Phosphorylated lipids are produced at cellular membranes during signaling events and contribute to the recruitment and activation of various signaling components. The role of phosphoinositide 3-kinase (PI3K), which catalyzes the production of phosphatidylinositol-3,4,5-trisphosphate, in cell survival pathways; the regulation of gene expression and cell metabolism; and cytoskeletal rearrangements are highlighted. The PI3K pathway is implicated in human diseases including diabetes and cancer, and understanding the intricacies of this pathway may provide new avenues for therapuetic intervention.

https://science.sciencemag.org/content/sci/296/5573/1655.full.pdf

The phosphoinositide 3-kinase pathway.

The epidemic of type 2 diabetes and impaired glucose tolerance is one of the main causes of morbidity and mortality worldwide. In both disorders, tissues such as muscle, fat and liver become less responsive or resistant to insulin. This state is also linked to other common health problems, such as obesity, polycystic ovarian disease, hyperlipidaemia, hypertension and atherosclerosis. The pathophysiology of insulin resistance involves a complex network of signalling pathways, activated by the insulin receptor, which regulates intermediary metabolism and its organization in cells. But recent studies have shown that numerous other hormones and signalling events attenuate insulin action, and are important in type 2 diabetes.

/pdf/insulin-signalling-and-the-regulation-of-glucose-and-lipid-6bdhstccqq.pdf

Insulin signalling and the regulation of glucose and lipid metabolism

The programmed cell death that occurs as part of normal mammalian development was first observed nearly a century ago (Collin 1906). It has since been established that approximately half of all neurons in the neuroaxis and >99.9% of the total number of cells generated during the course of a human lifetime go on to die through a process of apoptosis (for review, see Datta and Greenberg 1998; Vaux and Korsmeyer 1999). The induction of developmental cell death is a highly regulated process and can be suppressed by a variety of extracellular stimuli. The purification in the 1950s of the nerve growth factor (NGF), which promotes the survival of sympathetic neurons, set the stage for the discovery that peptide trophic factors promote the survival of a wide variety of cell types in vitro and in vivo (Levi-Montalcini 1987). The profound biological consequences of growth factor (GF) suppression of apoptosis are exemplified by the critical role of target-derived neurotrophins in the survival of neurons and the maintenance of functional neuronal circuits. (Pettmann and Henderson 1998). Recently, the ability of trophic factors to promote survival have been attributed, at least in part, to the phosphatidylinositide 38-OH kinase (PI3K)/c-Akt kinase cascade. Several targets of the PI3K/c-Akt signaling pathway have been recently identified that may underlie the ability of this regulatory cascade to promote survival. These substrates include two components of the intrinsic cell death machinery, BAD and caspase 9, transcription factors of the forkhead family, and a kinase, IKK, that regulates the NF-kB transcription factor. This article reviews the mechanisms by which survival factors regulate the PI3K/c-Akt cascade, the evidence that activation of the PI3K/c-Akt pathway promotes cell survival, and the current spectrum of c-Akt targets and their roles in mediating c-Akt-dependent cell survival.

/pdf/cellular-survival-a-play-in-three-akts-3wtxbzcnm7.pdf

Cellular survival: a play in three Akts

https://www.cell.com/cell/pdf/S0092-8674(03)00929-2.pdf

TSC2 mediates cellular energy response to control cell growth and survival.

https://www.cell.com/cell-metabolism/pdf/S1550-4131(15)00621-X.pdf

The Emerging Hallmarks of Cancer Metabolism

https://www.cell.com/current-biology/pdf/S0960-9822(00)00742-9.pdf

Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia.

In 1963, Lancet published a paper by Randle et al. that proposed a "glucose-fatty acid cycle" to describe fuel flux between and fuel selection by tissues. The original biochemical mechanism explained the inhibition of glucose oxidation by fatty acids. Since then, the principle has been confirmed by many investigators. At the same time, many new mechanisms controlling the utilization of glucose and fatty acids have been discovered. Here, we review the known short- and long-term mechanisms involved in the control of glucose and fatty acid utilization at the cytoplasmic and mitochondrial level in mammalian muscle and liver under normal and pathophysiological conditions. They include allosteric control, reversible phosphorylation, and the expression of key enzymes. However, the complexity is formidable. We suggest that not all chapters of the Randle cycle have been written.

The Randle cycle revisited: a new head for an old hat

It is now becoming evident that the liver has an important role in the control of whole body metabolism of energy nutrients. In this review, we focus on recent findings showing that AMP-activated protein kinase (AMPK) plays a major role in the control of hepatic metabolism. AMPK integrates nutritional and hormonal signals to promote energy balance by switching on catabolic pathways and switching off ATP-consuming pathways, both by short-term effects on phosphorylation of regulatory proteins and by long-term effects on gene expression. Activation of AMPK in the liver leads to the stimulation of fatty acid oxidation and inhibition of lipogenesis, glucose production and protein synthesis. Medical interest in the AMPK system has recently increased with the demonstration that AMPK could mediate some of the effects of the fat cell-derived adiponectin and the antidiabetic drugs metformin and thiazolidinediones. These findings reinforce the idea that pharmacological activation of AMPK may provide, through signalling and metabolic and gene expression effects, a new strategy for the management of metabolic hepatic disorders linked to type 2 diabetes and obesity.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2006.108506

Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders

PERSPECTIVES AND SUMMARy 618 GENERAL PROPERTIES OF GLUCONEOGENESIS AND GLYCOLYSIS IN THE LIVER 619 Gluconeogenesis 619 Glycolysis 619 Control Steps 620 ENZYME PROPERTIES 620 Pyruvate Carboxylase and Other Mitochondrial Involvement 620 Phosphoenolpyruvate Carboxykinase 623 Pyruvate Kinase 625 Fructose 1,6-Bisphosphatase 626 Fructose 2,6-Bisphosphatase 629 6-Phosphofructokinases 629 Glucose 6-Phosphatase 633 Glucokinase 634 THE CONTROL OF METABOLIC FLUX BY HORMONES AND OTHER EFFECTORS ...... 634 Cyclic AMP, Glucagon, and f3-Adrenergic Agents 634 Fructose 2,6-Bisphosphate 639 ex-Adrenergic Agents, Vasopressin, and Angiotensin 641 Glucocorticoids 643 Glucose 643 THE FUTILE CYCLES 644 Glucose/Glucose 6-Phosphate Cycle 644 Fructose 6-Phosphate/Fructose 1,6-Bisphosphate Cycle 646 Pyruvate/Phosphoenolpyruvate Cycle 647

Louis Hue

Papers

Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia.

The Randle cycle revisited: a new head for an old hat

Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders

Gluconeogenesis and Related Aspects of Glycolysis

Activation of AMP-Activated Protein Kinase Leads to the Phosphorylation of Elongation Factor 2 and an Inhibition of Protein Synthesis