Robert H. Fiser

Spontaneous and Amino Acid-Stimulated Glucagon Secretion in the Immediate Postnatal Period: RELATION TO GLUCOSE AND INSULIN

The extent and significance of spontaneous glucagon secretion in the immediate postnatal period were investigated in groups of normal infants studied cross-sectionally and longitudinally. Arginine-and alanine-stimulated glucagon secretion was also studied. Plasma glucagon concentrations were correlated with prevailing glucose and insulin concentrations. The characteristic fall in blood glucose, reaching a nadir within hours of birth, was associated with a significant increase in glucagon concentration. Despite persistence of relative glucopenia, glucagon did not change appreciably between 2 and 24 h of life. A further significant elevation in glucagon concentration occurred from day 1 to day 3 of life associated with a return of glucose to euglycemic levels. In contrast to the sluggishness of pancreatic glucagon release, glucagon-like immunoreactivity rose markedly to mean levels of approximately 2,000 pg/ml after introduction of formula feeding. No significant changes in insulin levels were observed in these studies. Arginine infusion via an umbilical vein catheter into six infants within 6 h of birth elicited a brisk, almost threefold increment in glucagon concentration (from 339+/-85 to 940+/-254 pg/ml) in blood obtained from, or close to, the portal circulation. Bolus injection of alanine (1 mmol/kg) into a peripheral vein to six infants resulted in significant increments in glucagon (mean maximal, 128 pg/ml) as well as glucose and insulin. The observations suggest that spontaneous glucagon secretion may be an important factor in neonatal glucose homeostasis. Secretion seems more brisk in response to amino acid stimulation than to a falling glucose concentration.

Effects of Oral Alanine Feeding on Blood Glucose, Plasma Glucagon and Insulin Concentrations in Small-for-Gestational-Age Infants

The effects of oral alanine feeding on glucose homeostasis were evaluated in 21 infants who were small for gestational age and 26 who were appropriate for gestational age. In the first 24 hours, basal plasma alanine concentrations were higher in the former. Oral alanine feedings produced a significant rise over baseline levels of plasma alanine and glucagon concentrations in both groups. The blood glucose and plasma insulin concentrations also increased significantly in infants who were appropriate but not in those who were small for gestational age. At 25 to 96 hours of age, plasma glucagon, insulin and blood glucose concentrations did not change after the alanine feeding in either group. These data indicate that in the normally nourished infant (appropriate forgestational age), gluconeogenic amino acid (alanine) enhances hepatic glucose output. This phenomenon is not observed in the mainourished infants (small for gestational age), a point that may reflect decreased glycogen stores and ineffective gluconeogenic enzyme system in such infants.

Activated charcoal in barbiturate and glutethimide poisoning of the dog

The effectiveness of orally administered activated charcoal in simulated acute barbiturate and glutethimide poisoning was assessed in fasting dogs. Twenty grams of activated charcoal was administered 30 minutes after a hypnotic dose of secobarbital, phenobarbital, or glutethimide. Differences greater than 50 per cent between control and experimental serum drug concentrations indicated significant inhibition of systemic absorption; this effect persisted over a 24 hour period. These studies show that activated charcoal is extremely effective in reducing barbiturate and glutethimide absorption in vivo and that the activated charcoal-drug complexes formed are essentially stable throughout the gastrointestinal tract.

Insulin-Glucagon Substrate Interrelations in the Fetal Sheep

Extract: Twenty-four studies were conducted in 14 sheep fetuses to investigate the pancreatic islet α and β cell responses to substrate infusions. The studies were conducted between 100 days gestation and near term, using indwelling vascular catheters for infusions and blood sampling. Constant glucose infusions (6 mg/kg/min) produced a significant rise in the mean concentration of insulin in plasma by 105 min, but no change in glucagon in plasma was observed. Near term (>135 days) the mean plasma insulin increment with constant glucose infusion was significantly greater and occurred sooner than in fetuses early in gestation (<110 days), but again no plasma glucagon response was observed. The mean steady state glucose concentration in response to the 6 mg/kg/min glucose infusion was similar early and late in gestation, even though the steady state plasma level of insulin in plasma was higher in the late gestation fetuses. Alanine infused into the fetus did not alter concentrations of glucose, insulin, or glucagon in plasma. These data suggest that changes in plasma concentrations of insulin and glucagon are not important in the regulation of substrate metabolism during fetal life. Moreover, the pancreatic islet β cell secretion response seems to mature earlier than the α cell response.Speculation: The failure of glucagon to respond to alanine stimulation during fetal life suggests immaturity of glucagon control of gluconeogenesis from amino acids. The low levels of activity of key glucagon-dependent gluconeogenic enzymes reported in liver of the newborn rat (7, 8) supports this view. These observations suggest the possibility that gluconeogenesis from amino acids may not represent a major metabolic pathway in the sheep fetus.

Endotoxemia in the Rhesus Monkey: Alterations in Host Lipid and Carbohydrate Metabolism

Extract: Experimentally induced endotoxemia in the rhesus monkey produced a two- to fourfold increase in plasma triglyceride concentration; glucose administration partially prevented this rise. Plasma free fatty acid and phospholipid values were depressed 40–50% of control values whereas cholesterol values were unchanged. Endotoxin-treated monkeys displayed slowed glucose disappearance (K values, 2.2 versus 1.1) and higher levels of sugar in blood when given glucose (72 ± 8 mg/100 ml versus 151 ± 11 mg/100 ml). These studies indicate that endotoxin has a marked effect on the pattern of substrate utilization by the host.Speculation: Alterations in lipid and carbohydrate metabolism affecting substrate utilization of the host may account for many of the clinicopathologic events associated with endotoxemia. Therapeutic measures designed to increase the availability of metabolic fuels for efficient cellular fuel utilization might be of value to patients during endotoxemia.

HEPATIC PHOSPHOENOL PYRUVATE CARBOXYKINASE (PEPCK) DEFICIENCY - A NEW CAUSE OF HYPOGLYCEMIA IN CHILDHOOD

A 9-month Mexican-American female has been followed for episodic hypoglycemia first documented in the immediate postnatal period. Three convulsions occurred with glucose levels (BS) 20 mg%. Physical exam has been normal to date. A 4 hr. fast resulted in hypoglycemia (30 mg%) and mild lacticacidemia. Basal and stimulated plasma growth hormone, glucagon and cortisol were normal. IV GTT normal; (K =1.6). Glucagon increased BS two-fold. Plasma insulin was < 5 μU/ml during hypoglycemia. IV substrate infusion results were:Fasting alanine levels also were increased. A liver biopsy, at 5 1/2 months, showed reduced levels of pyruvate carboxylase and markedly low or undetectable levels of PEPCK. All other gluconeogenic and glycogenolytic enzymes were normal. The data are compatible with an inborn error in gluconeogenesis at the level of PEPCK. The pyruvate carboxylase reduction is likely a secondary effect. This child represents the first documented case of PEPCK deficiency.

Plasma alanine: Relation to plasma glucose, glucagon, and insulin in the neonate

An attempt was made to determine if correlations exist among plasma concentrations of alanine, the major amino acid substrate for gluconeogenesis, and plasma concentrations of glucose, glucagon, and insulin in normal newborn infants. The effects of an intravenous infusion of cl -alanine (1 mMl/kg) to six neonates was also determined. Although a peak in alanine concentration coincided with a nadir in glucose concentration at 12 hours of life, no correlation existed between the observed changes in alanine and glucose, or alanine and glucagon. Infused alanine caused increases in both plasma glucose and glucagon concentrations, as in the adult; the responses, however, were of small magnitude. Our data indicate that reduced blood glucose concentrations in the normal newborn infant are not due to a deficiency of alanine substrate for gluconeogenesis. And, although alanine stimulates secretion of glucagon, there is no consistent correlation between plasma alanine and glucose, or plasma alanine and glucagon concentrations during the early neonatal period. thus the key factors in control of glucose concentrations in the newborn period cannot be deduced from simple relationships of these plasma constituents.

Alterations in Plasma and Brain Lipid Metabolism during Endotoxemia in the Neonatal Rat

Endotoxin in the neonatal rat produced marked elevations of plasma triglycerides, free fatty acids, and phospholipids. Incorporation of 3H-acetate into total lipids and cholesterol fraction of the brain was increased in rats given endotoxin, while incorporation into the phospholipid fraction in both brain and liver was decreased. These studies suggest that changes in plasma lipids provide not only a sensitive index of endotoxemia in the neonatal rat, but also reflect marked alterations in substrate utilization of the host during stress.

Intravenous infusion of diazoxide in the treatment of chlorpropamide-induced hypoglycemia.

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Metabolic and hormonal studies comparing three parenteral nutrition regimens in infants.

Metabolic and hormonal studies were performed in 6 infants during the first 3 months of life while receiving 3 different types of parenteral nutrition: 1) 20% glucose and a nitrogen source (Dudricks method) 2) 12% glucose, a nitrogen source and soybean fat emulsion (Intralipid method) and 3) 12% glucose, a nitrogen source and 1% alcohol (Babsons method). All three regimens provided positive nitrogen balance of similar magnitude. The substrate-hormone relationships were appropriate. After parenteral fat free nutrition (primary caloric source glucose) the plasma glucagon levels were significantly lower and the growth hormone levels significantly higher than after the fat emulsion therapy period. The Dudrick and Intralipid methods resulted in a higher caloric intake and weight gain than the Babson method. The former two regimens cannot be completely endorsed, however, since septic and central vein complications are unavoidable with the Dudrick method particularly in the small infant; and the long term effects of intralipid, particularly on the liver are still unknown.