Fetal rat hyperinsulinism and hyperglucagonism: effects on hepatic ketogenesis, lipogenesis, and gluconeogenesis.

To study the direct effects of hyperglucagonism and hyperinsulinism (both with glucose excess) on fetal intermediary metabolism, rat liver explants from 19-day-gestated fetuses were maintained in culture for 48 h. The liver cubes were exposed to 0, 250, or 500 mU/ml porcine insulin or 5 micrograms/ml glucagon. In addition, lipogenesis from 3H2O was cumulated throughout the 48 h. Chronic hyperinsulinism in the fetal rat doubled hepatic lipogenesis and curtailed hepatic gluconeogenesis and ketogenesis by 80% and 50%, respectively. Chronic hyperglucagonism was without effect; however, the fetal liver did yet respond to 1 mM (Bu)2cAMP.

An in vivo phosphorus nuclear magnetic resonance study of the variations with age in the phosphodiester content of human muscle.

Human gastrocnemius and slow twitch muscles contain phosphodiesters that may be detected in vivo by phosphorus nuclear magnetic resonance (NMR). This work represents a study of 354 spectra obtained from healthy subjects of various ages and from patients with peripheral vascular disease. The analysis of the data indicate a correlation between the concentration of phosphodiesters and age. By comparing the data obtained with healthy subjects and patients it is concluded that the increase in phosphodiesters is not due to disease, but to ageing itself. The significance of this increase is discussed.

Magnetic resonance spectroscopy of normal and diseased muscles.

Phosphorus magnetic resonance spectroscopy (P MRS) affords and innovative approach to the study of the oxidative enzyme content of normal and diseased muscles. Examples of the evaluation of the enzyme content of normal muscles by an exercise protocol are provided. The protocol affords a hyperbolic work/cost profile, the Vmax of which is calculated by the reciprocal plots giving the enzyme content and the "effective Michaelis constant" with an evaluation of the resting metabolism. This steady state protocol clearly illustrates enzyme adaptation, on the one hand, and tissue atrophy particularly in the case of tissue injury, Duchenne's dystrophy, and genetic deletion of specific enzymes, on the other hand. The method is rapid, safe, and affords a quantitative evaluation of the disease process and possibilities for following appropriate therapies. So far, approx 1000 examinations of normal and diseased human limbs have been carried out in our laboratory in over the past four years.

Diagnostic utility of hepatobiliary scintigraphy with 99mTc-DISIDA in neonatal cholestasis.

We retrospectively evaluated the utility of hepatobiliary scintigraphy and various clinical factors in differentiating intrahepatic cholestasis from biliary atresia in 28 consecutive infants with neonatal cholestasis. One millicurie of technetium-labeled diisopropyliminodiacetic acid (DISIDA) was administered intravenously, and images were obtained for up to 24 hours or until gastrointestinal excretion was noted. Nine separate studies in seven infants with biliary atresia were correctly interpreted as showing no gastrointestinal excretion of radionuclide. Of the 21 patients with intrahepatic cholestasis, only nine had gastrointestinal excretion on the first study; in eight without excretion, a second study was done, and five of these showed gut excretion. All infants with either neonatal hepatitis (six) or inspissated bile syndrome (three) had demonstrable gastrointestinal excretion either on the first or second DISIDA study. However, five of six infants with paucity of intrahepatic bile ducts, two of six infants with cholestasis secondary to total parenteral nutrition, and one infant with cholangiolitis did not show evidence of gastrointestinal excretion. The mean birth weight, mean gestational age, and mean weight at study were significantly greater (P less than 0.005) for infants with biliary atresia without excretion than for infants with intrahepatic cholestasis without excretion. The mean direct bilirubin concentration was 6.0 mg/dL for both infants with biliary atresia and infants with intrahepatic cholestasis without excretion; however, infants with excretion had a significantly lower (P less than 0.02) mean direct bilirubin value of 3.4 mg/dL. Excretion was noted in four infants with total bilirubin values greater than 10.0 mg/dL. The absence of gut excretion on the first DISIDA study was 100% sensitive but only 43% specific for biliary atresia. In infants without gut excretion of DISIDA, birth weight greater than 2200 g was 100% sensitive and 92% specific for biliary atresia. We conclude that DISIDA scanning, together with clinical data, is useful in differentiating extrahepatic from intrahepatic cholestasis. The absence of gut excretion on the first DISIDA study does not necessarily indicate extrahepatic obstruction; the study should be repeated if the diagnosis is not clear.

Cerebral metabolic effects of neonatal seizures measured with in vivo 31P NMR spectroscopy.

In vivo phosphorus 31 nuclear magnetic resonance (31P NMR) spectroscopy was used to evaluate changes in cerebral high-energy phosphate compounds in 8 infants with seizures. During the study 4 babies had seizures that caused a 50% decrease in the phosphocreatine to inorganic phosphate (PCr/Pi) ratio. Focal seizures caused lateralized decreases in the PCr/Pi ratio; generalized seizures caused bilateral decreases. Postictal spectra had increased PCr/Pi ratios, presumably due to postictal inhibition. Interictal 31P NMR spectra were normal. One patient's seizures were successfully treated with intravenously administered phenobarbital during NMR data acquisition, causing an immediate increase in the PCr/Pi ratio from 0.7 to 1.2. These studies indicate that cerebral PCr concentration decreases by approximately 33% and that oxidative metabolism increases by approximately 45% during neonatal seizures. Five babies had PCr/Pi ratios of less than 0.8 during seizures and subsequently developed long-term neurological sequelae, which suggests that neonatal seizures may cause or exacerbate cerebral injury by increasing cerebral metabolic demands above energy supply.

Muscle metabolism in older subjects using 31P magnetic resonance spectroscopy.

We used phosphorus magnetic resonance spectroscopy to study the calf muscles of elderly normal (mean +/- SD) (80.0 +/- 5.12 years), elderly impaired (80.7 +/- 0.58 years), old normal (66.8 +/- 1.92 years), and young normal people (24.6 +/- 4.72 years). Relative levels of inorganic phosphate (Pi), phosphocreatine (PCr), and adenosine triphosphate were measured with a 1.9-tesla, 30-cm bore magnet at rest and following plantra flexon exercise. No differences were found at rest or during recovery from exercise in the elderly normal subjects with respect to gender or the presence of stable medical problems treated with medication. At rest there was an age-related decrease in the ratio of PCr/Pi. After exercise, the time constant of PCr recovery increased with age. A mild 7-week exercise regimen consisting of plantar flexion had no effect on time constant of PCr recovery in the elderly subjects. Four elderly impaired subjects had lower PCr/Pi ratios at rest and slower time constant of PCr recovery after exercise than normal elderly subjects. We conclude that gender and the presence of stable medical problems had no effect on muscle metabolism in the elderly and that the elderly recovered slower than young controls. This slower recovery was not corrected with a mild exercise program.