Gluconeogenesis: An Overview | ScienceDirect Topics (2023)

Renal gluconeogenesis and lactate management

In a review of kidney diseaseGlukoneogenese, court and colleagues.³⁹comment that the kidney can be viewed as two separate organs since the proximal tubule produces and releases glucose from non-carbohydrate precursors, while glucose utilization occurs primarily in the medulla. Because the kidney is both a consumer and producer of glucose, net arteriovenous glucose differences in the kidney may not be informative because glucose consumption in the medulla may mask glucose release from the cortex.

court and colleagues³⁹also argue that the kidney is a major gluconeogenic organ in normal humans based on the following: (1) in overnight fasted humans, proximal tubular gluconeogenesis can reach 40% of whole body gluconeogenesis³⁹🇧🇷 (2) During liver transplantation, endogenous glucose release decreases to only 50% of control values ​​within 1 hour after liver removal⁴⁰🇧🇷 and (3) pathologically, in type 2 diabetes, renal glucose release increases by about the same fraction as hepatic glucose release.⁴¹Fat Zucker-diabetic rats also show a marked stimulation of gluconeogenesis compared to their lean littermate controls.⁴²

Lactate can reach the nephron through filtration or blood flow and can also be produced along the nephron. In the kidney, lactate (1) can be oxidized to generate energy with the formation of CO₂, a process that uses oxygen but produces ATP; or (2) converted to glucose by gluconeogenesis in the proximal tubule, a process that consumes oxygen and ATP. This is shown inFigure 5.9. Cohen Studies⁴³in an isolated whole kidney perfused with lactate alone as substrate showed a change in¹⁴Use of C-lactate depending on its concentration in the perfusate: At low concentrations, all lactate is oxidized (detected as CO).₂) for fuel transport and basal metabolism; if the lactate in the perfusate has risen above 2 mmol/l, part of the lactate has been used for glucose synthesis (gluconeogenesis); and with highly infused lactate, metabolic and synthetic rates approach maximum and some lactate is conserved (reabsorbed). However, it is not normal for lactate to be the only substrate and it is now known that lactate metabolism is affected by the presence of other substrates, for example lactate absorption and oxidation are inhibited in the presence of acids.^24,44

The kidney's ability to convert lactate into glucose provides evidence that it may be involved in the cell-to-cell transport of lactate, also known as the Cori cycle.⁴⁵This cycle is important when inhibiting oxidative phosphorylation in heavily exercised muscles that become hypoxic. In muscle, pyruvate is reduced to lactate to regenerate NAD.⁺of NADH, which is required for the continuous production of ATP by glycolysis. Lactate is released into the blood and can be taken up by tissues capable of gluconeogenesis, such as the liver and kidneys. In the proximal tubule, unoxidized lactate can be converted to glucose, and since this substrate is not used by the proximal tubule, glucose is reabsorbed into the blood where it is available for metabolism in exercised muscle. In general, this cycle is metabolically expensive: glycolysis produces 2 ATP molecules at the expense of 6 ATP molecules consumed in gluconeogenesis..Thus, the Cori cycle is an energy-consuming process that changes the metabolic load on the exercising muscle during hypoxia. This cell-to-cell transport of lactate could also occur within the kidney between the anaerobic lactate-producing segments of the nephron and the proximal tubule.

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Glukoneogenesefound in the liver and kidneys. Gluconeogenesis meets the need for plasma glucose between meals. Gluconeogenesis is stimulated by diabetogenic hormones (glucagon, growth hormone, epinephrine and cortisol). Gluconeogenic substrates include glycerol, lactate, propionate and certain amino acids. PEP carboxykinase catalyzes the rate-limiting reaction in gluconeogenesis. The dicarboxylic acid shuttle moves hydrocarbons from pyruvate to PEP in gluconeogenesis. Gluconeogenesis is a continuous process in carnivores and ruminants, so they rarely need to store glycogen in their liver cells. Of the amino acids transported from muscle to liver during exercise and starvation, Ala predominates. β-aminoisobutyrate, which results from the breakdown of pyrimidine, is a (minor) gluconeogenic substrate.

Defects in gluconeogenesis

GlukoneogeneseIt is the way glucose is synthesized from non-carbohydrate metabolites. The main gluconeogenic precursors are pyruvate and lactate, certain gluconeogenic amino acids and glycerol, which are mainly derived from lipid metabolism. Several congenital defects in gluconeogenesis cause hypoglycemia (cfTabla 90.17).

Fructose-1,6-bisphosphatase deficiency is an autosomal recessive disorder characterized by hyperventilation associated with severe ketoacidosis, hypoglycemia, seizures and lethargy sometimes leading to coma. Hepatomegaly and the degree of hepatic dysfunction are usually mild. The defect in gluconeogenesis leads to lactic acidosis. Diagnosis requires a biopsy of the liver, intestine, or kidney to analyze specific enzymes. Acute flare-ups are treated with glucose, which often successfully corrects hypoglycemia and ketoacidosis. Long-term treatment requires avoiding fasting and eliminating most fructose from the diet. As discussed for glycogen storage diseases, patients with fructose-1,6-bisphosphatase deficiency benefit from continuous night-time feeding or the use of raw cornstarch.

Pyruvate carboxylase (PC) deficiency may present in the neonatal period with hepatomegaly, hyperammonemia, lactic acidosis, citrullinaemia, hyperlysinaemia, and CNS structural abnormalities.¹³⁶Patients with the severe form of the disease in the neonatal period may not survive beyond the first few months of life. Patients with a less severe form of PC deficiency may do well by avoiding fasting, eating at night, and taking a citrate (which produces oxaloacetate, the product of the PC enzyme reaction) supplement.

Phosphoenolpyruvate carboxykinase (PEPCK) deficiency is a rare cause of neonatal hypoglycemia associated with lactic acidemia. There are two forms of this deficiency, corresponding respectively to the deficiency in the cytosolic form and the mitochondrial form of the enzyme. The clinical features of both forms are not fully characterized due to the rarity of these disorders. The diagnosis can be made by enzyme analysis or genetic testing.

Overview of gluconeogenesis

Circadian rhythm of gluconeogenesis

Circadian clocks align behavior related to nutrient availability and energy metabolism with the diurnal cycle.¹⁰⁰The mammalian circadian clock consists of heterodimeric complexes of the Kaput Locomotor Output Cycles (CLOCK) transcription factor and brain and muscle tRNA-like protein 1 (BMAL1), which regulate expression of period (PER) 1/2 and period 1/2 initiate cryptochrome (CRY) 1/2. PER1/2 and CRY1/2 repress CLOCK transcriptional activity through feedback inhibition. In addition, Bmal1 expression is stimulated by retinoid-related orphan receptors (RORs) and repressed by the nuclear hormone receptor REV-ERBa (also known as NR1D1). PER and CRY deterioration shortens the length of the circadian period, while CRY stabilization lengthens the period. In addition to suppressing CLOCK, suppresses CRY1GlukoneogeneseRegulation of CREB (cAMP Response Element Binding Protein)/cAMP signaling through rhythmic repression of the glucocorticoid receptor and decreased levels of nuclear FoxO1, which downregulates expression of gluconeogenic genes. It is known that the ubiquitination-mediated proteasomal degradation of CRY1 is regulated by several factors. Rodent studies have shown that macroautophagy affects the circadian clock by selectively depleting CRY1. CRY1 degradation removes its inhibitory effect on gluconeogenesis at a time of day when rodents are dependent on gluconeogenesis, thereby synchronizing CRY1 degradation with the need to maintain blood glucose levels when nutrients are unavailable. A high-fat diet accelerates CRY1 autophagy and contributes to obesity-associated hyperglycemia.¹⁰¹

Glucose production

Glucose production in the postabsorptive state is regulated to meet tissue demands, which may increase during exercise or stress such as infection and trauma. Normally, about 50% of the glucose released into the circulation is the result of hepatic glycogenolysis; the remaining 50% is dueGlukoneogenese(30% liver; 20% kidney).

The proportion of glucose produced by gluconeogenesis increases with the duration of the fast because glycogen stores are quickly depleted. The liver contains a total of 75 g glucose. Suppose the liver releases glucose from glycogen at a rate of 5 µmol kg⁻¹Minimum⁻¹, glycogen stores would be depleted in 20 hours. Therefore, the proportion due to gluconeogenesis must be increased such that after 72 hours the liver's glucose production is almost exclusively due to gluconeogenesis. In contrast, the kidney contains few glycogen stores and cells that could produce glycogen lack glucose-6-phosphatase; Consequently, all of the glucose released by the kidney is due to gluconeogenesis. (Renal gluconeogenesis is increased by fasting more than hepatic gluconeogenesis.) Insulin suppresses hepatic and renal glucose release; However, glucagon slightly increases hepatic glucose release, while catecholamines further stimulate renal glucose release.

Editor's Summary

Glukoneogeneserefers to the synthesis of new glucose from non-carbohydrate precursors, supplies glucose when food intake is insufficient or absent. It is also important in the regulation of acid-base balance, amino acid metabolism and the synthesis of carbohydrate-derived structural components. Gluconeogenesis takes place in the liver and kidneys. The precursors to gluconeogenesis are lactate, glycerol and amino acids with a minor contribution from propionate. The gluconeogenesis pathway consumes ATP, which mainly comes from the oxidation of fatty acids. The pathway uses several enzymes of glycolysis, except for the enzymes of the irreversible steps, namely pyruvate kinase, 6-phosphofructokinase, and hexokinase. The irreversible reactions of glycolysis are circumvented by four unique alternative reactions of gluconeogenesis. The four unique reactions of gluconeogenesis are pyruvate carboxylase located in the mitochondrial matrix, phosphoenolpyruate (PEP) carboxykinase located in the mitochondrial matrix and cytosol, fructose-1,6-bisphosphatase located in the cytosol, and glucose-6. -phosphatase localized to the endoplasmic reticulum (ER). ).

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protein synthesis:Daily protein turnover can reach 300 g, which means that the same amount has to be re-synthesized. The 20 basic amino acids are necessary for the synthesis of most of the more than 30,000 different proteins that make up the human body. The lack of any of them affects all bodily functions and ultimately is incompatible with life.

energy fuel:Eventually, almost all amino acids are completely oxidized to carbon dioxide, water, and urea. Some amino acids are only converted in very small amounts into compounds that are excreted in more complex forms. On average, the oxidation of amino acids in proteins contributes 4 kcal/g.

Synthesis of non-protein mediators:Many hormones are derived from amino acids but are not peptides. This category includes catecholamines, serotonin, and melatonin.

Virtually all organic compounds involved in neurotransmission or modulation of neuronal excitation are amino acids or amino acid metabolites. amino acids withsuch functions include glutamate, glycine and proline. Amino acid metabolites involved in neurotransmission include gamma-aminobutyrate (GABA), N-methyl-D-aspartate (NMDA), nitric oxide, serotonin, melatonin, histamine, and agmatine.

Nucleotide Synthesis:Two of the four carbons and one of the nitrogens in purines come from glycine. Aspartate provides two of the five nitrogens in adenosine nucleotides, one of the four nitrogens in guanosine nucleotides, and one of the nitrogens in pyrimidine nucleotides (uridine, thymine, and cytosine).

Liver metabolism on an empty stomach

During fasting, glucagon causes the liver to mobilize glucose from glycogen (glycogenolysis) and synthesize glucose from oxaloacetate and glycerol.Glukoneogenese🇧🇷 Glucagon stimulates an increase in cyclic adenosine monophosphate, resulting in increased phosphorylation by protein kinase A. The wave of phosphorylation that propagates through the liver cell simultaneously activates enzymes such as glycogen phosphorylase, which is involved in the breakdown of glycogen over time that it inhibits its synthesis. Glycogen synthase Inhibition of glycogen synthase prevents the useless resynthesis of glycogen from glucose-1-phosphate (G1P) via uridine diphosphoglucose. Glucose-6-phosphatase (G6Pase), a gluconeogenic enzyme present in the liver but not in muscle, then converts G6P to glucose for release into the blood.

Increased hepatic uptake of amino acids (derived from protein catabolism in muscle) during fasting supplies the carbon skeletons for gluconeogenesis (eg, alanine is transaminated to pyruvate). The highest concentrations of${{\text{N.H}}_4}^{+}$Amino acids resulting from deamination are metabolized in the liver by the urea cycle, leading to increased urinary excretion of urea and negative nitrogen balance.

Glycerol derived from lipolysis in adipose tissue is taken up by the liver and phosphorylated by glycerol kinase, contributing to the formation of additional carbon skeletons for hepatic gluconeogenesis.

Some of ketogenesis occurs in the liver, particularly during prolonged fasting, and ketone bodies are primarily directed to the muscles for alternative fuel. At this point, ketosis is mild and of no clinical significance.

Glukoneogenese

GlukoneogeneseIt is the process by which the liver and to a lesser but often significant extent the kidneys produce new glucose molecules from chemically simpler compounds. In humans, lactate is probably the most important glucose precursor, especially during exercise. Others, in order of importance, are alanine, pyruvate, glycerol, and some glucogenic amino acids, including glutamate. Glutamate is particularly important in gluconeogenesis in the kidney. The non-propionic fatty acids formed in the colon by bacterial fermentation of nonabsorbable carbohydrates do not serve to any appreciable extent as glucose precursors, but provide the conditions under which it can occur. The same goes for certain hormones like glucagon and cortisol.

Alanine's contribution to gluconeogenesis has probably been exaggerated. Although it is formed along with other amino acids by proteolysis of nonstructural muscle proteins during periods of prolonged fasting and starvation, its main function under normal conditions is to transport amino acid-derived three-carbon skeletons (eg, pyruvate) after transamination. Muscle glycogen to the liver, where it is converted to glucose during fasting.

Food inhibits gluconeogenesis primarily by increasing insulin levels and decreasing the effects of glucagon. Fasting produces the opposite effect. Alcohol specifically inhibits lactate gluconeogenesis but not other substrates such as alanine. It does this by negatively altering the redox potential in hepatocytes and decreasing the availability of nicotinamide adenine dinucleotide, which is an essential component in the formation of glucose from lactate. The inhibition of gluconeogenesis by very small amounts of alcohol can sometimes be so profound that people, especially children, with reduced hepatic glycogen stores can develop hypoglycemia, which can be fatal.