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Annals of the New York Academy of... Jan 2018The coordinated regulation between cellular glucose uptake and endogenous glucose production is indispensable for the maintenance of constant blood glucose... (Review)
Review
The coordinated regulation between cellular glucose uptake and endogenous glucose production is indispensable for the maintenance of constant blood glucose concentrations. The liver contributes significantly to this process by altering the levels of hepatic glucose release, through controlling the processes of de novo glucose production (gluconeogenesis) and glycogen breakdown (glycogenolysis). Various nutritional and hormonal stimuli signal to alter hepatic gluconeogenic flux, and suppression of this metabolic pathway during the postprandial state can, to a significant extent, be attributed to insulin. Here, we review some of the molecular mechanisms through which insulin modulates hepatic gluconeogenesis, thus controlling glucose production by the liver to ultimately maintain normoglycemia. Various signaling pathways governed by insulin converge at the level of transcriptional regulation of the key hepatic gluconeogenic genes PCK1 and G6PC, highlighting this as one of the focal mechanisms through which gluconeogenesis is modulated. In individuals with compromised insulin signaling, such as insulin resistance in type 2 diabetes, insulin fails to suppress hepatic gluconeogenesis, even in the fed state; hence, an insight into these insulin-moderated pathways is critical for therapeutic purposes.
Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Gene Expression Regulation; Gluconeogenesis; Glycogenolysis; Homeostasis; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Liver; Models, Animal; Obesity; Protein Kinases; Signal Transduction; Transcription, Genetic
PubMed: 28868790
DOI: 10.1111/nyas.13435 -
American Journal of Nephrology 2021The remarkable ability of the body to adapt to long-term starvation has been critical for survival of primitive man. An appreciation of these processes can provide the... (Review)
Review
BACKGROUND
The remarkable ability of the body to adapt to long-term starvation has been critical for survival of primitive man. An appreciation of these processes can provide the clinician better insight into many clinical conditions characterized by ketoacidosis.
SUMMARY
The body adapts to long-term fasting by conserving nitrogen, as the brain increasingly utilizes keto acids, sparing the need for glucose. This shift in fuel utilization decreases the need for mobilization of amino acids from the muscle for purposes of gluconeogenesis. Loss of urinary nitrogen is initially in the form of urea when hepatic gluconeogenesis is dominant and later as ammonia reflecting increased glutamine uptake by the kidney. The carbon skeleton of glutamine is utilized for glucose production and regeneration of consumed HCO3-. The replacement of urea with NH4+ provides the osmoles needed for urine flow and waste product excretion. Over time, the urinary loss of nitrogen is minimized as kidney uptake of filtered ketone bodies becomes more complete. Adjustments in urine Na+ serve to minimize kidney K+ wasting and, along with changes in urine pH, minimize the likelihood of uric acid precipitation. There is a sexual dimorphism in response to starvation. Key Message: Ketoacidosis is a major feature of common clinical conditions to include diabetic ketoacidosis, alcoholic ketoacidosis, salicylate intoxication, SGLT2 inhibitor therapy, and calorie sufficient but carbohydrate-restricted diets. Familiarity with the pathophysiology and metabolic consequences of ketogenesis is critical, given the potential for the clinician to encounter one of these conditions.
Topics: Adaptation, Physiological; Gluconeogenesis; Glucose; Glycogenolysis; Homeostasis; Humans; Ketone Bodies; Ketosis; Kidney; Natriuresis; Potassium; Proteins; Sex Factors; Starvation; Uric Acid
PubMed: 34350876
DOI: 10.1159/000517305 -
Molecules and Cells Jun 2007The maintenance of normal blood glucose levels at rest and during exercise is critical. The maintenance of blood glucose homeostasis depends on the coordination and... (Review)
Review
The maintenance of normal blood glucose levels at rest and during exercise is critical. The maintenance of blood glucose homeostasis depends on the coordination and integration of several physiological systems, including the sympathetic nervous system and the endocrine system. During prolonged exercise increased demand for glucose by contracting muscle causes to increase glucose uptake to working skeletal muscle. Increase in glucose uptake by working skeletal muscle during prolonged exercise is due to an increase in the translocation of insulin and contraction sensitive glucose transporter-4 (GLUT4) proteins to the plasma membrane. However, normal blood glucose level can be maintained by the augmentation of glucose production and release through the stimulation of liver glycogen breakdown, and the stimulation of the synthesis of glucose from other substances, and by the mobilization of other fuels that may serve as alternatives. Both feedback and feedforward mechanisms allow glycemia to be controlled during exercise. This review focuses on factors that control blood glucose homeostasis during prolonged exercise.
Topics: Animals; Blood Glucose; Exercise; Feedback, Physiological; Gluconeogenesis; Glucose; Glycogenolysis; Homeostasis; Humans; Liver; Models, Biological; Physical Endurance; Time Factors
PubMed: 17646701
DOI: No ID Found -
The Biochemical Journal Feb 2012Glycogen is a branched polymer of glucose that acts as a store of energy in times of nutritional sufficiency for utilization in times of need. Its metabolism has been... (Review)
Review
Glycogen is a branched polymer of glucose that acts as a store of energy in times of nutritional sufficiency for utilization in times of need. Its metabolism has been the subject of extensive investigation and much is known about its regulation by hormones such as insulin, glucagon and adrenaline (epinephrine). There has been debate over the relative importance of allosteric compared with covalent control of the key biosynthetic enzyme, glycogen synthase, as well as the relative importance of glucose entry into cells compared with glycogen synthase regulation in determining glycogen accumulation. Significant new developments in eukaryotic glycogen metabolism over the last decade or so include: (i) three-dimensional structures of the biosynthetic enzymes glycogenin and glycogen synthase, with associated implications for mechanism and control; (ii) analyses of several genetically engineered mice with altered glycogen metabolism that shed light on the mechanism of control; (iii) greater appreciation of the spatial aspects of glycogen metabolism, including more focus on the lysosomal degradation of glycogen; and (iv) glycogen phosphorylation and advances in the study of Lafora disease, which is emerging as a glycogen storage disease.
Topics: Amino Acid Sequence; Animals; Biology; Carbohydrate Metabolism; Concept Formation; Gluconeogenesis; Glycogen; Glycogenolysis; Humans; Metabolic Networks and Pathways; Mice; Models, Biological; Models, Molecular; Molecular Sequence Data; Sequence Homology, Amino Acid
PubMed: 22248338
DOI: 10.1042/BJ20111416 -
The Journal of Clinical Investigation Dec 2023Elevation of reactive oxygen species (ROS) levels is a general consequence of tumor cells' response to treatment and may cause tumor cell death. Mechanisms by which...
Elevation of reactive oxygen species (ROS) levels is a general consequence of tumor cells' response to treatment and may cause tumor cell death. Mechanisms by which tumor cells clear fatal ROS, thereby rescuing redox balance and entering a chemoresistant state, remain unclear. Here, we show that cysteine sulfenylation by ROS confers on aryl hydrocarbon receptor (AHR) the ability to dissociate from the heat shock protein 90 complex but to bind to the PPP1R3 family member PPP1R3C of the glycogen complex in drug-treated tumor cells, thus activating glycogen phosphorylase to initiate glycogenolysis and the subsequent pentose phosphate pathway, leading to NADPH production for ROS clearance and chemoresistance formation. We found that basic ROS levels were higher in chemoresistant cells than in chemosensitive cells, guaranteeing the rapid induction of AHR sulfenylation for the clearance of excess ROS. These findings reveal that AHR can act as an ROS sensor to mediate chemoresistance, thus providing a potential strategy to reverse chemoresistance in patients with cancer.
Topics: Humans; Reactive Oxygen Species; Drug Resistance, Neoplasm; Receptors, Aryl Hydrocarbon; Glycogenolysis; Neoplasms
PubMed: 38099490
DOI: 10.1172/JCI170753