Gluconeogenesis - an overview | ScienceDirect Topics (2023)

Renal Gluconeogenesis and Lactate Handling

In a review of renal gluconeogenesis, Gerich and colleagues³⁹ comment that the kidney can be considered two separate organs, because the proximal tubule makes and releases glucose from noncarbohydrate precursors, whereas glucose utilization occurs primarily in the medulla. Because the kidney is both a consumer and a producer of glucose, net arteriovenous glucose differences across the kidney can be uninformative, because glucose consumption in the medulla can mask glucose release by the cortex.

Gerich and colleagues³⁹ also make the case that the kidney is a significant gluconeogenic organ in normal humans based on the following: (1) in humans fasted overnight, proximal tubule gluconeogenesis can be as much as 40% of whole-body gluconeogenesis³⁹; (2) during liver transplantation, endogenous glucose release falls to only 50% of control levels by 1 hour after liver removal⁴⁰; and (3) pathologically in type 2 diabetes, renal glucose release is increased by about the same fraction as hepatic glucose release.⁴¹ Zucker diabetic fatty rats also exhibit marked stimulation of gluconeogenesis compared with their lean litter mate controls.⁴²

Lactate can reach the nephron by filtration or blood flow and can also be produced along the nephron. Within the kidney, lactate can be (1) oxidized to produce energy with generation of CO₂, a process that consumes oxygen but generates ATP; or (2) converted to glucose via gluconeogenesis in the proximal tubule, a process that consumes oxygen and ATP. This is shown inFig. 5.9. Studies by Cohen⁴³ in an isolated whole kidney perfused with just lactate as substrate demonstrated a change in¹⁴C–lactate utilization as a function of its concentration in the perfusate: at low concentrations, all the lactate was oxidized (detected as CO₂) in order to fuel transport and basal metabolism; when lactate in perfusate was raised above 2 mmol/L some of the lactate was used for synthesis of glucose (gluconeogenesis); and at high lactate in perfusate the metabolic and synthetic rates approach maximum, and some lactate is conserved (reabsorbed). However, it is not the normal circumstance that lactate is the sole substrate, and it is now appreciated that the metabolism of lactate is affected by the presence of other substrates—for example, lactate uptake and oxidation are inhibited in the presence of fatty acids.^24,44

The kidney's ability to convert lactate to glucose provides evidence that it can participate in cell–cell lactate shuttle, also known as the Cori cycle.⁴⁵ This cycle is important when oxidative phosphorylation is inhibited in vigorously exercising muscle, which becomes hypoxic. In the muscle, pyruvate is reduced to lactate to regenerate NAD⁺ from NADH, which is necessary for ATP production by glycolysis to continue. Lactate is released into the blood and can be taken up by tissues capable of gluconeogenesis, such as the liver and kidney. In the proximal tubule, the lactate that is not oxidized can be converted to glucose, and because this substrate is not used by the proximal tubule, glucose will be reabsorbed back into the blood, where it will be available for metabolism by the exercising muscle. Overall, this cycle is metabolically costly: glycolysis produces 2 ATP molecules at a cost of 6 ATP molecules consumed in the gluconeogenesis. Thus, the Cori cycle is an energy-requiring process that shifts the metabolic burden away from the exercising muscle during hypoxia. This cell–cell lactate shuttle could also operate within the kidney between nephron segments that produce lactate anaerobically and the proximal tubule.

Abstract:

Gluconeogenesis occurs in the liver and kidneys. Gluconeogenesis supplies the needs for plasma glucose between meals. Gluconeogenesis is stimulated by the 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 continual process in carnivores and ruminant animals, therefore they have little need to store glycogen in their liver cells. Of the amino acids transported to liver from muscle during exercise and starvation, Ala predominates. b-Aminoisobutyrate, generated from pyrimidine degradation, is a (minor) gluconeogenic substrate.

Gluconeogenesis Defects

Gluconeogenesis is the pathway by which glucose is synthesized from non-carbohydrate metabolites. The principal gluconeogenic precursors are pyruvate and lactate, certain gluconeogenic amino acids, and glycerol, which is derived mainly from fat metabolism. Several inborn errors of gluconeogenesis cause hypoglycemia (seeTable 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 liver dysfunction are generally mild. The defect in gluconeogenesis leads to lactic acidosis. Diagnosis requires a liver, intestine, or kidney biopsy for specific enzyme analysis. Acute episodes are treated with glucose administration, which is generally successful in correcting the hypoglycemia and ketoacidosis. Long-term treatment requires avoidance of fasting and removal of most fructose from the diet. As discussed for the glycogen storage diseases, patients with fructose-1,6-bisphosphatase deficiency benefit from continuous nighttime feedings or the use of uncooked cornstarch.

Pyruvate carboxylase (PC) deficiency can manifest in the neonatal period with hepatomegaly, hyperammonemia, lactic acidosis, citrullinemia, hyperlysinemia, and structural CNS malformations.¹³⁶ Patients who present with the severe form of the disease in the newborn period might not survive beyond the first few months of life. Patients who have a less severe form of PC deficiency may do well when they avoid fasting, have nighttime feedings, and receive supplementation with citrate (which yields oxaloacetate, the product of the PC enzyme reaction).

Phosphoenolpyruvate carboxykinase (PEPCK) deficiency is a rare cause of neonatal hypoglycemia associated with lactic acidemia. There are two forms of this deficiency, corresponding to deficiency of the cytosolic form and the mitochondrial form of the enzyme, respectively. The clinical features of both forms are incompletely characterized owing to the rarity of these disorders. The diagnosis can be accomplished by enzyme analysis or genetic testing.

Overview of Gluconeogenesis

Circadian Rhythm of Gluconeogenesis

Circadian clocks align nutrient availability-related behavior and energy metabolism with the diurnal cycle.¹⁰⁰ The mammalian circadian clock consists of heterodimeric complexes of the transcription factor locomotor output cycles kaput (CLOCK) and the brain and muscle Arnt-like protein 1 (BMAL1), which initiate expression of period (PER)1/2 and cryptochrome (CRY)1/2. PER1/2 and CRY1/2 represses the transcriptional activity of CLOCK by feedback inhibition. In addition, Bmal1 expression is stimulated by retinoid-related orphan receptors (RORs) and repressed by nuclear hormone receptor REV-ERBa (also known as NR1D1). Degradation of PER and CRY shortens the length of circadian period, whereas stabilization of CRY lengthens the period. In addition to repressing CLOCK, CRY1 suppresses hepatic gluconeogenesis by regulating CREB (cAMP response element-binding protein)/cAMP signaling via rhythmic repression of glucocorticoid receptor and decreasing levels of nuclear FoxO1 that down-regulates expression of gluconeogenic genes. Ubiquitination-mediated proteasomal degradation of CRY1 is known to be regulated by multiple factors. Studies on rodents have shown that macroautophagy affects the circadian clock by selectively degrading CRY1. Degradation of CRY1 removes its inhibitory effect on gluconeogenesis at a time of the day when rodents rely on gluconeogenesis, thus synchronizing CRY1 degradation with the need for maintaining blood glucose levels when nutrients are not available. A high-fat diet accelerates CRY1 autophagy, thereby contributing to obesity-associated hyperglycemia.¹⁰¹

Glucose Production

Glucose production in the postabsorptive state is regulated to match tissue demand, which may increase during exercise or stresses such as infection and trauma. Normally, approximately 50% of the glucose released into the circulation is the result of hepatic glycogenolysis; the remaining 50% is due to gluconeogenesis (30% liver; 20% kidney).

The proportion of glucose produced due to gluconeogenesis increases with the duration of the fast since glycogen stores are rapidly depleted. The liver contains a total of 75 g glucose. Assuming that the liver releases glucose from glycogen at a rate of 5 μmol kg⁻¹ min⁻¹, glycogen stores would be depleted within 20 h. Thus, the proportion due to gluconeogenesis must increase so that after 72 h, glucose production by the liver is almost exclusively due to gluconeogenesis. The kidney, in contrast, contains little glycogen stores and the cells that could make glycogen lack glucose-6-phosphatase; consequently, all the glucose released by the kidney is due to gluconeogenesis. (Renal gluconeogenesis increases with fasting to a greater extent than hepatic gluconeogenesis.) Insulin suppresses both hepatic and renal glucose release; however, glucagon promptly increases hepatic glucose release, whereas catecholamines stimulate more renal glucose release.

Publisher Summary

Gluconeogenesis refers to synthesis of new glucose from noncarbohydrate precursors, provides glucose when dietary intake is insufficient or absent. It also is essential in the regulation of acid-base balance, amino acid metabolism, and synthesis of carbohydrate derived structural components. Gluconeogenesis occurs in liver and kidneys. The precursors of gluconeogenesis are lactate, glycerol, amino acids, and with propionate making a minor contribution. The gluconeogenesis pathway consumes ATP, which is derived primarily from the oxidation of fatty acids. The pathway uses several enzymes of the glycolysis with the exception of enzymes of the irreversible steps namely pyruvate kinase, 6-phosphofructokinase, and hexokinase. The irreversible reactions of glycolysis are bypassed by four alternate unique reactions of gluconeogenisis. The four unique reactions of gluconeogenesis are pyruvate carboxylase, located in the mitochondrial matrix, phosphoenolpyruate (PEP) carboxykinase located in mitochondrial matrix and cytosol, fructose-1, 6-bisphosphatase located in the cytosol and glucose-6-phosphatase located in the endoplasmic reticulum (ER).

Function

Protein synthesis: Daily protein turnover may be as much as 300g, which means that the same amount has to be resynthesized. The 20 basic amino acids are required for the synthesis of most of the more than 30000 different proteins that constitute the human body. Deficiency of any single one affects all body functions and is ultimately not compatible with life.

Energy fuel: Eventually nearly all amino acids are fully oxidized to carbon dioxide, water and urea. Only very minor amounts of a few amino acids are converted into compounds that are excreted in a more complex form. On average, the oxidation of the amino acids in proteins provides 4 kcal/g.

Non-protein mediator synthesis: Several 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 neuron excitation are either amino acids or amino acid metabolites. Amino acids with such functions include glutamate, glycine, and proline. Amino-acid metabolites, which participate in neurotransmission, include gamma-amino butyrate (GABA), N-methyl D-aspartate (NMDA), nitric oxide, serotonin, melatonin, histamine, and agmatine.

Nucleotide synthesis: Two of the four carbons and one of the nitrogen atoms in purines come from glycine. Aspartate provides two of the five nitrogen atoms 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 in the Fasting State

In the fasting state, glucagon causes the liver to mobilize glucose from glycogen (glycogenolysis) and to synthesize glucose from oxaloacetate and glycerol (gluconeogenesis). Glucagon stimulates an increase in cyclic adenosine monophosphate leading to an increase in phosphorylation by protein kinase A. The wave of phosphorylation that spreads through the liver cell activates enzymes such as glycogen phosphorylase that are involved in glycogen degradation while simultaneously inhibiting glycogen synthesis. Inhibition of glycogen synthase prevents futile resynthesis of glycogen from glucose 1-phosphate (G1P) via uridine diphosphoglucose. Glucose-6-phosphatase (G6Pase), a gluconeogenic enzyme that is present in the liver but not in muscle, then converts G6P to glucose for release into the blood.

The increased liver uptake of amino acids (derived from protein catabolism in muscle) during fasting provides the carbon skeletons for gluconeogenesis (e.g., alanine is transaminated into pyruvate). The increased concentrations of ${{\text{NH}}_4}^{+}$ resulting from deamination of amino acids are metabolized in the liver by the urea cycle, leading to increased excretion of urea in urine and a negative nitrogen balance.

The glycerol that is derived from lipolysis in adipose tissue is taken up by the liver and phosphorylated by glycerol kinase, thus contributing additional carbon skeletons for hepatic gluconeogenesis.

Some ketogenesis occurs in the liver, especially with prolonged fasting, with ketone bodies primarily going to muscle as an alternative fuel. At this point, ketosis is mild and not clinically important.

Gluconeogenesis

Gluconeogenesis is the process wherein the liver and, to a smaller but often significant extent, the kidneys make 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 especially important in gluconeogenesis in the kidney. Fatty acids, apart from propionate formed in the colon by bacterial fermentation of nonabsorbable carbohydrates, do not serve as glucose precursors to any significant degree but do provide the conditions under which it can take place. So too do specific hormones, such as glucagon and cortisol.

The contribution by alanine to gluconeogenesis has probably been exaggerated. Although formed along with other amino acids by proteolysis of nonstructural muscle proteins during periods of prolonged fasting and starvation, its main role under normal conditions is to transport, after transamination, three-carbon skeletons (e.g., pyruvate) derived from muscle glycogen to the liver, where it is converted into glucose during fasting.

Eating inhibits gluconeogenesis mainly through an increase in insulin and decrease in glucagon action. Fasting produces the opposite effect. Alcohol specifically inhibits gluconeogenesis from lactate but not other substrates, such as alanine. It does so by adversely changing the redox potential within the hepatocytes and reducing the availability of nicotinamide adenine dinucleotide, which is an essential component in the formation of glucose from lactate. The inhibition of gluconeogenesis by quite modest amounts of alcohol can sometimes be so profound that people, especially children, with reduced liver glycogen stores may develop hypoglycemia of a severity that can be fatal.