What is Glucogenesis?

Glucogenesis is a metabolic pathway in which glucose is produced from carbon substrates that are not carbohydrates. This process is observed in plants, animals, fungi, bacteria and other micro organisms. The general  definition for glucogenesis or gluconeogenesis is as follows,

"The method of producing glucose from its own broken-down products or from lipid or protein’s broken-down products." 

Importance 

It is one of the two prominent mechanisms used by humans and many other species for the regulation of blood glucose levels and prevents its low levels, the other mechanism being glycogen degradation (glycogenolysis). Since rumen species appear to metabolize dietary carbohydrates, glucogenesis occurs in ruminants regardless of fasting, low-carbohydrate diets, or exercise. Fasting, malnutrition, low-carbohydrate diets, and vigorous exercise trigger the process in many other species.

In humans, glucogenesis substrates can be obtained from any non-carbohydrate source that can be converted to pyruvate or glycolysis  intermediates. These substrates come from the breakdown of proteins (but not ketogenic amino acids); from the breakdown of lipids (such as triglycerides), from glycerol, odd-chain fatty acids (but not even-chain fatty acids), and from other parts of metabolism like Cori cycle. Acetone derived from ketone bodies may also act as a substrate during extended fasting, providing a pathway from fatty acids to glucose. The liver is responsible for 90% of gluconeogenesis, but the kidney also plays a role. Insulin is a hormone that controls gluconeogenesis.

To increase blood glucose levels, the newly created glucose is released back into the bloodstream. The production of insulin is able to control glucogenesis directly. The glucogenesis pathway is an endergonic one. When it is connected to the hydrolysis of ATP or GTP, it becomes exergonic.

For example, to proceed spontaneously, the pathway from pyruvate to glucose-6-phosphate requires four molecules of ATP and two molecules of GTP. These ATPs are obtained by beta-oxidation from fatty acid catabolism. 

Precursors 

Lactate, glycerol (a component of the triacylglycerol molecule), alanine, and glutamine are the most common gluconeogenic precursors in humans. They are responsible for more than 90% of the total gluconeogenesis. Other glucogenic amino acids as well as all citric acid cycle intermediates (via conversion to oxaloacetate) can be used as gluconeogenesis substrates. Human intake of gluconeogenic substrates in food does not increase gluconeogenesis in most cases. 

Propionate is the primary substrate of glucogenesis in ruminants. Propionate, which is generated by the oxidation of odd-chain and branched-chain fatty acids in nonruminants, including humans, is a (relatively minor) substrate for gluconeogenesis. 

Lactate is transferred back to the liver, where the Cori cycle uses lactate dehydrogenase as the enzyme to convert it to pyruvate. Pyruvate, the gluconeogenic pathway's first designated substrate, can then be used to produce glucose. Amino acid transamination or deamination allows their carbon skeleton to join the cycle either directly (as pyruvate or oxaloacetate) or indirectly (via the citric acid cycle).

Fasting time increases the contribution of Cori cycle lactate to total glucose output. The contribution of Cori cycle lactate to glucogenesis was found to be 41%, 71%, and 92% after 12, 20, and 40 hours of fasting by humans respectively. 

Role 

The topic of conversion of even-chain fatty acids to glucose in animals has long been debated in biochemistry. Odd-chain fatty acids can be oxidized to produce acetyl-CoA and propionyl-CoA, with the latter acting as a precursor to succinyl-CoA, which can then be converted to pyruvate and join the gluconeogenesis process.

Even-chain fatty acids, on the other hand, are oxidized to create only acetyl-CoA, which involves the presence of a glyoxylate cycle (also known as a glyoxylate shunt) to produce four-carbon dicarboxylic acid precursors in order to enter glucogenesis. The glyoxylate shunt is found in fungi, plants, and bacteria and consists of two enzymes: malate synthase and isocitrate lyase.

Despite records of glyoxylate shunt enzymatic activity in animal tissues, genes encoding both enzymatic functions have only been identified in nematodes, where they are combined into a single bi-functional enzyme. Other metazoans, such as arthropods, echinoderms and even certain vertebrates have genes coding for malate synthase (but not isocitrate lyase). Monotremes (platypus) and marsupials (opossum) have been found to have the malate synthase gene, but not placental mammals. 

The glyoxylate cycle in humans has not been proven, and it is generally assumed that fatty acids cannot be converted directly to glucose in humans. The introduction of labeled atoms derived from acetyl-CoA into citric acid cycle intermediates that are interchangeable with those derived from other physiological sources, such as glucogenic amino acids, has been shown to result in glucose only when carbon-14 is supplied in fatty acids.

The 2-carbon acetyl-CoA produced from the oxidation of fatty acids cannot produce a net yield of glucose through the citric acid cycle in the absence of other glucogenic sources as two carbon atoms are released as carbon dioxide during the cycle. Acetyl-CoA from fatty acids produces ketone bodies, including acetone, during ketosis and up to 60% of acetone can be oxidized in the liver to the pyruvate precursors which are acetol and  methylglyoxal.

Thus, during starvation, ketone bodies derived from fatty acids could account for up to 11% of glucogenesis. Fatty acid catabolism also generates energy in the form of ATP which is needed for the glucogenesis pathway. 

Some Important Enzymes in Glucogenesis 

Glucose-6-phosphatase 

Glucose 6-phosphatase is an important enzyme that hydrolyzes glucose 6-phosphate, releasing a phosphate group and a free glucose in the process. This catalyzis and completes the last step in gluconeogenesis and thus plays a crucial role in blood glucose homeostasis. 

Pyruvate carboxylase 

Pyruvate carboxylase is a mitochondrial enzyme that catalyzes the anaplerotic carboxylation of pyruvate to oxaloacetate, a gluconeogenic substrate, in the presence of biotin and ATP. Not only pyruvate but also lactate and alanine, join the gluconeogenic pathway at this stage. 

Fructose-1,6-bisphosphatase 

In gluconeogenesis, fructose 1,6-bisphosphatase is an important enzyme. It catalyzes the hydrolysis of fructose 1,6-bisphosphate to produce fructose 6-phosphate, an essential biosynthetic precursor. In gluconeogenesis, it converts fructose-1,6-bisphosphate to fructose 6-phosphate. 

Location 

Glucogenesis was previously thought to be limited to the liver, kidney, intestine, and muscle in mammals but new research suggests that it also occurs in astrocytes in the brain. These organs use gluconeogenic precursors in somewhat different ways. Lactate, glycerol and glucogenic amino acids (especially alanine) are preferred by the liver while lactate, glutamine and glycerol are preferred by the kidney. Lactate produced by the Cori cycle is the most abundant source of substrate for gluconeogenesis, especially in the kidney. 

To generate glucose, the liver uses both glycogenolysis and glucogenesis, while the kidney only uses gluconeogenesis. The liver switches to glycogen synthesis after a meal, while the kidney raises gluconeogenesis. [Glutamine and glycerol are mostly used by the intestine.] 

Propionate is the primary substrate for glucogenesis in the ruminant liver, and when glucose demand is high, the ruminant liver can use more gluconeogenic amino acids (e.g., alanine). In calves and lambs, the ability of liver cells to use lactate for glucogenesis decreases as they progress from preruminant to ruminant stages. Very high rates of glucogenesis from propionate have been observed in sheep’s kidney tissue. 

Context and Applications 

This topic is significant in the professional exams for both undergraduate and graduate courses, especially for; 

Bachelors and Masters in Biochemistry and Molecular Biology.