On the Nature of Allosteric Transitions: A Plausible Model

Metabolism of isolated fat cells. i. effects of hormones on glucose metabolism and lipolysis.

The quantitative contributions of pancreatic responsiveness and insulin sensitivity to glucose tolerance were measured using the "minimal modeling technique" in 18 lean and obese subjects (88-206% ideal body wt). The individual contributions of insulin secretion and action were measured by interpreting the dynamics of plasma glucose and insulin during the intravenous glucose tolerance test in terms of two mathematical models. One, the insulin kinetics model, yields parameters of first-phase (phi 1) and second-phase (phi 2) responsivity of the beta-cells to glucose. The other glucose kinetics model yields the insulin sensitivity parameters, SI. Lean and obese subjects were subdivided into good (KG greater than 1.5) and lower (KG less than 1.5) glucose tolerance groups. The etiology of lower glucose tolerance was entirely different in lean and obese subjects. Lean, lower tolerance was related to pancreatic insufficiency (phi 2 77% lower than in good tolerance controls [P less than 0.03]), but insulin sensitivity was normal (P greater than 0.5). In contrast, obese lower tolerance was entirely due to insulin resistance (SI diminished 60% [P less than 0.01]); pancreatic responsiveness was not different from lean, good tolerance controls (phi 1: P greater than 0.06; phi 2: P greater than 0.40). Subjects (regardless of weight) could be segregated into good and lower tolerance by the product of second-phase beta-cell responsivity and insulin sensitivity (phi 2 . SI). Thus, these two factors were primarily responsible for overall determination of glucose tolerance. The effect of phi 1 was to modulate the KG value within those groups whose overall tolerance was determined by phi 2 . SI. This phi 1 modulating influence was more pronounced among insulin sensitive (phi 1 vs. KG, r = 0.79) than insulin resistant (obese, low tolerance; phi 1 vs. KG, r = 0.91) subjects. This study demonstrates the feasibility of the minimal model technique to determine the etiology of impaired glucose tolerance.

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Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose.

The ability to adapt to altered availability of free water is a fundamental property of living cells. The principles underlying osmoadaptation are well conserved. The yeast Saccharomyces cerevisiae is an excellent model system with which to study the molecular biology and physiology of osmoadaptation. Upon a shift to high osmolarity, yeast cells rapidly stimulate a mitogen-activated protein (MAP) kinase cascade, the high-osmolarity glycerol (HOG) pathway, which orchestrates part of the transcriptional response. The dynamic operation of the HOG pathway has been well studied, and similar osmosensing pathways exist in other eukaryotes. Protein kinase A, which seems to mediate a response to diverse stress conditions, is also involved in the transcriptional response program. Expression changes after a shift to high osmolarity aim at adjusting metabolism and the production of cellular protectants. Accumulation of the osmolyte glycerol, which is also controlled by altering transmembrane glycerol transport, is of central importance. Upon a shift from high to low osmolarity, yeast cells stimulate a different MAP kinase cascade, the cell integrity pathway. The transcriptional program upon hypo-osmotic shock seems to aim at adjusting cell surface properties. Rapid export of glycerol is an important event in adaptation to low osmolarity. Osmoadaptation, adjustment of cell surface properties, and the control of cell morphogenesis, growth, and proliferation are highly coordinated processes. The Skn7p response regulator may be involved in coordinating these events. An integrated understanding of osmoadaptation requires not only knowledge of the function of many uncharacterized genes but also further insight into the time line of events, their interdependence, their dynamics, and their spatial organization as well as the importance of subtle effects.

Osmotic Stress Signaling and Osmoadaptation in Yeasts

Glucose and related sugars repress the transcription of genes encoding enzymes required for the utilization of alternative carbon sources; some of these genes are also repressed by other sugars such as galactose, and the process is known as catabolite repression. The different sugars produce signals which modify the conformation of certain proteins that, in turn, directly or through a regulatory cascade affect the expression of the genes subject to catabolite repression. These genes are not all controlled by a single set of regulatory proteins, but there are different circuits of repression for different groups of genes. However, the protein kinase Snf1/Cat1 is shared by the various circuits and is therefore a central element in the regulatory process. Snf1 is not operative in the presence of glucose, and preliminary evidence suggests that Snf1 is in a dephosphorylated state under these conditions. However, the enzymes that phosphorylate and dephosphorylate Snf1 have not been identified, and it is not known how the presence of glucose may affect their activity. What has been established is that Snf1 remains active in mutants lacking either the proteins Grr1/Cat80 or Hxk2 or the Glc7 complex, which functions as a protein phosphatase. One of the main roles of Snf1 is to relieve repression by the Mig1 complex, but it is also required for the operation of transcription factors such as Adr1 and possibly other factors that are still unidentified. Although our knowledge of catabolite repression is still very incomplete, it is possible in certain cases to propose a partial model of the way in which the different elements involved in catabolite repression may be integrated.

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Yeast Carbon Catabolite Repression

Glucokinase and hexokinase in liver in relation to glycogen synthesis.

The utilization of glycerol by Candida utilis has been studied It has been found that this yeast has a permeability for glycerol and other three carbon compounds much greater than that of baker's yeast This permeability allows the entrance of glycerol in Candida cells rapidly enough to permit its efficient utilization even at low concentrations The inducibility of glycerol kinase has been established An increase in the concentration of the mitochondrial L-α-glycerophosphate oxidase when the yeast is grown on glycerol has also been observed

A model is presented for the substrate specificity pattern of glycerol kinase of C mycoderma It postulates the involvement of three hydroxyl groups in the spatial distribution corresponding to the formation of L-α-glycerophosphate from glycerol This requirement can be met by aldo-and ketotrioses in their respective hydrated forms

The pathway of glycerol formation in S cerevisiae has also been studied Evidence is shown of the existence of a NADH dependent enzymatic activity reducing triose phosphate to α-glycerophosphate which can roughly account for the glycerol production A low ionic strength seems to be required for the activity of this enzyme The α-glycerophosphatase is specific for the L from, the efficiency of α-glycerophosphatase on D-α-glycerophosphate being 1/30 of that on L-α-glycerophosphate The concentration of the α-glycerophosphatase in yeasts is higher when grown on hexoses than when grown on non-sugar carbon sources

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1968.tb00353.x

Glycerol metabolism in yeasts. Pathways of utilization and production.

Insulin-dependent synthesis of liver glucokinase in the rat.

Publisher Summary This chapter discusses the implications in metabolic regulation because of the concentrations of metabolites and binding sites. One important property of biological systems is its compartmentation. In this sense cellularity is a landmark in the evolutionary progress that leads to the actual complexity of higher organisms. Large increases in size of the organisms, probably a prerequisite for further increases in complexity, were greatly facilitated by multicellularity. As the cell is a thermodynamically open system that is constantly taking nutrients and other products from the outside and eliminating the wastes, the greater increment in volume than in surface of a cell with increasing size puts a limit to its growth. The eukaryotic cell of higher organisms represents a complex microcosmos in which practically all important metabolic reactions occur.

Alberto Sols

Papers

Glucokinase and hexokinase in liver in relation to glycogen synthesis.

Glycerol metabolism in yeasts. Pathways of utilization and production.

Insulin-dependent synthesis of liver glucokinase in the rat.

Concentrations of Metabolites and Binding Sites. Implications in Metabolic Regulation

Spontaneous and enzymatically catalyzed anomerization of glucose 6-phosphate and anomeric specificity of related enzymes.