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.
Gluconeogenesis is essentially the reversal of glycolysis. However, to bypass the three highly exergonic (and essentially irreversible) steps of glycolysis, gluconeogenesis utilizes four unique enzymes. The enzymes unique to gluconeogenesis are pyruvate carboxylase, PEP carboxykinase, fructose 1,6-bisphosphatase, and glucose 6-phosphatase. Because these enzymes are not present in all cell types, gluconeogenesis can only occur in specific tissues. In humans, gluconeogenesis takes place primarily in the liver and, to a lesser extent, the renal cortex.
Although gluconeogenesis can be broadly considered the reversal of glycolysis, it is not an identical pathway running in the opposite direction. Several enzymes catalyze reactions with small changes in free-energy, meaning they are easily reversible and function well in both pathways. However, three reactions of glycolysis are highly exergonic, resulting in largely negative free-energy changes that are irreversible and must be bypassed by different enzymes. The enzymes unique to gluconeogenesis are pyruvate carboxylase, PEP carboxykinase, fructose 1,6-bisphosphatase, and glucose 6-phosphatase.
Starting from pyruvate, the reactions of gluconeogenesis are as follows:
The major substrates of gluconeogenesis are lactate, glycerol, and glucogenic amino acids.
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.
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.
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.
In the absence of glucose-6-phosphatase, gluconeogenesis is impaired and this precipitates fasting hypoglycemia. This event can occur in Von Gierke's disease when this enzyme is deficient. Von Gierke disease takes an autosomal recessive inheritance pattern. Glycogenolysis is also limited in the absence of glucose-6-phosphatase because normally when glycogen is broken down to glucose-1-phosphate moiety, it is then converted to glucose-6-phosphate which requires glucose-6-phosphatase to convert it to usable glucose. So in the absence of this enzyme, gluconeogenesis, and glycogenolysis are both impaired. In addition to fasting hypoglycemia, other associated irregularities include hyperkalemia, hyperuricemia, and increased lactate levels. 
Treating Hyperglycemia in Diabetes
Diabetes is either the result of impaired insulin production or decreased insulin sensitivity. In addition to stimulating glucose uptake from the bloodstream, insulin is also a potent inhibitor of gluconeogenesis. Without adequate insulin production or the ability to respond to insulin properly, gluconeogenesis occurs at an unusually rapid rate, exacerbating hyperglycemia in the diabetic patient.
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.
Metformin also appears to directly inhibit glycerol 3-phosphate dehydrogenase, leading to an increase in NADH levels. 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. Gluconeogenesis is inhibited without the oxidation of lactate to pyruvate.
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.
Hypoglycemia as a Result of Ethanol Consumption
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.
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.
Hypoglycemia in the Preterm Infant
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.
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