Gluconeogenesis is important because it is your body’s backup system for making glucose when you haven’t eaten recently, and several organs, including the brain, kidneys, and red blood cells, depend on a steady glucose supply to survive. Without this process, even a missed meal could become dangerous. Your brain alone requires roughly 120 grams of glucose per day, and acute drops in blood sugar can damage both the brain and kidneys.
Which Organs Depend on Glucose
Not every cell in your body can switch to burning fat or other fuels when glucose runs low. Red blood cells have no mitochondria, so they can only use glucose. The inner part of the kidney (the renal medulla) and the testes also cannot survive long stretches without it. The brain is more flexible: it can partially shift to using ketone bodies during prolonged fasting, but it still needs a baseline of glucose to function safely.
This is why gluconeogenesis exists. It is literally the process of building new glucose from non-sugar raw materials, primarily in the liver, so these vulnerable tissues never run dry.
What Your Body Uses to Make Glucose
Gluconeogenesis converts three main types of raw material into glucose. Lactate comes from muscles and red blood cells that have broken down glucose without oxygen. Glycerol is released when fat cells break down stored fat. Amino acids come from the protein in your diet or, during starvation, from the breakdown of muscle tissue. All three of these compounds travel through the bloodstream to the liver, where they are reassembled into glucose and sent back out to fuel the rest of the body.
When Gluconeogenesis Kicks In
After you eat, your body stores some glucose as glycogen, a compact form kept mostly in the liver. In the first hour or so of fasting, the liver simply breaks down glycogen to release glucose. During this early phase, glycogen breakdown accounts for about 75% of glucose production, while gluconeogenesis contributes roughly 25%.
As fasting continues and glycogen stores shrink, the balance shifts. During extended fasting, glucose production splits roughly evenly between glycogen breakdown and gluconeogenesis. The liver handles about 30% of total gluconeogenesis, while the kidneys contribute around 20%. If fasting goes on even longer, the kidneys ramp up their contribution to about 40% of all new glucose production, a detail that surprises many people who think of the liver as the only organ involved.
The Cori Cycle: Recycling Lactate During Exercise
One of gluconeogenesis’s most practical roles plays out during intense exercise. When muscles work hard, they burn through glucose faster than oxygen can keep up, producing lactate as a byproduct. That lactate doesn’t just sit there. It travels through the bloodstream to the liver, which converts it back into glucose via gluconeogenesis. The fresh glucose then returns to the blood, available for muscles to use again. This loop is called the Cori cycle, first described in 1929 by Gerty and Carl Cori.
The cycle is not free. The liver spends six units of cellular energy (ATP) to rebuild each glucose molecule, while the muscle only extracted two ATP when it broke that glucose down. So the net cost is four ATP per cycle, which is why the liver shoulders a significant metabolic burden during intense physical activity. It also means the Cori cycle can’t sustain you indefinitely. It’s a temporary bridge that keeps muscles working and prevents dangerous lactate buildup until you rest or eat.
How Insulin and Glucagon Control the Process
Your body doesn’t leave gluconeogenesis running at full blast all the time. Two hormones act as the main switches. Glucagon, released by the pancreas when blood sugar drops, turns gluconeogenesis on by activating genes in the liver that produce the key enzymes needed to build glucose. Insulin, released after you eat, does the opposite: it suppresses gluconeogenesis by shutting down those same genes. In healthy people, a rise in insulin after a meal reduces gluconeogenesis by about 20%.
Insulin also works indirectly. It tells the pancreas to stop releasing glucagon, which removes the “on” signal for glucose production. And it acts on fat tissue and muscle to reduce the flow of raw materials (glycerol, amino acids, lactate) to the liver, starving the gluconeogenesis pathway of its building blocks. This layered control keeps blood sugar within a narrow, safe range throughout the day.
What Happens When Gluconeogenesis Goes Wrong
In type 2 diabetes, this tightly controlled system breaks down. Insulin resistance means the liver doesn’t respond normally to insulin’s “stop making glucose” signal. The result is that gluconeogenesis keeps running even after a meal, when blood sugar is already elevated from the food you just ate. This overproduction of glucose by the liver is one of the main reasons people with type 2 diabetes have high fasting blood sugar in the morning, even if they haven’t eaten overnight.
One of the most widely prescribed diabetes medications works specifically by dialing down this runaway gluconeogenesis in the liver, helping to reduce the excess glucose that spills into the bloodstream between meals.
Gluconeogenesis During Starvation and Ketosis
During prolonged starvation, gluconeogenesis and ketone production work in tandem. In early starvation, gluconeogenesis ramps up significantly, with one study measuring hepatic glucose production from non-sugar precursors at about 99 grams per day. As starvation continues and the body adapts, the brain shifts toward using ketone bodies for a larger share of its energy needs. This reduces the demand for glucose, and gluconeogenesis slows somewhat to conserve muscle protein, which would otherwise be broken down for amino acids.
The two processes are directly linked: the liver produces both ketones and new glucose from the same pool of incoming raw materials, and the rate of ketone production rises alongside gluconeogenesis during the transition into starvation. This coordinated response is what allows humans to survive weeks without food. Without gluconeogenesis maintaining a minimum blood glucose level, the organs that cannot use ketones would fail within days.