaired glucose-induced insulin secretion.
• Adult offspring showed glucose intolerance and insulin secretory dysfunction.

Conclusions:

• Late gestational hyperglycemia alters the fetal pancreatic islet transcriptome.
• Prenatal exposure to hyperglycemia increases offspring susceptibility to pancreatic islet dysfunction.
• These findings highlight a critical window during gestation where maternal metabolic status impacts offspring metabolic health.