Introduction
The brain, eye, and kidney are some of the organsthat have glucose as thesole metabolic fuel source. Prolonged fasting or vigorous exercise depletes glycogen stores, making the body switch to de-novo glucose synthesis tomaintain blood levels of this monosaccharide.Gluconeogenesis is theprocessthat allows the body toform glucose from non-hexose precursors, particularly glycerol, lactate, pyruvate, propionate, and glucogenic amino acids.[1]
Gluconeogenesis essentially reversesglycolysis (see Image. Gluconeogenesis). Four enzymes facilitate glucose synthesis by this pathway byreversing 3highly exergonic glycolytic steps, namely, pyruvate carboxylase, phosphoenol pyruvate carboxykinase (PEPCK),fructose-1,6-bisphosphatase, and glucose-6-phosphatase. However, these enzymes are not present in all cell types. Therefore, gluconeogenesis can only occur in specific tissues.In humans, gluconeogenesis takes place primarily in the liver and, to a lesser extent, the renal cortex.[2]
This article discusses gluconeogenesis and its clinical correlates.
Issues of Concern
Only a moderate amount of glucose can be synthesized by gluconeogenesis, but failure of this pathway is typically fatal.Acute hypoglycemia can damage the brain and kidneys because of their dependence on glucose for fuel. Gluconeogenesis is also one of the body's main clearing mechanisms for the muscle and erythrocyte metabolite, lactic acid. Lactic acidosis arising from shock is associated with increased mortality risk.[14]
Cellular Level
Gluconeogenesis Reactions And Enzymes
The primary stimulus for gluconeogenesis is low blood glucose. Startingwith pyruvate, the reactionsinvolved in gluconeogenesis are the following:
In the mitochondrion, pyruvate carboxylaseconverts pyruvate to oxaloacetate. Pyruvate carboxylase requires ATP and the coenzyme biotin for activation. This conversion is the firststep that reverses the nonequilibrium reaction catalyzed by the glycolytic enzymepyruvate kinase.
Oxaloacetate is converted to malate before it crosses the mitochondrial membrane. Malate is converted back to oxaloacetate once in the cytosol.
In the cytosol,PEPCK decarboxylates oxaloacetate, which then rearranges to form phosphoenol pyruvate (PEP).PEPCK requires GTP and magnesium ions for activation. Thistransformation is the secondstep that reverses the nonequilibrium reaction catalyzed by pyruvate kinase.
Enolase hydrates PEP to form 2-phosphoglycerate.
Phosphoglycerate mutase converts 2-phosphoglycerate to 3-phosphoglycerate.
Phosphoglycerate kinase phosphorylates 3-phosphoglycerate to form 1,3-bisphosphoglycerate. This reaction requires ATP.
Glyceraldehyde-3-phosphate dehydrogenase reduces 1,3-bisphosphoglycerate to glyceraldehyde 3-phosphate. Reduced nicotinamide adenine dinucleotide (NADH) is the electron donor.
Triose phosphate isomerase isomerizes glyceraldehyde 3-phosphate to form dihydroxyacetone phosphate (DHAP).
Aldolase combines glyceraldehyde 3-phosphate andDHAP to form fructose 1,6-bisphosphate.
Fructose-1,6-bisphosphatase dephosphorylates fructose 1,6-bisphosphate to formfructose 6-phosphate. This step reverses thenonequilibrium reaction catalyzed by the glycolytic enzyme phosphofructokinase-1.
Phosphohexose isomerase converts fructose 6-phosphate to glucose 6-phosphate.
Glucose-6-phosphatase dephosphorylates glucose 6-phosphate to form glucose, whichcan enter the bloodstream freely.Thislast reactionreverses the nonequilibrium reaction catalyzed by the glycolytic enzyme hexokinase.
Substrates Of Gluconeogenesis
The major substrates of gluconeogenesis are lactate, glycerol, and glucogenic amino acids.
Lactate isa product of anaerobic glycolysis.This ATP-generating process occurs whenoxygen is limited, eg, during vigorous exercise or low-perfusion states. Cells that use this pathway, such as the erythrocytes, lack mitochondriaandare not equipped for oxidative phosphorylation. The liveruses lactate in the blood to produce glucose via gluconeogenesis. Glucose gets released into the bloodstream, travels back to the erythrocytes and exercising muscles,and is metabolized back intolactate. This process iscalled the Cori cycle.[2]
Glycerol comes from adipose tissue lipolysis. This process breaks down triglycerides to formfatty acids and glycerol molecules. In the liver, glycerol kinase phosphorylates glycerol to formglycerol phosphate. Glycerol phosphate dehydrogenaseoxidizes glycerol phosphateinto the glycolytic intermediate,DHAP.[3]
Glucogenic amino acids enter the gluconeogenesis pathway via the citric acid cycle (see Image. Glucogenic Amino Acids). The first step is the deamination of the glucogenic amino acids into α-ketoacids, which are substrates in the citric acid cycle. From there, these α-ketoacids are converted tooxaloacetate, the substrate for PEPCK.
Regulation Of Gluconeogenesis
Gluconeogenesis reactions are highly endergonic and, thus, easily reversible. Controls at various levels ensure that each reaction moves forward until free glucose is produced.Glucagon is the most important promoter of gluconeogenesis. Secondary ones include the catecholamines, growth hormone, cortisol, and gluconeogenic substrates.[4][5]
The pancreatic alpha cells secrete glucagon in response to falling blood glucose levels. This hormone increases the concentration of cyclic adenosine monophosphate (cAMP), which inactivates glycolytic enzymeswhile activating gluconeogenic ones. Catecholamines produce the same effect by enhancing intracellular cAMP concentration.[6][7]
Insulin is a potent inhibitor of gluconeogenesis.[8]Falling insulin levels during fasting activategluconeogenesis and the processes that increase the availability of gluconeogenic substrates.[4]
Table
Table 1. Effect of Different Hormones on Key Glycolytic and Gluconeogenic Enzymes.
The alanine cycle,aka the Cahill cycle, augments gluconeogenic glucose production during fasting.In skeletal muscle, alanine aminotransferase (ALT) transfers an α-amino group from glutamate to pyruvate, producing alanine and α-ketoglutarate. Alanine is released from skeletal muscle and taken up by the liver for transamination back to pyruvate. Pyruvate can then be used for gluconeogenesis.[9][10]
Organ Systems Involved
During the first 18 to 24 hours of fasting, gluconeogenesis mostly occurs in the liver. Prolonged starvation forces the kidneys to assume as much as 20% of the totalglucose production by this pathway.Only the liver and kidneys have thegluconeogenic enzyme glucose-6-phosphatase and, thus, have the ability to convertglucose 6-phosphateinto free glucose.[1][2]
Function
Gluconeogenesis maintains blood glucose levels during starvation. Some tissues in the human body rely almost exclusively on glucose as a metabolic fuel source. The brain, for example, requires approximately 120 g of glucose per day. Ketone bodies can serve as the brain's alternative fuel source. However, the testes, renal medulla, and erythrocytes cannot survive long periods without glucose.Gluconeogenesis starts 4 to 6 hours after fasting begins, peaking after 24whenhepatic glycogen is depleted.[1][2][15]
Pathophysiology
Von Gierke disease is an autosomal recessive condition notable for deficiency of the key gluconeogenic enzyme glucose-6-phosphatase. Gluconeogenesis is impaired, resulting infasting hypoglycemia. Glycogenolysis is also affected, as free glucose in the last step of this pathway needs the same enzyme for conversionfromglucose 6-phosphate.Other metabolicabnormalitiesthat can manifest in von Gierke disease are hyperkalemia, hyperuricemia, and lactic acidosis.[11]
Clinical Significance
Treating Hyperglycemia in Diabetes
Diabetesmay resultfrom impaired insulin production or decreased insulin sensitivity. Besidesstimulating glucose uptake from the bloodstream, insulin is also a potent gluconeogenesis inhibitor. Gluconeogenesis occurs atan unusually rapid rate in insulin deficiency or insensitivity, increasing the risk of hyperglycemia in patients with diabetes mellitus.[1]
Metformin, the first-line agent fortype 2 diabetes mellitus management, has been shown to suppress hepatic gluconeogenesisby various mechanisms.This drugactivates adenosine monophosphate-activated protein kinase (AMPK), which, in turn, inhibits hepatic lipogenesis and increases insulin sensitivity.AMPK activation also increases cAMP breakdown, furthersuppressing gluconeogenesis.[1][12]
Metformin also appears to directly inhibit glycerol-3-phosphate dehydrogenase, increasingNADH levels.[1][12]High intracellular NADH favors the formation of lactate over pyruvate by thelactate dehydrogenasereaction. Gluconeogenesis using lactate as a substrate cannot proceed without this molecule's conversion back to pyruvate.
At high doses, metformin also inhibits complex I of the electron transport chain, the ATP production that drives highly endergonic processes likegluconeogenesis.[1]
Hypoglycemia as a Result of Ethanol Consumption
Ethanol clearance from the body begins with its oxidation intoacetaldehyde by hepaticalcohol dehydrogenase. This enzyme uses oxidized nicotinamide adenine dinucleotide (NAD+) as an electron acceptor. Aldehyde dehydrogenase oxidizesacetaldehyde further into acetate, which is readily excreted by the body.Aldehyde dehydrogenase also requires NAD+ as a cofactor.Thus,ethanolmetabolism results in NADH accumulation.[13]
As previously mentioned, high intracellular NADHincreaseslactic acid formation, which can inhibit gluconeogenesis. Thus, heavy ethanol consumptioncan lead to both lactic acidosis and hypoglycemia.[13]
Hypoglycemia in the Preterm Infant
Preterm infants are particularlyat risk of developing hypoglycemia. Low-birth-weight neonates have limited glycogen and fat stores but also express gluconeogenic enzymes at suboptimal levels. Preterm infants' energy stores can diminish quickly,as they cannot mountan adequatecounterregulatory response.[4]
Figure
Glucogenic Amino Acids. This illustration showshow the glucogenic amino acids enter the Krebs cycle. Image courtesy Dr Chaigasame
References
- 1.
Zhang X, Yang S, Chen J, Su Z. Unraveling the Regulation of Hepatic Gluconeogenesis. Front Endocrinol (Lausanne). 2018;9:802. [PMC free article: PMC6353800] [PubMed: 30733709]
- 2.
Chung ST, Chacko SK, Sunehag AL, Haymond MW. Measurements of Gluconeogenesis and Glycogenolysis: A Methodological Review. Diabetes. 2015 Dec;64(12):3996-4010. [PMC free article: PMC4657587] [PubMed: 26604176]
- 3.
da Silva IV, Rodrigues JS, Rebelo I, Miranda JPG, Soveral G. Revisiting the metabolic syndrome: the emerging role of aquaglyceroporins. Cell Mol Life Sci. 2018 Jun;75(11):1973-1988. [PubMed: 29464285]
- 4.
Sharma A, Davis A, Shekhawat PS. Hypoglycemia in the preterm neonate: etiopathogenesis, diagnosis, management and long-term outcomes. Transl Pediatr. 2017 Oct;6(4):335-348. [PMC free article: PMC5682372] [PubMed: 29184814]
- 5.
Bankir L, Bouby N, Speth RC, Velho G, Crambert G. Glucagon revisited: Coordinated actions on the liver and kidney. Diabetes Res Clin Pract. 2018 Dec;146:119-129. [PubMed: 30339786]
- 6.
Droppelmann CA, Sáez DE, Asenjo JL, Yáñez AJ, García-Rocha M, Concha II, Grez M, Guinovart JJ, Slebe JC. A new level of regulation in gluconeogenesis: metabolic state modulates the intracellular localization of aldolase B and its interaction with liver fructose-1,6-bisphosphatase. Biochem J. 2015 Dec 01;472(2):225-37. [PubMed: 26417114]
- 7.
Borrebaek B, Bremer J, Davis EJ, Davis-Van Thienen W, Singh B. The effect of glucagon on the carbon flux from palmitate into glucose, lactate and ketone bodies, studied with isolated hepatocytes. Int J Biochem. 1984;16(7):841-4. [PubMed: 6468742]
- 8.
Honma K, Kamikubo M, Mochizuki K, Goda T. Insulin-induced inhibition of gluconeogenesis genes, including glutamic pyruvic transaminase 2, is associated with reduced histone acetylation in a human liver cell line. Metabolism. 2017 Jun;71:118-124. [PubMed: 28521864]
- 9.
Sarabhai T, Roden M. Hungry for your alanine: when liver depends on muscle proteolysis. J Clin Invest. 2019 Nov 01;129(11):4563-4566. [PMC free article: PMC6819091] [PubMed: 31545302]
- 10.
Hatazawa Y, Qian K, Gong DW, Kamei Y. PGC-1α regulates alanine metabolism in muscle cells. PLoS One. 2018;13(1):e0190904. [PMC free article: PMC5760032] [PubMed: 29315328]
- 11.
Bali DS, El-Gharbawy A, Austin S, Pendyal S, Kishnani PS. Glycogen Storage Disease Type I. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. University of Washington, Seattle; Seattle (WA): Apr 19, 2006. [PubMed: 20301489]
- 12.
Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi SE, Schumann WC, Petersen KF, Landau BR, Shulman GI. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000 Dec;49(12):2063-9. [PMC free article: PMC2995498] [PubMed: 11118008]
- 13.
Tsai WW, Matsumura S, Liu W, Phillips NG, Sonntag T, Hao E, Lee S, Hai T, Montminy M. ATF3 mediates inhibitory effects of ethanol on hepatic gluconeogenesis. Proc Natl Acad Sci U S A. 2015 Mar 03;112(9):2699-704. [PMC free article: PMC4352786] [PubMed: 25730876]
Disclosure: Erica Melkonian declares no relevant financial relationships with ineligible companies.
Disclosure: Edinen Asuka declares no relevant financial relationships with ineligible companies.
Disclosure: Mark Schury declares no relevant financial relationships with ineligible companies.
