This postdoctoral research training program is designed to provide a context for the trainee to develop new expertise in diabetes and perinatal biology while also tackling an important research problem. Intrauterine growth restriction (IUGR) is a major medical problem for the fetus and newborn infant and appears to have metabolic programming effects that result in chronic disease in adults. IUGR offspring are small for gestational age (SGA) at birth;however, as adults, they exhibit an increased incidence of impaired glucose tolerance, hyperlipidemia, hypertension, Type 2 Diabetes, and cardiovascular disease. One possible mechanism for this intrauterine programming during IUGR is the elevation in fetal catecholamines, which can inhibit insulin secretion. This represents a potential mechanism for both the intrauterine impairment of fetal growth and the dysfunction of insulin secretion observed later in life. The role of chronic exposure to catecholamines in 2-cell function has not yet been investigated, and the proposed studies intend to fill this gap. Thus, the goal of this research project is to determine the impact of chronic catecholamine suppression on 2-cell dysfunction that is observed in intrauterine growth restriction fetuses. Understanding potential mechanisms for the adverse programming effects of IUGR is required to identify and eventually test therapeutic targets that may alleviate the burden of intrauterine programming on the incidence of chronic adulthood diseases. These studies thus align with the mission of the NIDDK to address the suffering and cost of chronic metabolic diseases. The proposed studies will use a placental insufficiency (PI)-induced IUGR fetal sheep model that produces fetal hypoxemia throughout the last trimester. Hypoxemia elevates circulating norepinephrine, which in this situation appears to chronically inhibit insulin secretion. However, fetal islets appear to compensate for this suppression, as evidenced by experiments acutely blocking norepinephrine in PI-IUGR fetuses, which demonstrate improved glucose stimulated insulin secretion. If persistent, this phenomenon could lead to long-term inadequacies in 2-cell responsiveness. The proposed experiments test the hypothesis that chronically elevated catecholamine (CA) concentrations act to inhibit insulin secretion in PI-IUGR fetuses and investigate the mechanisms of this inhibition. Specifically, in these experiments, surgical and chemical impairment of catecholamine secretion allows for the determination of catecholamine-specific effects at both the whole animal and islet levels. These experiments will measure in vivo glucose- and arginine-stimulated insulin secretion;in vitro islet insulin stimulus secretion coupling and glucose oxidation;and signaling and molecular mechanisms potentially explaining changes in islet function. )
Intrauterine growth restriction (IUGR) is a significant public health challenge and results in the offspring having increased risk of chronic adulthood diseases like Type 2 Diabetes. Understanding the mechanisms for how conditions during pregnancy influence an individual's later risk for disease is important to developing treatments. Our studies investigate high fetal levels of the hormones catecholamines during IUGR pregnancies as a potential mechanism for some of the problems with insulin secretion that appear later in life and ultimately result in the development of Type 2 Diabetes. )
