Gluconeogenesis

Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. From breakdown of proteins, these substrates include glucogenic amino acids (although not ketogenic amino acids); from breakdown of lipids (such as triglycerides), they include glycerol, odd-chain fatty acids (although not even-chain fatty acids, see below); and from other steps in metabolism they include pyruvate and lactate. Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. From breakdown of proteins, these substrates include glucogenic amino acids (although not ketogenic amino acids); from breakdown of lipids (such as triglycerides), they include glycerol, odd-chain fatty acids (although not even-chain fatty acids, see below); and from other steps in metabolism they include pyruvate and lactate. Gluconeogenesis is one of several main mechanisms used by humans and many other animals to maintain blood glucose levels, avoiding low levels (hypoglycemia). Other means include the degradation of glycogen (glycogenolysis) and fatty acid catabolism. Gluconeogenesis is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis takes place mainly in the liver and, to a lesser extent, in the cortex of the kidneys. In ruminants, this tends to be a continuous process. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise. The process is highly endergonic until it is coupled to the hydrolysis of ATP or 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. Gluconeogenesis is often associated with ketosis. Gluconeogenesis is also a target of therapy for type 2 diabetes, such as the antidiabetic drug, metformin, which inhibits glucose formation and stimulates glucose uptake by cells. In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In humans the main gluconeogenic precursors are lactate, glycerol (which is a part of the triacylglycerol molecule), alanine and glutamine. Altogether, they account for over 90% of the overall gluconeogenesis.Other glucogenic amino acids as well as all citric acid cycle intermediates, the latter through conversion to oxaloacetate, can also function as substrates for gluconeogenesis. In ruminants, propionate is the principal gluconeogenic substrate. In nonruminants, including human beings, propionate arises from the β-oxidation of odd-chain and branched-chain fatty acids is a (relatively minor) substrate for gluconeogenesis. Generally, consumption of gluconeogenic substrates in food does not result in increased gluconeogenesis.. 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. 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. 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. Whether even-chain fatty acids can be converted into glucose in animals has been a longstanding question in biochemistry. It is known that odd-chain fatty acids can be oxidized to yield propionyl-CoA, a precursor for succinyl-CoA, which can be converted to pyruvate and enter into gluconeogenesis. In plants, specifically seedlings, the glyoxylate cycle can be used to convert fatty acids (acetate) into the primary carbon source of the organism. The glyoxylate cycle produces four-carbon dicarboxylic acids that can enter gluconeogenesis. In 1995, researchers identified the glyoxylate cycle in nematodes. In addition, the glyoxylate enzymes malate synthase and isocitrate lyase have been found in animal tissues. Genes coding for malate synthase have been identified in other metazoans including arthropods, echinoderms, and even some vertebrates. Mammals found to possess these genes include monotremes (platypus) and marsupials (opossum) but not placental mammals. Genes for isocitrate lyase are found only in nematodes, in which, it is apparent, they originated in horizontal gene transfer from bacteria. The existence of glyoxylate cycles in humans has not been established, and it is widely held that fatty acids cannot be converted to glucose in humans directly. However, carbon-14 has been shown to end up in glucose when it is supplied in fatty acids. Despite these findings, it is considered unlikely that the 2-carbon acetyl-CoA derived from the oxidation of fatty acids would produce a net yield of glucose via the citric acid cycle – however, acetyl-CoA can be converted into pyruvate and lactate through the ketogenic pathway. Put simply, acetic acid (in the form of acetyl-CoA) is used to partially produce glucose; acetyl groups can only form part of the glucose molecules (not the 5th carbon atom) and require extra substrates (such as pyruvate) in order to form the rest of the glucose molecule. But a roundabout pathway does lead from acetyl-coA to pyruvate, via acetoacetate, acetone, hydroxyacetone (acetol) and then either propylene glycol or methylglyoxal. In mammals, gluconeogenesis has been believed to be restricted to the liver, the kidney, the intestine, and muscle, but recent evidence indicates gluconeogenesis occurring in astrocytes of the brain. 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. Lactate from the Cori cycle is quantitatively the largest source of substrate for gluconeogenesis, especially for the kidney. The liver uses both glycogenolysis and gluconeogenesis to produce glucose, whereas the kidney only uses gluconeogenesis. After a meal, the liver shifts to glycogen synthesis, whereas the kidney increases gluconeogenesis. The intestine uses mostly glutamine and glycerol.