Peter A. J. Adam

Glucose Production in Pregnant Women at Term Gestation: SOURCES OF GLUCOSE FOR HUMAN FETUS

The effects of pregnancy and diabetes on systemic glucose production rates and the sources of glucose for the human fetus in utero were evaluated in five normal, four gestationally diabetic, and one insulin-dependent diabetic subject undergoing elective caesarean section at term gestation. Five normal nonpregnant women were studied for comparison. Systemic glucose production rates were measured with stable tracer [1-(13)C]glucose according to the prime-constant rate infusion technique. Even though the plasma glucose concentration during normal pregnancy had declined as compared with the nonpregnant subjects (P < 0.0005), the systemic glucose production rate was 16% greater, a rate sufficient to provide the glucose requirement of the fetus at term gestation. The decline in glucose concentration could be the result of an increase in apparent volume of distribution of glucose. Systemic glucose production rates in well-controlled, gestationally diabetic subjects were similar to those in normal pregnant subjects (2.07+/-0.53 vs. 2.42+/-0.51 mg/kg.min). The sources of glucose for the human fetus at term gestation were evaluated by comparing (a) natural variation in (13)C:(12)C ratio of plasma glucose and (b) enriched (13)C:(12)C ratio of plasma glucose during [1-(13)C]glucose infusion in maternal and fetal blood at delivery in both normal and diabetic subjects. These data showed that the fetal glucose pool was in equilibrium with the maternal glucose pool in both normal and diabetic subjects, indicating that a brief maternal fast did not initiate systemic glucose production in human fetus. A materno-fetal gradient was observed for betahydroxybutyrate.

Human Fetal Insulin Metabolism Early in Gestation: Response to Acute Elevation of the Fetal Glucose Concentration and Placental Transfer of Human Insulin-I-131

Although insulin has been demonstrated in human fetal pancreas as early as thirteen weeks of gestation, the controls of insulin secretion in the human fetus and the magnitude of placental insulin transfer to the fetus are unknown. In pregnant women, scheduled for therapeutic abortions by abdominal hysterolomy at fifteen to twenty weeks of gestation, the fetal plasma insulin response to glucose infusion and insulin transfer across the placenta were studied as follows: (1) glucose was infused to eight fetuses in situ, and (2) insulin-I-131 was infused continuously for four to six hours to eight pregnant women via peripheral vein. Insulin was measured radioimmunologically and, following the infusion studies, was precipitated quantitatively by a double antibody method. During fasting, no difference was observed between fetal and maternal plasma glucose or in insulin levels. Although glucose administered to the fetus raised the fetal plasma glucose concentration without changing the maternal level, both fetal and maternal plasma insulin concentrations were unchanged at five and ten minutes. Human insulin-I-131 was not transferred across the placenta and no sequestration of insulin-I-131 occurred in the placenta. Early in human gestation the fetal pancreas appears to be the major source of fetal insulin, and the fetal insulin secretion rate may be relatively unresponsive to acute changes in blood glucose concentration. The placenta acts as a barrier to human insulin-I-131 but does not appear to sequester and catabolize insulin-I-131, as was previously demonstrated in human pregnancies at term.

Human Fetal Insulin Response to Sustained Maternal Hyperglycemia

Abstract Hyperglycemia was maintained in normal mothers before delivery both at term and early in gestation to study the fetal pancreatic response to glucose. Normal controls and gestationally diabetic mothers were infused with saline. At term the human fetal pancreas responded to elevated blood glucose levels by increasing plasma insulin, and there was a direct correlation between blood glucose and plasma insulin concentrations (r equal to 0.75, p less than 0.001). In early gestation there was an attenuated plasma insulin response. Infants of gestationally diabetic mothers had increased umbilical plasma insulin levels — 23.3 ± 6.9 μU per milliliter (mean ± S.E.M.) — as compared to those of normal controls - 6.4 ± 1.3 μU per milliliter (mean ± S.E.M.) — even though the umbilical blood glucose levels in these two groups were similar. The data support the concept that hyperglycemia leads to hyperinsulinism in infants of diabetic mothers.

Control of Glucose Metabolism in the Human Fetus and Newborn Infant

Publisher Summary As normal human gestation progresses, the secretion of a hormone that is unique to the trophoblast—human placental lactogen—begins early in pregnancy and increases toward term, and the concentration of this hormone in maternal plasma rises progressively. In association with the high plasma levels sustained at term, resistance to the normal enhancement of glucose uptake by insulin develops in pregnant women. Thus, the rate of glucose metabolism by the fasting pregnant woman declines, and the decreased maternal uptake of glucose helps to preserve the fasting plasma level of glucose even though it diffuses continuously to the fetus. Although insulin resistance can be demonstrated in late pregnancy, normal glucose tolerance is maintained; after the ingestion of glucose, the plasma insulin response is enhanced. Thus, at the end of gestation, a hormonal factor other than placental lactogen causes an excessive insulin response to glucose stimuli. Throughout pregnancy, there is a net placental diffusion of glucose from the mother to the fetus as long as the mother remains either normoglycemic or hyperglycemic; but the protein hormones which could participate in the control of fetal glucose metabolism are transferred poorly.

Glucose Production and Utilization in the Newborn Puppy

Extract: A steady-state radioglyucose dilution technique was used to determine new glucose production in six newborn (1–4 days) and two adult dogs in the postabsorptive state, and during a 90-min glucagon infusion.Basal new glucose production rates were 2.0 and 2.2 mg/kg body weight per minute in the adults. In contrast, basal rates in the newborn were 2–4 times (4.1–7.9 mg/kg/min) the values for the adults.During glucagon-induced hyperglycemia in the adult, glucose production increased to 2.5 times the basal level, while plasma glucose concentration rose to a peak at 30 min. The newborn dog responded with only a 40% increment above basal production while glucose concentation rose continuously. The adult responded with a rise in plasma insulin level but no change was observed in the newborn. The fractional rate of glucose utilization during the glucagon-induced hyperglycemia was observed to decline in newborn dogs; no decline was observed in the adults. Glucose metabolism in the newborn differs from that in the adult dog as follows: 1) basal glucose production and utilization per unit body weight are rathter in the newborn; and 2) during glucagon-stimulated hyperglycemia the newborn adaps with less acceleration of both the production and the utilization of glucose.Speculation: If the human newborn responds similarly to the puppy, then hepatic glucose output appears to be near maximum in order to meet basal requirements for glucose. Conditions that accelerate peripheral tissue glucose uptake will, therefore, rapidly result in hypoglycemia. Conversely, a reduction in hepatic output may result in low blood glucose concentration.

Insulin Response to Arginine in Normal Newborn Infants and Infants of Diabetic Mothers

The effect of maternal diabetes during pregnancy on insulin release of the newborn infant was examined employing arginine infusion as stimulus. At age two hours, eight normal newborn infants, six of gestationally diabetic mothers (IGDM) and four of insulin-dependent diabetic mothers (IDM) were infused with arginine hyd-rochloride 0.5 gm. per kilogram body weight for thirty minutes. Eight additional normal newborn infants were infused with isotonic saline. A small but definite rise in plasma IRI was observed in the normal newborns receiving arginine; however, the infants of gestationally diabetic mothers responded with an enhanced blood glucose and plasma insulin rise compared with the normal newborns. It seemed that intermittent or sustained hyperglycemia in utero may have potentiated the neonatal insulin response to arginine.

The effects of protein hydrolysate-monosaccharide infusion on low-birth-weight infants

Four neonates who weighed between 940 and 1,200 Gm. at birth were studied for themetabolic effects of the infusion of a solution of 4.5 per cent protein hydrolysate with 13.5 per cent monosaccharide. Infusion for 48 hours resulted in increased serum and urine osmolality, positive potassium balance, negative sodium balance, increased serum urea nitrogen, increased blood glucose and total hexose, and decreased aortic arterial pH. One infant developed Candida albicans sepsis. From these limited data it is concluded that before prolonged parenteral alimentation is applied clinically to the care of low-birth-weight neonates, the relationship of benefit to risk must be evaluated by controlled studies.

Quantitative Estimation of Systemic Glucose Production in Normal and Diabetic Pregnancy

Fasting during pregnancy is accompanied by a decline in plasma glucose and glycogenic amino acid concentration and an early recruitment of alternate fuel by mobilizing fatty acids from adipose tissue stores. Systemic glucose production rates were measured in normal, gestationally diabetic, and juvenile-onset diabetic subjects using (1-13C)glucose and (6,6-2H2)glucose tracers according to the constant-rate infusion technique. Even though the plasma glucose concentration during normal pregnancy had declined after an overnight fast, as compared with the nonpregnant subject (P < 0.0005), the systemic glucose production rate was 16% greater, a rate sufficient to provide the glucose requirement of the fetus at term gestation. The decline in glucose concentration could be the result of an increase in apparent volume of distribution of glucose. Systemic glucose production rates in well-regulated gestationally diabetic and insulin-dependent diabetic subjects were similar to those in normal pregnant subjects. These data suggest that the early disturbance in diabetes is the inability to assimilate exogenously administered glucose and other nutrients. Hormonal-fuel relationship during pregnancy suggests that during fasting, the insulin/glucagon molar ratio is maintained similar to that in nonpregnant subjects. Adrenal catecholamines do not appear to play a significant role in the regulation of hepatic glucose production. However, their role may be important in the early recruitment of alternate fuels.

Glucose Production in the Newborn Dog. I. Effects of Glucagon in Vivo

Extract: Systemic glucose production rates were evaluated 4 hr after feeding in 14 newborn beagle dogs at ages between 1 and 5 days. After a prime injection of radioisotopic tracers, glucose production was determined during infusion of intermixed tracer [2-3H]glucose and [1-14C]glucose at a constant rate. Seven of the newborn dogs served as controls throughout the 3-hr period of infusion, while seven of their littermates, infused simultaneously, received glucagon at a constant rate of 3.3 μg/min between 90 and 180 min of study. In control dogs, mean glucose production, determined by dilution of [2-3H]glucose, was 55 ± 3 μmol/min · kg body weight. During the control period, their littermates produced glucose at a similar rate; however, glucagon infusion raised glucose production to 81 ± 4 μmol/min · kg.The average glucose production rate estimated with [1-14C]glucose was 88% of that with the 3H tracer during the initial control period and 77% during the glucagon infusion. In order to confirm that this discrepancy reflected the recycling of 14C and the early development of gluconeogenesis, an additional 14 newborn dogs were infused with potential substrates for [14C]glucose. In separate studies, [U-14C]lactate, [3-14C]lactate, [U-14C]alanine, and [6-14C]-glucose were incorporated into glucose and [1-14C]glucose. Quantification of gluconeogenesis by simultaneous infusion of [6-3H]glucose and [3-14C]lactate in a 5-day-old dog demonstrated that 25% of the glucose produced originated from lactate, whereas 10% was incorporated into carbon 1. Thus, systemic glucose production was established rapidly in newborn dogs and responded to stimulation with glucagon. A significant proportion of the glucose originated from recycling via the gluconeogenic pathway.Speculation: Even in well nourished newborn mammals, recycling of glucose is important in maintaining homeostasis during the postabsorptive period. Based on comparisons between dogs infused with [3-14C]lactate or [6-14C]glucose, 25% or more of hepatic glucose production may originate from glucose recycled through lactate and pyruvate. Presumably most of the rest is derived from hepatic glycogen stored in utero..

Prevention of Hypoglucosemia by Fructose in Infants of Diabetic Mothers

HYPOGLUCOSEMIA occurs consistently in infants of insulin-dependent diabetic mothers during the initial hours of life.1 2 3 4 Previous studies have not clearly related symptomatology to the level of...