Gluconeogenesis is a metabolic pathway that generates glucose from non-carbohydrate sources when dietary intake is insufficient. It primarily takes place in the liver, with a smaller contribution from the kidneys. This pathway is not simply the reverse of glycolysis, the process that breaks down glucose, but a specialized series of reactions.
The Purpose of Creating New Glucose
The primary function of gluconeogenesis is to maintain stable blood glucose levels, a state known as glucose homeostasis. Certain organs and cells, such as the brain and red blood cells, depend on a continuous supply of glucose for their energy needs. During periods of fasting, such as overnight, the body’s glycogen stores in the liver deplete. Gluconeogenesis becomes active after about eight hours of fasting to compensate.
Other situations also prompt this process. During strenuous and long-duration exercise, the demand for glucose by muscles can outpace the available supply, activating gluconeogenesis. Individuals following very low-carbohydrate or ketogenic diets also rely on this pathway to generate the glucose their bodies require. The process is distinct from glycogenolysis, the breakdown of stored glycogen. In contrast, gluconeogenesis is a slower, more sustained process, while glycogenolysis offers a rapid release of stored glucose.
Building Blocks for New Glucose
The body constructs new glucose using several non-carbohydrate precursors sourced from different metabolic activities. The main building blocks include lactate, glycerol, and specific amino acids. Together, these components account for over 90% of the glucose produced through this pathway.
Lactate is a significant precursor, primarily produced by muscles during intense anaerobic exercise and by red blood cells. Through a process called the Cori cycle, lactate travels through the bloodstream to the liver, where it is converted back into pyruvate and then into glucose. Another key building block is glycerol, which is released from adipose (fat) tissue when triglycerides are broken down for energy. This glycerol is transported to the liver to be used in the gluconeogenic pathway.
Amino acids serve as a source, particularly during longer periods of fasting or starvation. When the body breaks down proteins from muscle tissue, it yields glucogenic amino acids. These amino acids can be converted into intermediates of the citric acid cycle, which then enter the gluconeogenesis pathway to ultimately form glucose.
How the Body Controls Glucose Production
The regulation of gluconeogenesis is managed by hormones to ensure glucose is produced only when needed, preventing blood sugar levels from becoming too high or low. The system operates through a push-and-pull relationship between two primary hormones secreted by the pancreas: glucagon and insulin.
Glucagon acts as the primary “on” switch for gluconeogenesis. When blood glucose levels fall, such as during fasting, the alpha cells of the pancreas release glucagon. This hormone signals the liver to ramp up the production of new glucose by stimulating the activity of key enzymes in the gluconeogenic pathway. It effectively tells the liver that the body needs more sugar, initiating the conversion of precursors like lactate and amino acids into glucose.
Conversely, insulin functions as the main “off” switch. After a carbohydrate-containing meal, blood glucose levels rise, prompting the beta cells of the pancreas to release insulin. Insulin is an inhibitor of gluconeogenesis, signaling the liver to halt glucose production. This response ensures the glucose from the meal is used or stored, preventing an unnecessary increase in blood sugar. Other hormones, such as the stress hormone cortisol, can also promote gluconeogenesis to ensure energy availability during “fight or flight” situations.
Gluconeogenesis and Health Conditions
When the regulation of gluconeogenesis falters, it can contribute to health problems. This dysregulation plays a role in type 2 diabetes. In a healthy individual, rising insulin levels after a meal effectively shut down glucose production in the liver. The failure of this process contributes to the high fasting blood sugar levels often observed in individuals with the condition.
In type 2 diabetes, the liver becomes “insulin resistant,” meaning it no longer responds effectively to insulin’s signal to stop making glucose. Consequently, the liver continues to produce and release glucose into the bloodstream, even when blood sugar levels are already elevated. The medication metformin, a common treatment for type 2 diabetes, works in part by inhibiting gluconeogenesis in the liver, thereby helping to lower blood glucose levels.
Issues can also arise if gluconeogenesis is impaired. A failure of this pathway can lead to hypoglycemia, a condition of abnormally low blood sugar. Certain rare genetic disorders affecting the enzymes of gluconeogenesis can lead to severe hypoglycemia because the body cannot produce its own glucose during periods of fasting.