Fetal growth restriction followed by early catch-up growth impairs pancreatic islet morphology in male rats

Abstract

Fetal growth restriction (FGR), followed by postnatal early catch-up growth, is associated with an increased risk of metabolic dysfunction, including type 2 diabetes in humans. This study aims to determine the effects of FGR and early catch-up growth after birth on the pathogenesis of type 2 diabetes, with particular attention to glucose tolerance, pancreatic islet morphology, and fibrosis, and to elucidate its mechanism using proteomics analysis. The FGR rat model was made by inducing mild intrauterine hypoperfusion using ameroid constrictors (ACs). On day 17 of pregnancy, ACs were affixed to the uterine and ovarian arteries bilaterally, causing a 20.9% reduction in birth weight compared to sham pups. On postnatal day 4 (P4), the pups were assigned to either the good nutrition (GN) groups with 5 pups per dam to ensure postnatal catch-up growth or poor nutrition groups with 15 pups per dam to maintain lower body weight. After weaning, all pups were fed regular chow food ad libitum (P21). Rats in both FGR groups developed glucose intolerance; however, male rats in the FGR good nutrition (FGR-GN) group also developed hypertriglyceridemia and dysmorphic pancreatic islets with fibrosis. A comprehensive and functional analysis of proteins expressed in the pancreas showed that FGR, followed by early catch-up growth, severely aggravated cell adhesion-related protein expression in male offspring. Thus, FGR and early catch-up growth caused pancreatic islet morphological abnormalities and fibrosis associated with the disturbance of cell adhesion-related protein expressions. These changes likely induce glucose intolerance and dyslipidemia in male rats.

RISING STARS: Mechanistic insights into maternal–fetal cross talk and islet beta-cell development

“…Epidemiological studies have consistently shown that individuals who were born with FGR have an increased risk of developing insulin resistance, which is a key factor in the development of T2D in adulthood ( Van Assche et al 1977 , Veening et al 2002 ). Animal models of FGR support the hypothesis that beta-cell development deficits and insulin secretion defects observed in these models contribute to poor glucose metabolism ( Akhaphong et al 2018 , Jabary et al 2023 ). The effects of FGR in beta-cell development is well-documented by several review publications ( Boehmer et al 2017 , Mohan et al 2018 ).…”

The impact of maternal intrahepatic cholestasis during pregnancy on the growth trajectory of offspring: a population-based nested case‒control cohort study

“…Interestingly, initial rapid catch-up growth leads to morphological abnormalities in pancreatic islets and fibrosis, which are linked to alterations in the expression of cell adhesion-related proteins. This process subsequently results in glucose intolerance and dyslipidemia in male rats [38]. Although the offspring of individuals with ICP may achieve relatively normal growth trajectories, the long-term impacts of ICP on these offspring necessitate ongoing surveillance.…”