ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Endocrinology. 2018 Feb 1;159(2):1035-1049

Placental insufficiency leads to intrauterine growth restriction (IUGR) which in the fetus leads to hypoxemia and hypoglycemia. IUGR fetuses are charaterised by having higher circulating catecholamine concentrations and lower circulating insulin concentrations, as well as impaired glucose stimulated insulin secretion. In cases of severe IUGR, fetuses have smaller and less vascularized pancreatic islets with fewer pancreatic beta cells. In less severe IUGR the pancreatic defects are less pronounced. This suggests that the degree of impaired islet development may correlate with the severity of placental insufficiency, a phenomenon observed in animal models of placental insufficiency. These findings also show that reduced insulin secretion in IUGR fetuses is not solely due to smaller islets and less beta cells. Thus, the fetal beta cell links fetal nutrient supply with fetal nutrient metabolism and anabolic signals for growth. Children and adults that were formerly SGA fetuses develop insulin resistance and type 2 diabetes mellitus later in life. The risk for developing type 2 diabetes is due to a combination of both an increased risk of insulin resistance and an increased risk of impaired beta cell development and function. In this study, in order to get a better understanding of how IUGR leads to changes in islet function the authors assessed the impact of IUGR on the islet transcriptome over a time course of 2 and 10 weeks in a rat model. At 2 weeks of age the the rats were midly glucose intolerant whereas at 10 weeks they were frankly hyperglycemic. The transcriptome and gene analysis showed important temporal changes in the IUGR islets. There were significant changes (increased expression) at 2 weeks of in genes regulating amino acid metabolism, genes regulating the extracellular matrix and mesenchymal stromal cell-derived factors. In contrast some of these same genes were decreased in adult islets. A key finding of this study was the observation that multiple genes regulating fibrosis in IUGR islets at 2 weeks of age were differentially expressed, suggesting fibrogenesis participates fundamentally in the initiation of the abnormal islet phenotype in diabetes. Fibrogenesis induces immune-cell trafficking and remodeling of the extracellular matrix. Stellate-cell activation and fibrosis were the most enriched pathways in 2- and 10-week-old IUGR islets, and fibrogenesis was also identified as a dysregulated pathway in human diabetic islets. This study underscoring the importance of performing analyses at time points before the development of diabetes and during the progression of the disease.