Functional Maturation of Pancreatic ß Cells during Development

Abstract

Insulin is crucial for intrauterine growth of the fetus and insulin secretion must be maintained irrespective of maternal plasma glucose variations. This is achieved through a maturational islet adaptation which persists during the first postnatal days and can lead to prolonged neonatal hypoglycemia. We aimed to investigate the characteristics of insulin release in the fetal and perinatal period. We performed perifusions of human fetal islet samples at 18-20 weeks gestation and of rat islets between embryonic day (e)22 and postnatal day (P)14. Human fetal islets at 18-20 weeks gestation released insulin in response to lower glucose concentrations (1-2 mM), compared to adult islets (3-5 mM). Similarly, rat islets at e22-P1 also had a lower glucose threshold for insulin release (3mM), compared to P14 islets (5 mM). BCH, a leucine analog that activates glutamate dehydrogenase, also stimulated insulin release at a lower concentration in e22-P1 rat islets (1mM), compared to P14 islets (3mM). This suggests that the mechanism of the islet adaptation in intrauterine life lies distal to glycolysis and fuel oxidation, potentially in differences in membrane depolarization or repolarization. In addition, human fetal islets released insulin in response to lactate, while late embryonic rat islets did not, suggesting insulin release in response to other nutrient stimuli may also be part of this maturational islet adaptation. Ongoing experiments are further exploring substrate-induced insulin release in immature islets, in parallel with the characterization of β cell transcriptomic maturation at the single cell level in both human and rat. Understanding the functional maturation of β cells during the fetal and neonatal period, coupled with the insight into the molecular mechanisms responsible for this maturation, can lead of the development of molecular markers of a dysregulated β cell function that is may persist beyond early neonatal period. Disclosure D.E. Stanescu: Employee; Spouse/Partner; GlaxoSmithKline plc.. C. Li: None. J. Yang: None. D. Yau: None. C.A. Stanley: None.