https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2870%2980569-5

The control of glycogen metabolism in the liver.

Regulation of adenosine 3:5-monophosphate-dependent protein kinase.

The hypothesis that physiological and developmental regulatory mechanisms are similar has been presented. Well-known developmental systems chosen illustrate the capability of the model to suggest a simple mechanism underlying the effects on development of a diverse group of chemicals. This hypothesis might be applied to other systems including the induction of the lens, limb regeneration, and the induction of the head of hydra (124). 

I have proposed this hypothesis not only because it permits consideration of a complex and varied array of experimental observations as reflections of a simple basic biochemical mechanism, but because recent technical advances in instrumentation and methods allow it to be directly tested. The fluorescent antibody method for the cytochemical measurement of cyclic nucleotides provides a means for investigating changes in the concentrations of cyclic nucleotides in developing cells and could also be used to detect neurotransmitters in developing cells. Similarly, the scanning electron microscope in the emitted x-ray mode provides a method for measuring changes in the content and distribution of cations within developing cells. 

The hypothesis presented here suggests pleasing asceticism on the part of eukaryotes. It suggests that simple derivatives of metabolites, including neurotransmitters and cyclic nucleotides, are linked together as regulatory molecules throughout the eukaryotes. The neurotransmitters are suggested to have a more general role in information transmission in eukaryotes than is generally accepted. They are hypothesized to have progressed during evolution from being intracellular messengers to a role as intercellular messengers for the relatively slow communication of developmental informaton; and, finally, this process has culminated with their participation in the rapid intercellular communication mediated by nerves. The thought that the complex pictures of physiological regulation and of the construction of a complex multicellular organism like man might be painted with so few colors is quite satisfying.

https://science.sciencemag.org/content/sci/185/4156/1012.full.pdf

Chemical messengers in development: a hypothesis.

Regulation of Adenosine 3',5'-Monophosphate-dependent Protein Kinase I. PRELIMINARY CHARACTERIZATION OF THE ADIPOSE TISSUE ENZYME IN CRUDE EXTRACTS

Hepatic parenchymal cells from adult rats, established in vitro as a monolayer, have been evaluated by electron microscopy. Within 24 h after the initial seeding, the incubated cells were polygonal and in close apposition with three to six neighboring cells. The ultrastructure of the monolayer cells was examined at this time and after 3 and 10 days of incubation. With the exception of a few enlarged mitochondria, organelles in both the 1- and 3-day monolayer cells were indistinguishable quantitatively and morphologically from those found in the intact liver. After 10 days of incubation, however, the rough-surfaced endoplasmic reticulum (RER) had become dilated and vesiculated. In all cells studied, portions of RER were found in a close spatial relationship to mitochondria. From its frequency, this association appeared to be more than fortuitous, and the organelle complex may represent a functional unit necessary for new membrane formation, as suggested previously. The Golgi complexes of 1- and 3-day cells contained very low density lipoprotein-sized particles, which suggests that the monolayer cells synthesize lipoproteins. These electron microscope observations demonstrate that adult hepatic parenchymal cells in monolayer retain for several days the subcellular structural elements characteristic of normally functioning hepatocytes.

/pdf/parenchymal-cells-from-adult-rat-liver-in-nonproliferating-2rtin6f3n7.pdf

Parenchymal cells from adult rat liver in nonproliferating monolayer culture. II. Ultrastructural studies.

It is now well established that insulin exerts direct effects on mammalian liver to inhibit the production of glucose and urea and to promote the uptake of potassium ions. It has been proposed that these effects of insulin may be partly due to a decrease in liver cyclic AMP.l The proposal is based on the following observations: ( 1) insulin produces a small but significant decrease in the level of cyclic AMP in the perfused rat liver; (2) depletion of insulin in vivo by treatment with insulin antiserum or alloxan results in a twofold increase in liver cyclic AMP; (3) exogenous cyclic AMP and hormones such as glucagon and epinephrine which raise the level of cyclic AMP produce effects on the liver which are opposite to those caused by insulin; (4) insulin antagonizes the actions of epinephrine, glucagon, or cyclic AMP in the perfused liver; and ( 5 ) insulin reduces the accumulation of liver cyclic AMP in the presence of glucagon. In this article we will present more recent observations on the interaction of glucagon, epinephrine, and insulin in the control of hepatic metabolism. The investigations have employed the isolated rat liver perfused by a modification of the technique of Mortimore.* The perfusion medium consisted of Krebs-Henseleit bicarbonate buffer containing 3 % bovine albumin and 20% bovine erythrocytes. Livers were from fed rats weighing 100-150 g and the perfusion flow rate was about 7 ml per minute. The perfusions were carried out in two ways. In most cases, livers were perfused for one hour with recirculating medium and hormones were infused into the portal vein at a constant rate. In these experiments, the hormone concentrations were calculated by dividing the quantity of hormone infused during the hour by the final volume of perfusate. Since this does not allow for degradation of hormone, the values are doubtlessly overestimated. In the second type of experiment livers were perfused initially for 20 minutes with recirculating media containing no additions in order to establish steady metabolic rates and levels of cyclic AMP. The perfusion system was then changed to one with nonrecirculating medium by diverting the perfusate leaving the liver into a beaker. After a six-minute control period, infusions of hormone were commenced and livers and effluent media were sampled at designated intervals. In these experi-

R. J. Ho

Papers

The role of cyclic amp in the interaction of glucagon and insulin in the control of liver metabolism

The role of cyclic AMP in the control of hepatic glucose production by glucagon and insulin.