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Introduction
Some organs, such as the brain, the eye, and the kidney, contain tissues that utilize glucose
as their preferred or sole metabolic fuel source. During a prolonged fast or vigorous
exercise, glycogen stores become depleted, and glucose must be synthesized de novo in
order to maintain blood glucose levels. Gluconeogenesis is the pathway by which glucose is
formed from non-hexose precursors such as glycerol, lactate, pyruvate, and glucogenic
amino acids.[1]
Cellular
The major substrates of gluconeogenesis are lactate, glycerol, and glucogenic amino acids.
Lactate is a product of anaerobic glycolysis. When oxygen is limited (such as during
vigorous exercise or in low perfusion states) cells must perform anaerobic glycolysis to
produce ATP. Cells that lack mitochondria (e.g., erythrocytes) cannot perform oxidative
phosphorylation, and as a result rely strictly on anaerobic glycolysis to meet energy
demands. Lactate generated from anaerobic glycolysis gets shunted to the liver, where it
can be converted back to glucose through gluconeogenesis. Glucose gets released into the
bloodstream, where it travels back to erythrocytes and exercising the skeletal muscle to
be broken down again by anaerobic glycolysis, forming lactate. This process is called the
Cori cycle.[2]
Glycerol comes from adipose tissue. The breakdown of triacylglycerols in adipose tissue
yields free fatty acids and glycerol molecules, the latter of which can circulate freely in the
bloodstream until it reaches the liver[3]. Glycerol is then phosphorylated by the hepatic
enzyme glycerol kinase to yield glycerol phosphate. Next, the enzyme glycerol phosphate
dehydrogenase oxidizes glycerol phosphate to yield dihydroxyacetone phosphate, a
glycolytic intermediate.
Glucogenic amino acids enter gluconeogenesis via the citric acid cycle. Glucogenic amino
acids are catabolized into citric acid cycle metabolites such as alpha-ketoglutarate, succinyl
CoA, and fumarate. Through the citric acid cycle, these alpha-ketoacids converts to
oxaloacetate, the substrate for the gluconeogenic enzyme PEP carboxykinase.
Due to the highly endergonic nature of gluconeogenesis, its reactions are regulated at a
variety of levels. The bulk of regulation occurs through alterations in circulating glucagon
levels and availability of gluconeogenic substrates. However, fluctuations in
catecholamines, growth hormone, and cortisol levels also play a role.[4][5]
Glucagon is produced by pancreatic alpha cells in response to falling blood glucose levels.
It regulates glucose production by altering the activity of both glycolytic and
gluconeogenic enzymes. In response to glucagon, fructose 1,6-bisphosphatase activity is
upregulated while its glycolytic counterpart, phosphofructokinase-1, is suppressed.[6]
Moreover, glucagon binds to an extracellular G protein-coupled receptor that results in
the activation of adenylate cyclase and a subsequent increase in the concentration of
cAMP.[7] cAMP activates cAMP-dependent protein kinase, which then phosphorylates and
inactivates the glycolytic enzyme pyruvate kinase. Pyruvate kinase is the enzyme
responsible for converting PEP to pyruvate, one of the irreversible reactions of glycolysis.
Lastly, glucagon upregulates expression of the gene encoding PEP-carboxykinase, further
increasing PEP concentrations and favoring glucose production.[7]
Insulin is a potent inhibitor of gluconeogenesis.[8] During a fast, falling insulin levels have
a permissive effect on gluconeogenesis. Moreover, a decrease in insulin allows for the
catabolism of fat and protein leading to increased gluconeogenic substrate availability.[4]
During the first 18 to 24 hours of a fast, the vast majority of gluconeogenesis occurs in the
liver. Following prolonged periods of starvation, however, the kidneys adapt to generate as
much as 20% of total glucose produced. Only the liver and kidney can release free glucose
from glucose 6-phosphate; other tissues lack the enzyme glucose 6-phosphatase.[1][2]
Function
The purpose of gluconeogenesis is to maintain blood glucose levels during a fast. In the
human body, some tissues rely almost exclusively on glucose as a metabolic fuel source.
The brain, for example, requires approximately 120 g of glucose in 24 hours. While the
brain is also capable of utilizing ketone bodies as an alternative fuel source, the testes, renal
medulla, and erythrocytes all rely exclusively on glucose breakdown through glycolysis.
For these tissues to function correctly, a steady influx of glucose into the bloodstream is
essential. Hepatic glycogen stores are depleted following a 24-hour fast, after which time
gluconeogenesis functions to synthesize glucose de novo from non-hexose precursors and
maintain blood glucose levels.[1][2]
Pathophysiology
Clinical Significance
Metformin, the first-line agent for the management of type 2 diabetes, has been shown to
suppress hepatic gluconeogenesis through a variety of mechanisms. Metformin activates
AMPK, which in turn inhibits hepatic lipogenesis and increases insulin sensitivity. AMPK
activation also leads to increased cAMP breakdown, further inhibiting gluconeogenesis.[1]
[10]
At high doses, metformin also inhibits complex I of the electron transport chain, impairing
ATP production necessary for highly endergonic processes (like gluconeogenesis) to take
place.[1]
Ethanol cannot be eliminated from the human body without changes. To excrete ethanol, it
must first be oxidized to form acetaldehyde by the liver enzyme alcohol dehydrogenase,
which utilizes NAD+ as an electron acceptor. Next, acetaldehyde must be further oxidized
to form acetate (a molecule readily excreted by the body). This reaction, catalyzed
by aldehyde dehydrogenase, also requires NAD+ as an electron acceptor. Thus, the
metabolism of ethanol results in a significant accumulation of NADH.[11]
If concentrations of NADH are high enough, the lactate dehydrogenase reaction will favor
the formation of lactate over the formation of pyruvate, and lactate will begin to
accumulate. Without the oxidation of lactate to pyruvate, gluconeogenesis is inhibited. As a
consequence, heavy ethanol consumption can lead to both lactic acidosis and
hypoglycemia.[11]
Preterm infants are at a particularly high risk of developing hypoglycemia. Neonates of low
birth weight have limited glycogen and fat stores, but also express gluconeogenic enzymes
at sub-optimal levels. As such, preterm infants can deplete their energy stores quickly
without mounting a proper counter-regulatory response.[4]
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] [PubMed]
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] [PubMed]
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]
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]
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]
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]
9.Bali DS, El-Gharbawy A, Austin S, Pendyal S, Kishnani PS. Glycogen Storage Disease Type I. In:
Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM, Amemiya A,
editors. GeneReviews® [Internet]. University of Washington, Seattle; Seattle (WA): Apr 19, 2006.
[PubMed]
10.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] [PubMed]
11.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] [PubMed]
Publication Details
Author Information
Authors
Erica A. Melkonian1; Edinen Asuka2; Mark P. Schury3.
Affiliations
1
Michigan State University
2
All Saints University School of Medicine, Dominica.
3
McLaren Oakland
Publication History