During nighttime or prolonged fasts, there is less glucose readily available for the tissues of the body. However, the high-glucose requirements of certain tissues such as the brain and kidneys remains. To meet these requirements, the liver begins producing glucose from a variety of substrates. These include pyruvate (from glycolysis), lactate (from anaerobic metabolism), glycerol (from triglycerides), and various glucogenic amino acids.
Glucagon and cortisol are two hormones that act in opposition of insulin. When blood glucose is low, such as in fasting states, glucagon and cortisol are released from the pancreas and adrenal glands, respectively. These hormones signal tissues to begin synthesizing glucose so that it can be released into the blood for the rest of the body's tissues to use. Glucagon acts on G-protein receptors on hepatocytes, activating adenylate cyclase. Adenylate cyclase activates PKA, which then activates phosphorylase kinase. This activates glycogen phosphorylase, releasing stored glucose. PKA also phosphorylates pyruvate kinase, halting glycolysis.
The first step in gluconeogenesis requires pyruvate. This pyruvate can come from a variety of sources, namely the amino acids serine, threonine, glycine and cysteine. Some pyruvate can also come from stored glycogen.
This mitochondrial enzyme is unique to gluconeogenesis, and is used to convert pyruvate into oxaloacetate. This enzyme requires CO2, biotin, and energy in the form of ATP. Its activity is upregulated by acetyl-CoA.
Oxaloacetate may be the second intermediary in gluconeogenesis, but it is the main fuel source for this pathway. Almost all glucogenic amino acids are converted into oxaloacetate before entering gluconeogenesis. In order to exit the mitochondria, oxaloacetate is temporarily converted to malate so that it can be transported via the malate-aspartate shuttle into the cytosol. Oxaloacetate is reconstituted in the cytosol.
This cytosolic enzyme is responsible for the conversion of oxaloacetate to phosphoenolpyruvate, or PEP. It does this using GTP as a phosphate donor. Increased transcription of the PEPCK gene is mediated by glucagon and glucocorticoids.
This gluconeogenic intermediary is the final product of the pathway used to bypass pyruvate kinase, and thus glycolysis. The formation of PEP constitutes one of the rate-limiting steps in gluconeogenesis.
All of the steps and enzymes involved in gluconeogenesis from PEP to fructose-1,6-bisphosphate are identical to those in glycolysis. However, in order to bypass phosphofructokinase-1 (in glycolysis), the process of gluconeogenesis utilizes an alternative enzyme which is upregulated by citrate and downregulated by AMP and fructose-2,6 bisphosphate.
This rate limiting enzyme is located in the cytosol. It is responsible for converting fructose-1,6,-bisphosphate to fructose-6-phosphate. Its activity is downregulated by AMP and fructose-2,6-phosphate, and upregulated by citrate.
This intermediary is common to both glycolysis and gluconeogenesis. It is important to note that dietary fructose enters the gluconeogenic pathway as fructose-1-phosphate, which is then converted into fructose-1,6-bisphosphate.
This molecule is the final intermediary in gluconeogenesis before we arrive at glucose. This molecule is only able to be converted into glucose by tissues with glucose 6-phosphatase activity, mainly the liver and kidneys. In tissues lacking this enzyme (like muscle), G6P is shunted towards glycogen formation.
This enzyme is located in the endoplasmic reticulum of the liver and kidneys, mainly. It converts glucose-6-phosphate to glucose, representing the final step in gluconeogenesis. In tissues with low or absent glucose 6-phosphatase activity (like skeletal muscle), excess glucose-6-phosphate is converted into glycogen. Von Gierke Disease is caused by a deficiency of this enzyme.
Glucose is created as the last step and released into the bloodstream for use by other tissues by the liver and kidneys, mainly. Tissues that rely primarily on glucose for fuel include the eyes, RBCs, and the brain.
This disease represents a deficiency in the enzyme glucose 6-phosphatase. Since these patients are unable to convert glucose 6-phosphate into glucose, it is shunted towards glycogen formation. Patients present with massively increased glycogen stores and resulting hepatomegaly, hypoglycemia, ketosis, lactic acidosis, hyperuricemia and hyperlipidemia.
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