Glucose metabolism and adaptation to pregnancy in adult offspring of adolescent ewes

Abstract

Adolescent pregnancy is associated with fetal growth restriction and preterm birth, indicating a suboptimal in utero environment secondary to competition for nutrients between the physiologically immature mother and her developing fetus. The in utero environment can alter the developmental course of an individual, resulting in an increased risk of metabolic disease in adulthood. Despite this association, little is known about the impact of an adolescent pregnancy on the glucose-insulin axis in the offspring. The hypothesis of this thesis was that glucose homeostasis would be impaired in adult offspring of adolescent ewes as a result of a poor in utero environment. Furthermore, as the adaptation to pregnancy is dependent on modified maternal glucose metabolism for normal fetal growth, this adaptation would be disturbed, with effects becoming amplified with increasing age and parity in the offspring of adolescent ewes. Experimental animals were generated by mating three-year and eight-month old ewes. Offspring underwent ivGTT at 18 months and at approximately 63 days of their first pregnancy. At 42 months offspring underwent DXA scanning, ivGTT and hyperinsulinaemic-euglycaemic clamp prior to mating and again at day 62-65 of their third pregnancy. Plasma glucose and insulin concentrations were measured, and peripheral muscle biopsies were analysed using Western Blotting. Offspring of adolescent ewes weighed 15% less at birth; however, there was no difference in body weight or composition in adulthood compared to offspring of mature ewes. Glucose tolerance and insulin sensitivity was not different between groups at 42 months before or during pregnancy. During ivGTT, glucose response increased (p=0.03) and insulin secretion decreased (p=0.001) with age in all animals. Glucose tolerance during pregnancy was not affected by increasing age or parity. These experiments refuted the hypothesis that glucose-insulin axis function would be altered in adult offspring of adolescent pregnancy. Adaptations in offspring of both mature and adolescent ewes occurred during pregnancy, so that despite worsening prepregnant glucose tolerance with age due to decreased insulin secretion, glucose metabolism was remarkably similar during the first and third pregnancies. This novel finding of pregnancy related glucose homeostasis across pregnancies, and the underlying mechanisms, warrant further exploration.