View source for Gluconeogenesis

{{Short description|Biosynthesis of glucose molecules}}
{{Distinguish|Glucuronidation|Glycogenesis|Glyceroneogenesis|Glycogenolysis|Glycolysis}}
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'''Gluconeogenesis''' ('''GNG''') is a [[metabolic pathway]] that results in the biosynthesis of [[glucose]] from certain non-[[carbohydrate]] carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms.<ref>{{cite book| vauthors = Nelson DL, Cox MM |url= https://archive.org/details/lehningerprincip01lehn/page/724 |title=Lehninger Principles of Biochemistry|publisher=Worth Publishers|year=2000|isbn=978-1-57259-153-0|location=USA|page=[https://archive.org/details/lehningerprincip01lehn/page/724 724]}}</ref> In vertebrates, gluconeogenesis occurs mainly in the [[liver]] and, to a lesser extent, in the [[renal cortex|cortex]] of the [[Kidney (vertebrates)|kidneys]]. It is one of two primary mechanisms – the other being degradation of [[glycogen]] ([[glycogenolysis]]) – used by humans and many other animals to maintain [[blood sugar level]]s, avoiding low levels ([[hypoglycemia]]).<ref>{{cite web| vauthors = Silva P |title=The Chemical Logic Behind Gluconeogenesis|url=http://www2.ufp.pt/~pedros/bq/gng.htm|archive-url=https://web.archive.org/web/20090826043311/http://www2.ufp.pt/~pedros/bq/gng.htm|archive-date=August 26, 2009|access-date=September 8, 2009}}{{self-published inline|date=May 2025}}</ref> In [[ruminant]]s, because dietary carbohydrates tend to be metabolized by [[rumen]] organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc.<ref name="Beitz2004" />  In many other animals, the process occurs during periods of [[fasting]], [[starvation]], [[low-carbohydrate diet]]s, or intense [[exercise]].

In humans, substrates for gluconeogenesis may come from any non-carbohydrate sources that can be converted to [[pyruvic acid|pyruvate]] or intermediates of [[glycolysis]] (see figure). For the breakdown of [[protein]]s, these substrates include [[glucogenic amino acid]]s (although not [[ketogenic amino acid]]s); from breakdown of [[lipid]]s (such as [[triglyceride]]s), they include [[glycerol]], odd-chain fatty acids (although not even-chain fatty acids, see below); and from other parts of [[metabolism]] that includes [[lactic acid|lactate]] from the [[Cori cycle]]. Under conditions of prolonged fasting, acetone derived from [[ketone bodies]] can also serve as a substrate, providing a pathway from fatty acids to glucose.<ref name=":0">{{cite journal | vauthors = Kaleta C, de Figueiredo LF, Werner S, Guthke R, Ristow M, Schuster S | title = In silico evidence for gluconeogenesis from fatty acids in humans | journal = PLOS Computational Biology | volume = 7 | issue = 7 | article-number = e1002116 | date = July 2011 | pmid = 21814506 | pmc = 3140964 | doi = 10.1371/journal.pcbi.1002116 | bibcode = 2011PLSCB...7E2116K | doi-access = free }}</ref> Although most gluconeogenesis occurs in the liver, the relative contribution of gluconeogenesis by the kidney is increased in diabetes and prolonged fasting.<ref name="pmid30370538">{{cite journal | vauthors = Swe MT, Pongchaidecha A, Chatsudthipong V, Chattipakorn N, Lungkaphin A | title = Molecular signaling mechanisms of renal gluconeogenesis in nondiabetic and diabetic conditions | journal = Journal of Cellular Physiology | volume = 234 | issue = 6 | pages = 8134–8151 | date = June 2019 | pmid = 30370538 | doi = 10.1002/jcp.27598 }}</ref>

The gluconeogenesis pathway is highly [[endergonic]] until it is coupled to the hydrolysis of [[Adenosine triphosphate|ATP]] or [[Guanosine triphosphate|GTP]], effectively making the process [[exergonic]]. For example, the pathway leading from [[pyruvate]] to [[glucose-6-phosphate]] requires 4 molecules of ATP and 2 molecules of GTP to proceed spontaneously. These ATPs are supplied from [[Fatty acid metabolism|fatty acid catabolism]] via [[beta oxidation]].<ref>{{Cite book| vauthors = Rodwell V |title=Harper's illustrated Biochemistry, 30th edition|publisher=McGraw Hill|year=2015|isbn=978-0-07-182537-5|location=USA|page=193}}</ref>

==Precursors==
[[File:Amino acid catabolism revised.png|thumb|300px|class=skin-invert-image|Catabolism of [[proteinogenic amino acid]]s. Amino acids are classified according to the abilities of their products to enter gluconeogenesis:<ref>{{cite book|chapter=20. Amino Acid Degradation and Synthesis | vauthors = Ferrier DR, Champe PC, Harvey RA |title=Biochemistry | series = Lippincott's Illustrated Reviews |publisher=Lippincott Williams & Wilkins |location= Hagerstwon, MD |isbn=978-0-7817-2265-0 |date=1 August 2004}}</ref> {{unordered list
 | [[Glucogenic amino acid]]s have this ability
 | [[Ketogenic amino acid]]s do not. These products may still be used for [[ketogenesis]] or [[lipid synthesis]].
 | Some amino acids are catabolized into both glucogenic and ketogenic products.}}]]
In humans the main gluconeogenic precursors are [[lactic acid|lactate]], [[glycerol]] (which is a part of the [[triglyceride]] molecule), [[alanine]] and [[glutamine]]. Altogether, they account for over 90% of the overall gluconeogenesis.<ref name="pmid11213896">{{cite journal | vauthors = Gerich JE, Meyer C, Woerle HJ, Stumvoll M | title = Renal gluconeogenesis: its importance in human glucose homeostasis | journal = Diabetes Care | volume = 24 | issue = 2 | pages = 382–91 | date = February 2001 | pmid = 11213896 | doi = 10.2337/diacare.24.2.382 | doi-access = free }}</ref>
Other [[glucogenic amino acid]]s and all [[citric acid cycle]] intermediates (through conversion to [[oxaloacetate]]) can also function as substrates for gluconeogenesis.<ref name = Garrett/>  Generally, human consumption of gluconeogenic substrates in food does not result in increased gluconeogenesis.<ref name="pmid18561209" />

In [[ruminant]]s, propionate is the principal gluconeogenic substrate.<ref name=Beitz2004>{{cite book | vauthors = Beitz DC | date = 2004 | chapter = Carbohydrate metabolism. | veditors = Reese WO | title = Dukes' Physiology of Domestic Animals | edition = 12th | publisher = Cornell Univ. Press | pages = 501–15 |isbn=978-0-8014-4238-4}}</ref><ref>{{cite book | vauthors = Van Soest PJ | date = 1994 | title = Nutritional Ecology of the Ruminant | edition = 2nd | publisher = Cornell Univ. Press|isbn=978-1-5017-3235-5}}</ref> In nonruminants, including human beings, propionate arises from the β-oxidation of odd-chain and branched-chain fatty acids, and is a (relatively minor) substrate for gluconeogenesis.<ref>{{cite book | vauthors = Rodwell VW, Bender DA, Botham KM, Kennelly PJ, Weil PA | title = Harper's Illustrated Biochemistry | edition = 31st | date = 2018 | publisher = McGraw-Hill Publishing Company }}</ref><ref>{{cite book | vauthors = Baynes J, Dominiczak M | title = Medical Biochemistry | edition = 4th | date = 2014 | publisher = Elsevier }}</ref>

Lactate is transported back to the liver where it is converted into [[pyruvate]] by the [[Cori cycle]] using the enzyme [[lactate dehydrogenase]]. Pyruvate, the first designated substrate of the gluconeogenic pathway, can then be used to generate glucose.<ref name = Garrett>{{cite book |title=Principles of Biochemistry with a Human Focus | vauthors = Garrett RH, Grisham CM |year=2002 |publisher=Brooks/Cole, Thomson Learning |location=USA |isbn=978-0-03-097369-7 |pages=578, 585 }}</ref> [[Transamination]] or [[deamination]] of amino acids facilitates entering of their carbon skeleton into the cycle directly (as pyruvate or oxaloacetate), or indirectly via the citric acid cycle. The contribution of Cori cycle lactate to overall glucose production increases with [[fasting]] duration.<ref name="pmid9725823">{{cite journal | vauthors = Katz J, Tayek JA | title = Gluconeogenesis and the Cori cycle in 12-, 20-, and 40-h-fasted humans | journal = The American Journal of Physiology | volume = 275 | issue = 3 | pages = E537–42 | date = September 1998 | pmid = 9725823 | doi = 10.1152/ajpendo.1998.275.3.E537 }}</ref> Specifically, after 12, 20, and 40 hours of fasting by human volunteers, the contribution of Cori cycle lactate to gluconeogenesis was 41%, 71%, and 92%, respectively.<ref name="pmid9725823" />

Whether even-chain [[fatty acid]]s can be converted into glucose in animals has been a longstanding question in biochemistry.<ref name = Figueiredo>{{cite journal | vauthors = de Figueiredo LF, Schuster S, Kaleta C, Fell DA | title = Can sugars be produced from fatty acids? A test case for pathway analysis tools | journal = Bioinformatics | volume = 25 | issue = 1 | pages = 152–8 | date = January 2009 | pmid = 19117076 | doi = 10.1093/bioinformatics/btn621 | doi-access = free }}</ref> [[Odd-chain fatty acid]]s can be oxidized to yield [[acetyl-CoA]] and [[propionyl-CoA]], the latter serving as a precursor to [[succinyl-CoA]], which can be converted to oxaloacetate and enter into gluconeogenesis. In contrast, even-chain fatty acids are oxidized to yield only acetyl-CoA, whose entry into gluconeogenesis requires the presence of a [[glyoxylate cycle]] (also known as glyoxylate shunt) to produce four-carbon dicarboxylic acid precursors.<ref name = Garrett/> The glyoxylate shunt comprises two enzymes, malate synthase and isocitrate lyase, and is present in fungi, plants, and bacteria. Despite some reports of glyoxylate shunt enzymatic activities detected in animal tissues, genes encoding both enzymatic functions have only been found in [[nematode]]s, in which they exist as a single bi-functional enzyme.<ref name="Liu">{{cite journal | vauthors = Liu F, Thatcher JD, Barral JM, Epstein HF | title = Bifunctional glyoxylate cycle protein of Caenorhabditis elegans: a developmentally regulated protein of intestine and muscle | journal = Developmental Biology | volume = 169 | issue = 2 | pages = 399–414 | date = June 1995 | pmid = 7781887 | doi = 10.1006/dbio.1995.1156 | doi-access = free }}</ref><ref name="Kondrashov" /> Genes coding for malate synthase alone (but not isocitrate lyase) have been identified in other [[animal]]s including [[arthropod]]s, [[echinoderm]]s, and even some [[vertebrate]]s. Mammals found to possess the malate synthase gene include [[monotreme]]s ([[platypus]]) and [[marsupial]]s ([[opossum]]), but not [[placental mammal]]s.<ref name="Kondrashov">{{cite journal | vauthors = Kondrashov FA, Koonin EV, Morgunov IG, Finogenova TV, Kondrashova MN | title = Evolution of glyoxylate cycle enzymes in Metazoa: evidence of multiple horizontal transfer events and pseudogene formation | journal = Biology Direct | volume = 1 | page = 31 | date = October 2006 | pmid = 17059607 | pmc = 1630690 | doi = 10.1186/1745-6150-1-31 | doi-access = free }}</ref>

The existence of the glyoxylate cycle in humans has not been established, and it is widely held that fatty acids cannot be converted to glucose in humans directly. [[Carbon-14]] has been shown to end up in glucose when it is supplied in fatty acids,<ref name="Weinman">{{cite journal | vauthors = Weinman EO, Strisower EH, Chaikoff IL | title = Conversion of fatty acids to carbohydrate; application of isotopes to this problem and role of the Krebs cycle as a synthetic pathway | journal = Physiological Reviews | volume = 37 | issue = 2 | pages = 252–72 | date = April 1957 | pmid = 13441426 | doi = 10.1152/physrev.1957.37.2.252 }}</ref> but this can be expected from the incorporation of labelled atoms derived from acetyl-CoA into [[citric acid cycle]] intermediates which are interchangeable with those derived from other physiological sources, such as glucogenic amino acids.<ref name="Figueiredo" /> In the absence of other glucogenic sources, the 2-carbon [[acetyl-CoA]] derived from the oxidation of fatty acids cannot produce a net yield of glucose via the [[citric acid cycle]], since an equivalent two carbon atoms are released as carbon dioxide during the cycle. During [[ketosis]], however, acetyl-CoA from fatty acids yields [[ketone bodies]], including [[acetone]], and up to ~60% of acetone may be oxidized in the liver to the pyruvate precursors acetol and [[methylglyoxal]].<ref>{{cite journal | vauthors = Reichard GA, Haff AC, Skutches CL, Paul P, Holroyde CP, Owen OE | title = Plasma acetone metabolism in the fasting human | journal = The Journal of Clinical Investigation | volume = 63 | issue = 4 | pages = 619–26 | date = April 1979 | pmid = 438326 | doi = 10.1172/JCI109344 | pmc = 371996 }}</ref><ref name=":0" /> Thus ketone bodies derived from fatty acids could account for up to 11%{{citation needed|date=February 2025}} of gluconeogenesis during starvation. [[Fatty acid metabolism|Catabolism of fatty acids]] also produces energy in the form of ATP that is necessary for the gluconeogenesis pathway.

== Bodily location ==
In mammals, gluconeogenesis has been believed to be restricted to the liver,<ref name="vander96">{{cite book| vauthors = Widmaier E |title=Vander's Human Physiology|url=https://archive.org/details/vandershumanphys00widm|url-access=registration|year=2006|publisher=McGraw Hill|isbn=978-0-07-282741-5|page=[https://archive.org/details/vandershumanphys00widm/page/96 96]}}</ref> the kidney,<ref name=vander96 /> the intestine,<ref name = Mithieux>{{cite journal | vauthors = Mithieux G, Rajas F, Gautier-Stein A | title = A novel role for glucose 6-phosphatase in the small intestine in the control of glucose homeostasis | journal = The Journal of Biological Chemistry | volume = 279 | issue = 43 | pages = 44231–44234 | date = October 2004 | pmid = 15302872 | doi = 10.1074/jbc.R400011200 | doi-access = free }}</ref> and muscle,<ref>{{cite journal | vauthors = Chen J, Lee HJ, Wu X, Huo L, Kim SJ, Xu L, Wang Y, He J, Bollu LR, Gao G, Su F, Briggs J, Liu X, Melman T, Asara JM, Fidler IJ, Cantley LC, Locasale JW, Weihua Z | display-authors = 6 | title = Gain of glucose-independent growth upon metastasis of breast cancer cells to the brain | journal = Cancer Research | volume = 75 | issue = 3 | pages = 554–565 | date = February 2015 | pmid = 25511375 | pmc = 4315743 | doi = 10.1158/0008-5472.CAN-14-2268 }}</ref> but recent evidence indicates gluconeogenesis occurring in [[astrocyte]]s of the brain.<ref name="pmid28101056">{{cite journal | vauthors = Yip J, Geng X, Shen J, Ding Y | title = Cerebral Gluconeogenesis and Diseases | journal = Frontiers in Pharmacology | volume = 7 | page = 521 | year = 2017 | pmid = 28101056 | pmc = 5209353 | doi = 10.3389/fphar.2016.00521 | doi-access = free }}</ref>  These organs use somewhat different gluconeogenic precursors.  The liver preferentially uses lactate, glycerol, and glucogenic amino acids (especially [[alanine]]) while the kidney preferentially uses lactate, [[glutamine]] and glycerol.<ref name=Gerich2010>{{cite journal | vauthors = Gerich JE | title = Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications | journal = Diabetic Medicine | volume = 27 | issue = 2 | pages = 136–142 | date = February 2010 | pmid = 20546255 | pmc = 4232006 | doi = 10.1111/j.1464-5491.2009.02894.x }}</ref><ref name="pmid11213896" />  Lactate from the [[Cori cycle]] is quantitatively the largest source of substrate for gluconeogenesis, especially for the kidney.<ref name="pmid11213896" />  The liver uses both [[glycogenolysis]] and gluconeogenesis to produce glucose, whereas the kidney only uses gluconeogenesis.<ref name="pmid11213896" /> After a meal, the liver shifts to [[Glycogenesis|glycogen synthesis]], whereas the kidney increases gluconeogenesis.<ref name="pmid18561209">{{cite journal | vauthors = Nuttall FQ, Ngo A, Gannon MC | title = Regulation of hepatic glucose production and the role of gluconeogenesis in humans: is the rate of gluconeogenesis constant? | journal = Diabetes/Metabolism Research and Reviews | volume = 24 | issue = 6 | pages = 438–458 | date = September 2008 | pmid = 18561209 | doi = 10.1002/dmrr.863 }}</ref> The intestine uses mostly glutamine and glycerol.<ref name = Mithieux />

Propionate is the principal substrate for gluconeogenesis in the ruminant liver, and the ruminant liver may make increased use of gluconeogenic amino acids (e.g., alanine) when glucose demand is increased.<ref>{{cite journal | vauthors = Overton TR, Drackley JK, Ottemann-Abbamonte CJ, Beaulieu AD, Emmert LS, Clark JH | title = Substrate utilization for hepatic gluconeogenesis is altered by increased glucose demand in ruminants | journal = Journal of Animal Science | volume = 77 | issue = 7 | pages = 1940–51 | date = July 1999 | pmid = 10438042 | doi = 10.2527/1999.7771940x }}</ref>  The capacity of liver cells to use lactate for gluconeogenesis declines from the preruminant stage to the ruminant stage in calves and lambs.<ref name="pmid7601789"/>  In sheep kidney tissue, very high rates of gluconeogenesis from propionate have been observed.<ref name="pmid7601789">{{cite journal | vauthors = Donkin SS, Armentano LE | title = Insulin and glucagon regulation of gluconeogenesis in preruminating and ruminating bovine | journal = Journal of Animal Science | volume = 73 | issue = 2 | pages = 546–51 | date = February 1995 | pmid = 7601789 | doi = 10.2527/1995.732546x }}</ref>

In all species, the formation of [[oxaloacetate]] from [[pyruvate]] and TCA cycle intermediates is restricted to the mitochondrion, and the enzymes that convert [[Phosphoenolpyruvic acid]] (PEP) to glucose-6-phosphate are found in the cytosol.<ref name="Voet556" >{{cite book |title= Fundamentals of Biochemistry |url= https://archive.org/details/fundamentalsbioc00voet |url-access = limited | vauthors = Voet D, Voet J, Pratt C |year= 2008 |publisher= John Wiley & Sons Inc |isbn=978-0-470-12930-2 |page=[https://archive.org/details/fundamentalsbioc00voet/page/n586 556]}}</ref>  The location of the enzyme that links these two parts of gluconeogenesis by converting [[oxaloacetate]] to PEP – [[phosphoenolpyruvate carboxykinase|PEP carboxykinase]] (PEPCK) – is variable by species: it can be found entirely within the [[mitochondria]], entirely within the [[cytosol]], or dispersed evenly between the two, as it is in humans.<ref name="Voet556" />  Transport of PEP across the [[mitochondrial membrane]] is accomplished by dedicated transport proteins; however no such proteins exist for [[oxaloacetate]].<ref name="Voet556" />  Therefore, in species that lack intra-mitochondrial PEPCK, [[oxaloacetate]] must be converted into [[malate]] or [[aspartate]], exported from the [[mitochondrion]], and converted back into [[oxaloacetate]] in order to allow gluconeogenesis to continue.<ref name="Voet556" />
[[File:Gluconeogenesis pathway.png|thumb|300px|class=skin-invert-image|Gluconeogenesis pathway with key molecules and enzymes. Many steps are the opposite of those found in the [[glycolysis]].]]

==Pathway==
Gluconeogenesis is a pathway consisting of a series of eleven enzyme-catalyzed reactions. The pathway will begin in either the liver or kidney, in the mitochondria or cytoplasm of those cells, this being dependent on the substrate being used. Many of the reactions are the reverse of steps found in [[glycolysis]].<ref>{{Citation |last1=Melkonian |first1=Erica A. |title=Physiology, Gluconeogenesis |date=2025 |work=StatPearls |url=http://www.ncbi.nlm.nih.gov/books/NBK541119/ |access-date=2025-06-22 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31082163 |last2=Asuka |first2=Edinen |last3=Schury |first3=Mark P.}}</ref>
* Gluconeogenesis begins in the mitochondria with the formation of oxaloacetate by the carboxylation of pyruvate. This reaction also requires one molecule of [[adenosine triphosphate|ATP]], and is catalyzed by [[pyruvate carboxylase]]. This enzyme is stimulated by high levels of [[acetyl-CoA]] (produced in [[β-oxidation]] in the liver) and inhibited by high levels of ADP and glucose.
* Oxaloacetate is reduced to [[malate]] using [[Nicotinamide adenine dinucleotide|NADH]], a step required for its transportation out of the mitochondria.
* Malate is oxidized to oxaloacetate using NAD<sup>+</sup> in the cytosol, where the remaining steps of gluconeogenesis take place.
* Oxaloacetate is decarboxylated and then phosphorylated to form [[phosphoenolpyruvate]] using the enzyme [[phosphoenolpyruvate carboxykinase|PEPCK]]. A molecule of [[guanosine triphosphate|GTP]] is hydrolyzed to [[guanosine diphosphate|GDP]] during this reaction.
* The next steps in the reaction are the same as reversed [[glycolysis]].  However, [[fructose 1,6-bisphosphatase]] converts [[fructose 1,6-bisphosphate]] to [[fructose 6-phosphate]], using one water molecule and releasing one phosphate (in glycolysis, [[phosphofructokinase 1]] converts F6P and [[Adenosine triphosphate|ATP]] to F1,6BP and [[Adenosine diphosphate|ADP]]).  This is also the rate-limiting step of gluconeogenesis.
* [[Glucose-6-phosphate]] is formed from [[fructose 6-phosphate]] by [[phosphoglucoisomerase]] (the reverse of step 2 in glycolysis). Glucose-6-phosphate can be used in other metabolic pathways or dephosphorylated to free glucose. Whereas free glucose can easily diffuse in and out of the cell, the phosphorylated form (glucose-6-phosphate) is locked in the cell, a mechanism by which intracellular glucose levels are controlled by cells.
* The final step in gluconeogenesis, the formation of glucose, occurs in the [[lumen (anatomy)|lumen]] of the [[endoplasmic reticulum]], where glucose-6-phosphate is hydrolyzed by [[glucose-6-phosphatase]] to produce glucose and release an inorganic phosphate. Like two steps prior, this step is not a simple reversal of glycolysis, in which [[hexokinase]] catalyzes the conversion of glucose and ATP into G6P and ADP. Glucose is shuttled into the cytoplasm by [[glucose transporter]]s located in the endoplasmic reticulum's membrane.
{| class="toccolours collapsible collapsed" width="100%" style="text-align:left"
! Metabolism of common [[monosaccharide]]s, including [[glycolysis]], gluconeogenesis, [[glycogenesis]] and [[glycogenolysis]]
|-
|[[File:Metabolism of common monosaccharides, and related reactions.png|none|1000px]]
|}

==Regulation==
While most steps in gluconeogenesis are the reverse of those found in [[glycolysis]], three regulated and strongly endergonic reactions are replaced with more kinetically favorable reactions. [[Hexokinase]]/[[glucokinase]], [[phosphofructokinase]], and [[pyruvate kinase]] enzymes of glycolysis are replaced with [[glucose-6-phosphatase]], [[fructose-1,6-bisphosphatase]], and [[PEP carboxykinase]]/pyruvate carboxylase.  These enzymes are typically regulated by similar molecules, but with opposite results.  For example, [[acetyl CoA]] and [[citrate]] activate gluconeogenesis enzymes (pyruvate carboxylase and fructose-1,6-bisphosphatase, respectively), while at the same time inhibiting the glycolytic enzyme [[pyruvate kinase]].  This system of reciprocal control allow glycolysis and gluconeogenesis to inhibit each other and prevents a [[futile cycle]] of synthesizing glucose to only break it down. Pyruvate kinase can be also bypassed by 86 pathways<ref>{{cite journal |last1=Chinopoulos |first1=Christos |title=From Glucose to Lactate and Transiting Intermediates Through Mitochondria, Bypassing Pyruvate Kinase: Considerations for Cells Exhibiting Dimeric PKM2 or Otherwise Inhibited Kinase Activity |journal=Frontiers in Physiology |date=December 2020 |volume=11 |article-number=543564 |doi=10.3389/fphys.2020.543564 |doi-access=free |pmid=33335484 |pmc=7736077 }}</ref> not related to gluconeogenesis, for the purpose of forming pyruvate and subsequently lactate; some of these pathways use carbon atoms originated from glucose.

The majority of the [[enzymes]] responsible for gluconeogenesis are found in the [[cytosol]]; the exceptions are mitochondrial [[pyruvate carboxylase]] and, in animals, [[phosphoenolpyruvate carboxykinase]]. The latter exists as an isozyme located in both the [[mitochondrion]] and the [[cytosol]].<ref name="pmid15917397">{{cite journal | vauthors = Chakravarty K, Cassuto H, Reshef L, Hanson RW | title = Factors that control the tissue-specific transcription of the gene for phosphoenolpyruvate carboxykinase-C | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 40 | issue = 3 | pages = 129–54 | year = 2005 | pmid = 15917397 | doi = 10.1080/10409230590935479 }}</ref>  The rate of gluconeogenesis is ultimately controlled by the action of a key enzyme, [[fructose-1,6-bisphosphatase]], which is also regulated through signal transduction by [[Cyclic adenosine monophosphate|cAMP]] and its phosphorylation.

Global control of gluconeogenesis is mediated by [[glucagon]] (''released when blood glucose is low''); it triggers phosphorylation of enzymes and regulatory proteins by [[Protein kinase A|Protein Kinase A]] (a cyclic AMP regulated kinase) resulting in inhibition of glycolysis and stimulation of gluconeogenesis. [[Insulin]] counteracts glucagon by inhibiting gluconeogenesis. Type 2 diabetes is marked by excess glucagon and [[insulin resistance]] from the body.<ref>{{cite journal | vauthors = He L, Sabet A, Djedjos S, Miller R, Sun X, Hussain MA, Radovick S, Wondisford FE | display-authors = 6 | title = Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein | journal = Cell | volume = 137 | issue = 4 | pages = 635–46 | date = May 2009 | pmid = 19450513 | pmc = 2775562 | doi = 10.1016/j.cell.2009.03.016 }}</ref> Insulin can no longer inhibit the gene expression of enzymes such as PEPCK which leads to increased levels of hyperglycemia in the body.<ref>{{cite journal | vauthors = Hatting M, Tavares CD, Sharabi K, Rines AK, Puigserver P | title = Insulin regulation of gluconeogenesis | journal = Annals of the New York Academy of Sciences | volume = 1411 | issue = 1 | pages = 21–35 | date = January 2018 | pmid = 28868790 | pmc = 5927596 | doi = 10.1111/nyas.13435 | bibcode = 2018NYASA1411...21H }}</ref> The anti-diabetic drug [[metformin]] reduces blood glucose primarily through inhibition of gluconeogenesis, overcoming the failure of insulin to inhibit gluconeogenesis due to insulin resistance.<ref name="pmid29115403">{{cite journal | vauthors = Wang Y, Tang H, Ji X, Zhang Y, Xu W, Yang X, Deng R, Liu Y, Li F, Wang X, Zhou L | display-authors = 6 | title = Expression profile analysis of long non-coding RNAs involved in the metformin-inhibited gluconeogenesis of primary mouse hepatocytes | journal = International Journal of Molecular Medicine | volume = 41 | issue = 1 | pages = 302–310 | date = January 2018 | pmid = 29115403 | pmc = 5746302 | doi = 10.3892/ijmm.2017.3243 }}</ref>

Studies have shown that the absence of hepatic glucose production has no major effect on the control of fasting plasma glucose concentration. Compensatory induction of gluconeogenesis occurs in the kidneys and intestine, driven by [[glucagon]], [[glucocorticoids]], and acidosis.<ref name = Mutel>{{cite journal | vauthors = Mutel E, Gautier-Stein A, Abdul-Wahed A, Amigó-Correig M, Zitoun C, Stefanutti A, Houberdon I, Tourette JA, Mithieux G, Rajas F | display-authors = 6 | title = Control of blood glucose in the absence of hepatic glucose production during prolonged fasting in mice: induction of renal and intestinal gluconeogenesis by glucagon | journal = Diabetes | volume = 60 | issue = 12 | pages = 3121–31 | date = December 2011 | pmid = 22013018 | pmc = 3219939 | doi = 10.2337/db11-0571 }}</ref>

==Insulin resistance==
In the liver, the [[FOX proteins|FOX protein]] [[FOXO6]] normally promotes gluconeogenesis in the fasted state, but [[insulin]] blocks FOXO6 upon feeding.<ref name="pmid28213398">{{cite journal | vauthors = Lee S, Dong HH | title = FoxO integration of insulin signaling with glucose and lipid metabolism | journal = The Journal of Endocrinology | volume = 233 | issue = 2 | pages = R67–R79 | date = May 2017 | pmid = 28213398 | pmc = 5480241 | doi = 10.1530/JOE-17-0002 }}</ref> In a condition of [[insulin resistance]], insulin fails to block FOXO6 resulting in continued gluconeogenesis even upon feeding, resulting in high blood glucose ([[hyperglycemia]]).<ref name="pmid28213398" />

Insulin resistance is a common feature of [[metabolic syndrome]] and [[type 2 diabetes]]. For this reason, gluconeogenesis is a target of therapy for type 2 diabetes, such as the [[antidiabetic drug]] [[metformin]], which inhibits gluconeogenic glucose formation, and stimulates glucose uptake by cells.<ref name = Hundal>{{cite journal | vauthors = Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi SE, Schumann WC, Petersen KF, Landau BR, Shulman GI | display-authors = 6 | title = Mechanism by which metformin reduces glucose production in type 2 diabetes | journal = Diabetes | volume = 49 | issue = 12 | pages = 2063–2069 | date = December 2000 | pmid = 11118008 | pmc = 2995498 | doi = 10.2337/diabetes.49.12.2063 }} {{cite journal | vauthors = Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi SE, Schumann WC, Petersen KF, Landau BR, Shulman GI | display-authors = 6 | title = Mechanism by which metformin reduces glucose production in type 2 diabetes | journal = Diabetes | volume = 49 | issue = 12 | pages = 2063–2069 | date = December 2000 | pmid = 11118008 | pmc = 2995498 | doi = 10.2337/diabetes.49.12.2063 }}&nbsp;{{small|(82&nbsp;[[Kibibyte|KiB]])}}</ref>

== Origins ==
Gluconeogenesis is considered one of the most ancient anabolic pathways and is likely to have been exhibited in the [[last universal common ancestor]].<ref>{{cite journal | vauthors = Harrison SA, Lane N | title = Life as a guide to prebiotic nucleotide synthesis | journal = Nature Communications | volume = 9 | issue = 1 | article-number = 5176 | date = December 2018 | pmid = 30538225 | doi = 10.1038/s41467-018-07220-y | pmc = 6289992 | bibcode = 2018NatCo...9.5176H }}</ref> Rafael F. Say and Georg Fuchs stated in 2010 that "all archaeal groups as well as the deeply branching bacterial lineages contain a bifunctional fructose 1,6-bisphosphate (FBP) aldolase/phosphatase with both FBP aldolase and FBP phosphatase activity. This enzyme is missing in most other Bacteria and in Eukaryota, and is heat-stabile even in mesophilic marine Crenarchaeota". It is proposed that fructose 1,6-bisphosphate aldolase/phosphatase was an ancestral gluconeogenic enzyme and had preceded glycolysis.<ref>{{cite journal | vauthors = Say RF, Fuchs G | title = Fructose 1,6-bisphosphate aldolase/phosphatase may be an ancestral gluconeogenic enzyme | journal = Nature | volume = 464 | issue = 7291 | pages = 1077–1081 | date = April 2010 | pmid = 20348906 | doi = 10.1038/nature08884 | bibcode = 2010Natur.464.1077S }}</ref> However, a prebiotic glycolysis would follow the same chemical mechanisms as gluconeogenesis, due to microscopic reversibility, and in this view would have occurred at the same time. [[Fructose 1,6-bisphosphate]] is shown to be nonenzymatically synthesized within a freezing solution.<ref>{{cite journal | vauthors = Messner CB, Driscoll PC, Piedrafita G, De Volder MF, Ralser M | title = Nonenzymatic gluconeogenesis-like formation of fructose 1,6-bisphosphate in ice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 28 | pages = 7403–7407 | date = July 2017 | pmid = 28652321 | pmc = 5514728 | doi = 10.1073/pnas.1702274114 | doi-access = free | bibcode = 2017PNAS..114.7403M }}</ref> The synthesis is accelerated in the presence of amino acids such as glycine and lysine. Some of the other reactions of gluconeogenesis can also proceed nonenzymatically.<ref>{{cite journal | vauthors = Muchowska KB, Varma SJ, Moran J | title = Nonenzymatic Metabolic Reactions and Life's Origins | journal = Chemical Reviews | volume = 120 | issue = 15 | pages = 7708–7744 | date = August 2020 | pmid = 32687326 | doi = 10.1021/acs.chemrev.0c00191 | url = https://hal.archives-ouvertes.fr/hal-03024701 }}</ref> Such chemistry could have occurred in hydrothermal environments, including temperature gradients and cycling of freezing and thawing. Mineral surfaces might have played a role in the phosphorylation of metabolic intermediates from gluconeogenesis and have to been shown to produce tetrose, hexose phosphates, and pentose from [[formaldehyde]], glyceraldehyde, and glycolaldehyde.<ref>{{Cite journal |last=Ralser |first=Markus |date=2018-08-30 |title=An appeal to magic? The discovery of a non-enzymatic metabolism and its role in the origins of life |journal=The Biochemical Journal |volume=475 |issue=16 |pages=2577–2592 |doi=10.1042/BCJ20160866 |pmc=6117946 |pmid=30166494 }}</ref>

== See also ==
* [[Bioenergetics]]

== References ==
{{reflist}}

== External links ==
* [http://themedicalbiochemistrypage.org/gluconeogenesis.html Overview at indstate.edu]
* [https://web.archive.org/web/20060615191544/http://ull.chemistry.uakron.edu/Pathways/gluconeogenesis/index.html Interactive diagram at uakron.edu]
* [http://homepage.ufp.pt/pedros/bq/gng.htm The chemical logic behind gluconeogenesis ]
* [http://www.metpath.teithe.gr/?part=gluconeogenesis&lang=en ''metpath'': Interactive representation of gluconeogenesis]

{{Carbohydrate metabolism}}
{{Gluconeogenesis}}
{{MetabolismMap}}

[[Category:Biochemical reactions]]
[[Category:Carbohydrate metabolism]]
[[Category:Diabetes]]
[[Category:Exercise biochemistry]]
[[Category:Glycobiology]]
[[Category:Hepatology]]
[[Category:Metabolic pathways]]