# Effect of Maternal Hyperglycemia on Fetal Pancreatic Islet Development

## TL;DR

Maternal high blood sugar disrupts the development of the fetal pancreas, potentially affecting long-term metabolic health.

## Contribution

This study reveals how maternal hyperglycemia alters ECM protein deposition and transcription factors in fetal pancreatic islets.

## Key findings

- Hyperglycemia weakens deposition of laminin and increases integrin alpha 3 in the fetal endocrine pancreas.
- Endocrine cell proliferation is reduced, and beta-cell area is increased in hyperglycemic fetuses.
- Pdx1 expression is lower, while Pax4 expression is higher in hyperglycemic conditions.

## Abstract

Maternal hyperglycemia during fetal development can disrupt the development of vital fetal organs, including the endocrine pancreas (islets of Langerhans). This may have lifelong consequences for energy homeostasis and glucose metabolism. In this study, we investigated the effects of maternal hyperglycemia on the deposition patterns of extracellular matrix (ECM) proteins in the fetal endocrine pancreas. The ECM plays a critical role in the proper organization and function of endocrine pancreatic cells. We observed that hyperglycemia altered the deposition pattern of key ECM proteins. These changes were accompanied by an increased presence of immature islets of Langerhans and a disrupted distribution of endocrine cell types. Additionally, we noted abnormalities in the expression of specific transcription factor proteins that regulate gene expression involved in endocrine cell proliferation and maturation. Together, these findings suggest that ECM alterations contribute to the dysfunction of the endocrine pancreas induced by maternal hyperglycemia, with potential long-term effects on the metabolic health of the offspring.

Hyperglycemia during fetal development disturbs extracellular matrix (ECM) synthesis and deposition patterns, which disrupts organogenesis and adult organ function. Although the ECM cooperates in pancreas development, little is known about the effects of hyperglycemia on the pancreatic ECM during development. This study investigates the effect of severe maternal hyperglycemia on ECM composition and endocrine pancreas development in E19.0 mouse fetuses. Deposition patterns of pan-laminin, laminin (alpha 1 and gamma 1 chains) and integrin alpha 3 were evaluated by immunostaining. The proliferative index of islet cells and alpha and beta cell distribution were evaluated by PCNA, glucagon and insulin immunostaining, respectively. Pdx1 and Pax4 expressions were analyzed by RT-qPCR. While for pan-laminin and laminin (alpha1 and gamma1 chains) deposition was weaker in the endocrine pancreas of hyperglycemic mothers’ fetuses, integrin alpha 3 deposition in the basement membrane was increased. The proliferative index of endocrine cells was lower in the hyperglycemic group, while the beta-cell area was increased. In addition, there was a tendency towards lower Pdx1 and increased Pdx4 expression. These data suggest that maternal hyperglycemia alters fetal endocrine pancreas morphogenesis by modifying peri-islet basement membrane molecule patterns, promoting a decrease in endocrine cell proliferation associated with changes in the expression of important growth factors for the beta cells differentiated and the proliferative state.