Role of Glucoregulatory Hormones in Hepatic Glucose Metabolism During the Perinatal Period

Fetal Metabolism in Healthy Pregnancies

During the first trimester, maternal insulin sensitivity is increased, which results in maternal fat deposition. This is reversed in later pregnancy, when increasing insulin resistance allows mobilization of these stores. ^, The gravid mother increases glucose production by 15% to 30% in late gestation to provide for the increasing needs of the growing fetus. Fetal glucose uptake from the placenta is equivalent to fetal glucose utilization, and fetal glucose levels are maintained at about 70% of maternal levels. The fetal liver and kidneys do not normally produce glucose, but in adverse conditions such as placental insufficiency or maternal starvation the fetal liver and kidney adapt from their normal focus on the anabolic processes of glycogen and lipid storage with upregulation of enzymes for gluconeogenesis (GNG) ( Fig. 38.1 ). The fetus maintains oxidative phosphorylation in the face of a relatively low oxygen tension. Although energy is produced predominantly by aerobic metabolism, the fetus has the potential for a significant level of anaerobic metabolism and can use lactate efficiently. Ketone bodies can be used as an alternative source of fuel by the fetus as well as providing precursors for glucose production (see Fig. 38.1 ). ^{, ,}

Fetal Hormonal Secretion

Glucocorticoids and insulin mediate the rate of glycogen accumulation in fetal life, with 40% of glucose taken up by the fetus being converted to glycogen or lipid. Insulin and glucagon are detected in most species early in gestation, with a high insulin to glucagon molar ratio in the fetus, promoting growth. The pancreatic islet cells contain three cell types that support glucose regulation. β Cells, which make up 60% to 80% of the islets, can be detected from 14 weeks of gestation and secrete insulin from 18 weeks. Fetal insulin secretion increases during the last trimester of pregnancy in humans and is critical for normal fetal growth, with increased insulin concentrations leading to increased rates of protein synthesis and increased glucose uptake. Insulin has a positive correlation with plasma glucose and amino acid levels after 20 weeks of gestation. The high insulin to glucagon ratio appears to be important in maintaining glycogen synthesis while suppressing GNG during fetal life. The secretion of insulin and glucagon is regulated by ATP-sensitive potassium channels and voltage-gated calcium channels in the islet cells and is dependent on the blood glucose level. Glycogen is synthesized from the ninth week of gestation and stored in the liver, lung, heart, skeletal muscle, kidney, intestine, and brain. Glycogen synthesis increases with gestation and is activated by insulin and induced by glucocorticosteroid. The healthy term baby has two to three times the adult level of glycogen stores. α Cells make up 15% to 20% of the islet cells and secrete glucagon, which increases GNG. Glucagon can be detected in fetal plasma by 15 weeks’ gestation and peaks at 24 to 26 weeks’ gestation. The remaining delta cells (5% to 10%) release somatostatin and a small number of cells release incretins.

Disruptions to Fetal Physiology

Acute changes in glucose levels that would lead to significant changes in either insulin or glucagon secretion in adults do not produce this effect in the fetus. However, chronic hyperglycemic exposure in pregnancies complicated by maternal diabetes increases fetal insulin secretion and β-cell hyperplasia. Chronic hyperglycemia then leads to increased fetal glycogen and fat deposition and fetal macrosomia. Furthermore, this chronic exposure to hyperglycemia throughout early pregnancy with β-cell hyperplasia has more impact on newborn glucose control than the acute effects of maternal glucose levels immediately before delivery. ^,

Insulin has indirect actions on growth through its regulation of IGF-1 and by increasing the cellular availability of glucose. Both IGF-1 and IGF-2 are the primary endocrine regulators of fetal growth as levels of both isoforms increase gradually until about 33 weeks of gestation and then increase two- to threefold until term. IGFs have roles in cell proliferation, differentiation, and metabolism and are found in the circulation by 15 weeks’ gestation, but activity is regulated by a family of binding proteins, which are developmentally and nutritionally regulated. ^,

In contrast, with reduced glucose delivery to the fetus, such as in pregnancies complicated by placental insufficiency, insulin levels are low and growth and fat deposition are reduced. Reduced plasma IGF-1 and IGF-2, a consequence of low insulin levels, play key roles in the regulation of fetoplacental growth, with cord blood insulin and C-peptide as well as IGF-1 levels correlating with size at birth. The fetal insulin to glucose ratio is lower in small for gestational age fetuses compared with those where growth is appropriate for gestational age. Cord blood levels correlate with birth weight, and low levels of IGF-1 are found following fetal growth restriction. ^,

Polymorphic variation in the fetal genome, in particular in fetal growth and imprinted genes, can lead to maternal metabolic alterations. Alterations in the imprinted H19 gene and IGF-2 control element leads to pups that are heavier than their unaffected litter mates, with increased circulating glucose concentrations in late pregnancy in comparison with those of genetically matched controls. Similarly, associations have been shown in humans between SNP alleles from 15 fetal imprinted genes and maternal glucose concentrations in late pregnancy.