ESPE Abstracts

Background: Intrauterine growth restriction (IUGR) is associated with higher risk of cardiometabolic disease. Perturbation of endoplasmic reticulum (ER) homeostasis activates a set of ER-to-nucleus signaling pathways known as unfolded protein response (UPR). We previously showed that IUGR is associated with the activation of hepatic UPR and abnormal glucose profile in male Sprague-Dawley rats. Herein, we report the impact of IUGR on pancreas UPR in the same experimental model.

Objective and hypotheses: To longitudinally evaluate UPR in islets of Langerhans of male IUGR rats.

Methods: On day 19 of gestation, Sprague-Dawley pregnant rats were anesthetized and suture placed around both the uterine arteries and then either tied or withdrawn before closing the abdomen. Dams recovered quickly from uterine artery ligation and sham procedures, and resumed feeding the same day. After recovery, rats had ad libitum access to food and water. The pregnant rats were allowed to deliver spontaneously. The offspring was either weighed and killed at 8 hrs after delivery or followed up to 105 d. Results from 6 IUGR animals were compared with those from 6 SHAM offspring and analysed separately according to the gender. Densitometric analysis of immunofluorescence was performed on pancreatic islets.

Results: IUGR animals had significantly lower birth weight than controls (P<0.001). At PND 20, IUGR male rats showed reduced islet area (P = 0.05), downregulation of PDX1 gene (P=0.02), increased expression of XBP1s (P=0.02) and reduced proinsulin expression (P=0.05). No difference in mass islets, activation of cleaved caspase 3 and insulin expression was observed. At PND 105, IUGR rats showed increased pancreatic islet area (P=0.01), downregulation of PDX1 expression (P=0.02), increased activation of cleaved caspase 3 (P=0.02), decreased expression of Xbp1s (P=0.01) and reduced proinsulin expression (P=0.03). No significant difference in insulin expression was observed.

Conclusion: The offspring of mothers exposed to uteroplacental insufficiency shows intense pancreatic UPR activation which changes over time. These findings suggest that pancreas ER stress/UPR signaling may play a role in the metabolic risk associated with IUGR.