Glucose serves as the primary energy source for the body’s cells and tissues. Hepatic gluconeogenesis is a metabolic pathway that enables the liver to produce new glucose from non-carbohydrate sources. This process is an important mechanism for maintaining stable blood sugar levels, particularly when dietary glucose is unavailable. The liver, along with the kidneys to a lesser extent, plays a central role in this glucose production, preventing blood sugar from dropping too low.
The Body’s Need for Glucose
Glucose is the primary fuel for all organisms. The brain and red blood cells rely almost exclusively on glucose for their energy needs. Red blood cells lack mitochondria and depend entirely on anaerobic glycolysis to produce adenosine triphosphate (ATP) for energy. The brain, while capable of using ketone bodies during prolonged fasting, primarily functions on glucose, and maintaining its supply is a priority.
The body obtains glucose through the digestion of dietary carbohydrates. However, when carbohydrate intake is insufficient or during periods without food, the body needs alternative ways to generate glucose to sustain these glucose-dependent organs. Without a constant supply, functions could be impaired, leading to serious health issues. The liver, acting as the body’s fuel reservoir, helps to keep circulating blood glucose levels steady.
How the Liver Makes New Glucose
The liver is the primary site for gluconeogenesis, producing approximately 90% of the body’s new glucose, with the kidneys contributing the remaining 10%. This process converts non-carbohydrate precursors into glucose, rather than simply reversing glycolysis. Several specific enzymes are involved in bypassing the irreversible steps of glycolysis.
The main non-carbohydrate precursors include lactate, amino acids, and glycerol. Lactate, often produced during intense muscle activity or by red blood cells, is transported to the liver and converted into pyruvate. Amino acids can be derived from protein breakdown and enter the pathway as pyruvate or oxaloacetate. Glycerol, released from the breakdown of triglycerides (fats), is another significant precursor. The pathway begins in the mitochondria with the conversion of pyruvate to oxaloacetate, which then undergoes further transformations in both the mitochondria and cytoplasm to ultimately form glucose.
When Gluconeogenesis is Active
Hepatic gluconeogenesis becomes active when the body’s immediate glucose stores, such as liver glycogen, begin to deplete. This occurs after about 8 hours of fasting, when dietary glucose is no longer readily available. As fasting continues, gluconeogenesis becomes the primary mechanism for glucose production.
Intense or prolonged exercise also stimulates gluconeogenesis as muscle glycogen stores are depleted and the demand for glucose remains high. States of stress can also activate this pathway. Hormones play an important role in regulating gluconeogenesis. Glucagon, secreted by the pancreas in response to low blood glucose, stimulates gluconeogenesis by increasing the expression of specific enzymes. Cortisol, a stress hormone, also promotes gluconeogenesis, while insulin, released when blood glucose is high, inhibits it.
Gluconeogenesis in Health and Disease
The ability of the liver to perform gluconeogenesis is important for maintaining overall metabolic health. This process is a defense mechanism against hypoglycemia, or dangerously low blood sugar, which can impair brain function and lead to complications. By continuously producing glucose from available non-carbohydrate sources, the body ensures that glucose-dependent organs receive a steady supply of energy.
However, dysregulation of hepatic gluconeogenesis can contribute to metabolic disorders, most notably type 2 diabetes. In individuals with type 2 diabetes, there is an overproduction of glucose by the liver through gluconeogenesis, contributing to persistently high blood sugar levels. This can be influenced by factors such as insulin resistance in the liver and elevated glucagon levels. Certain medications, like metformin, are used to manage type 2 diabetes partly by reducing hepatic gluconeogenesis. The relative contribution of gluconeogenesis by the kidney also increases in diabetes and prolonged fasting.