Studies on the control of fatty acid oxidation in liver preparations from chick embryos

The characteristics and developmental pattern of the metabolic pathway for fatty acid oxidation were investigated in liver slices and mitochondria prepared from chick embryos of varying ages. In 8-day-old chick embryos, hepatic fatty acid oxidation was readily measurable. The incorporation of labelled palmitate into CO2 was increased twofold by carnitine in liver slices of 8-day-old chick embryos but by nearly sixfold to tenfold in tissues prepared from 10- or 12-day-old embryos. A similar increase was seen in the degree of augmentation of ketogenesis induced by carnitine in liver slices prepared from the 10-day-old embryo, suggesting an increased carnitine palmitoyltransferase activity in liver cells during the stage of development from 8 to 10 days. Palmitoyl-CoA was not metabolized in the absence of carnitine, whereas the palmitoyl portion of palmitoylcarnitine readily supported respiration by embryonic chick liver mitochondria. In the presence of adequate amounts of albumin, good respiratory control was evident.The administration of glucose to chick eggs which had previously been incubated for approximately 4.5 days resulted in changes in the metabolism of embryos killed 5 days later, which indicated that tissues of the chick embryo were capable of integrative metabolic adaptations in response to changes in substrate supply. </jats:p

Pulsatile glucagon delivery enhances glucose production by perifused rat hepatocytes

We have compared the effects of pulsatile and continuous glucagon administration on hepatocyte glucose production in order to clarify the physiological role of pulsatile hormone secretion. Two identical columns containing freshly isolated rat hepatocytes mixed with polyacrylamide gel beads were perifused with oxygenated tissue culture medium. A fixed total amount of glucagon was delivered to one column as a continuous 90-min infusion and to the other column as a series of six 3-min pulses. A 15-min interpulse interval was chosen in order to approximate the 10- to 12-min interval observed in primates while permitting the resolution of individual hepatocyte responses. With this protocol, the EC50 values for pulsatile and continuous glucagon administration were 186 +/- 41 and 884 +/- 190 (SD) pg/ml, respectively. For glucagon concentrations less than 1,000 pg/ml, pulsatile administration always led to greater hepatocyte glucose production than continuous administration (P = 0.008) and, in the dose range equivalent to concentrations in portal plasma, pulsed glucagon enhanced glucose production twofold. The data suggest that pulsatile secretion is the more efficient means for islet A cells to stimulate hepatic glucose production.</jats:p

Glucoregulation during insulin and glucagon deficiency: role of catecholamines

Glucose production decreases markedly following acute reduction in insulin and glucagon secretion (induced by somatostatin). After about an hour, however, glucose production is restored nearly to basal rates. To study the mechanism by which this occurs, islet hormone deficiency was superimposed on beta-adrenergic blockade. It was found that the hypoglycemia that accompanies insulin and glucagon deficiency is an adequate stimulus for catecholamine secretion. During combined hormone deficiency and beta-blockade, glucose production fell and remained very low for 2-3 h. This resulted in a profound hypoglycemia (glucose less than 30 mg/dl). We conclude from these studies that restoration of glucose production during sustained insulin and glucagon deficiency is not attributable to a) onset of insulin deficiency because insulin is equally depressed in both experimental settings, b) glucose autoregulation even though adequate substrate is available, or c) an alpha-adrenergic mechanism because plasma catecholamines were very high and alpha-receptors were not blocked. Rather, the glucose counterregulation during insulin and glucagon deficiency must be heavily dependent on a beta-adrenergic mechanism. </jats:p

A model for augmentation of hepatocyte response to pulsatile glucagon stimuli

We have reported that in the physiological concentration range pulsatile glucagon delivery (6 pulses in 90 min) is a more effective stimulus of rat hepatocyte glucose production than is continuous infusion of the same amount of hormone (pulsatile EC50 = 186 +/- 41 pg/ml, continuous EC50 = 884 +/- 190 pg/ml). At supraphysiological glucagon concentrations, however, the maximal response to continuous glucagon infusion exceeds the response to pulses (241 +/- 14 vs. 140 +/- 11 mumol X G-1 X 90 min-1). In an effort to explain these observations we derived a model for the 90-min hepatocyte responses to pulsatile and continuous glucagon delivery based on the waveform of the hepatocyte response to a transient glucagon stimulus. The model demonstrated that the time constant for response decay was an important determinant of the relative efficacy of the two patterns of hormone delivery. For the observed decay constant value of 0.132 +/- 0.02 min-1 the model predicted the following dose-response parameters: pulsatile EC50 = 131 pg/ml, Rmax = 119 mumol X G-1 X 90 min-1, continuous EC50 = 656 pg/ml, Rmax = 272 mumol X G-1 X 90 min-1. The ability of a model based only on the kinetics of a single pulse to simulate the observed dose-response relationship suggests that pulsatile stimulation is intrinsically more effective than continuous hormonal stimulation. </jats:p

Metabolic changes during maturation of male monkeys: possible signals for onset of puberty

There is a close relationship between the metabolic status of a maturing animal and the timing of puberty onset. However, the signals linking metabolic status to the maturation of the reproductive axis remain unknown. We looked for metabolic differences before and after puberty by comparing plasma profiles of insulin, glucose, amino acids, beta-hydroxybutyrate, and glycerol between juvenile and adult monkeys in fed and fasted states. Thirteen juvenile and 13 adult male crab-eating macaques (Macaca fascicularis) were fed a mixed meal, and blood samples were collected at intervals between 1.5 and 52 h after the meal. Plasma insulin concentrations decreased in a similar manner in both groups during the first 16 h of fasting. By 20 h after a meal, basal insulin levels were significantly lower (P less than 0.025) in juveniles compared with adults and remained so until the end of the fast. Circulating levels of glucose were similar in juveniles and adults immediately after a meal and then decreased significantly (P less than 0.025) in juveniles by 28 h of fasting and in adults by 52 h of fasting. Plasma concentrations of all large neutral amino acids (i.e., tyrosine, tryptophan, phenylalanine, valine, leucine, and isoleucine, LNAA) except tryptophan decreased more precipitously in juveniles than in adults during the first 20 h of fasting. However, the ratios of tyrosine to other LNAA and tryptophan to other LNAA were similar in juveniles and adults at all times. beta-Hydroxybutyrate concentrations were low in both groups until 24 h after a meal, at which time plasma levels increased more rapidly and attained higher values in juveniles compared with adults.(ABSTRACT TRUNCATED AT 250 WORDS)</jats:p

Lack of effect of morphine, reserpine, and halothane on oscillation of plasma insulin in M. mulatta

Oscillating plasma insulin levels, with periods averaging 9 min, in fasting rhesus monkeys have been previously reported by us. To test whether an oscillator in the central nervous system might be driving these oscillations, we subjected five male rhesus monkeys to morphine, reserpine, and halothane, agents known to affect the central nervous system, in an attempt to either disrupt or change the frequency of the oscillations. We could demonstrate no significant effect of any of the three drugs on the oscillations. We conclude, therefore, that the oscillations in plasma insulin are not driven by an oscillator in the central nervous system. Coupled with the results of others, these data suggest that these oscillations are probably due to an intrinsic pancreatic pacemaker. </jats:p