Does the Liver Make Glucose? How It Works

The liver makes glucose through two key processes, glycogenolysis and gluconeogenesis, ensuring the body maintains a steady blood glucose supply during fasting, sleep and exercise. As the central organ of glucose homeostasis, the liver both produces and stores glucose depending on the body's needs, guided by hormones such as insulin and glucagon. Understanding how the liver makes glucose is particularly relevant for people with type 2 diabetes, where this process becomes dysregulated. This article explains the mechanisms involved, what triggers glucose release, how diabetes affects liver function, and practical steps to support healthy blood sugar control.

Does the liver make glucose, and how does it work?

The liver makes glucose through glycogenolysis, which breaks down stored glycogen, and gluconeogenesis, which builds new glucose from non-carbohydrate precursors such as lactate, glycerol and amino acids. Both processes are regulated by insulin and glucagon secreted by the pancreas.

Yes, the liver does make glucose, and it does so through two main biochemical processes: glycogenolysis and gluconeogenesis. Together, these processes ensure the body has a continuous supply of glucose, particularly during fasting, sleep or periods of physical exertion when dietary glucose is unavailable.

Glycogenolysis is the breakdown of glycogen, a stored form of glucose held within liver cells (hepatocytes). The liver can store on the order of tens to roughly 100 grams of glycogen, though this varies between individuals.^[1] This reserve can be mobilised relatively quickly in response to falling blood glucose levels. As fasting continues and glycogen stores are progressively drawn upon, gluconeogenesis plays an increasingly important role. Rather than a simple switch, both processes run in parallel, with their relative contributions shifting over time: glycogenolysis predominates in the early hours of a fast, while gluconeogenesis becomes progressively more important as fasting is prolonged.^[4][1]

Gluconeogenesis is the synthesis of new glucose molecules from non-carbohydrate precursors, including lactate, glycerol and certain amino acids such as alanine.^[3][1] Although the liver is the primary site of gluconeogenesis, the kidneys also contribute to glucose production, particularly during prolonged fasting.^[1][4]

This glucose-producing capacity is tightly regulated by hormones, primarily insulin and glucagon, which are secreted by the pancreas. Insulin suppresses hepatic glucose output, while glucagon stimulates it. The balance between these two hormones determines how much glucose the liver releases into the bloodstream at any given moment.

It is worth noting that the liver also performs the opposite function: after a meal, when blood glucose rises, the liver absorbs excess glucose from the portal circulation and converts it back into glycogen for storage. This dual role, both producing and storing glucose, makes the liver central to maintaining blood glucose homeostasis throughout the day and night.

What triggers the liver to release glucose into the blood?

The liver releases glucose primarily in response to falling blood glucose, signalled by glucagon from pancreatic alpha cells. Exercise, prolonged fasting, stress hormones such as adrenaline and cortisol, and low insulin levels are all additional triggers.

The liver releases glucose into the blood primarily in response to falling blood glucose levels, a state detected and signalled by the hormone glucagon, which is secreted by alpha cells in the pancreatic islets of Langerhans.^[8][7] When blood glucose drops, glucagon binds to receptors on hepatocytes and activates intracellular signalling cascades that stimulate both glycogenolysis and gluconeogenesis, increasing hepatic glucose output.

Several other physiological triggers also prompt the liver to release glucose:

• Physical exercise: During moderate to intense activity, counter-regulatory hormones, including adrenaline (epinephrine) and glucagon, rise and stimulate hepatic glucose output to meet the increased demand from working muscles. In many people, particularly during vigorous exercise, these responses can maintain or even transiently raise blood glucose rather than cause a fall.

• Prolonged fasting or overnight sleep: As the body goes without food for several hours, glycogen stores are gradually drawn upon and gluconeogenesis becomes progressively more important. Fasting plasma glucose is measured after a fast of at least eight hours; morning sampling is common for practical reasons, but the test can be performed at any time of day provided the fasting period has been observed.^[11]

• The dawn phenomenon: In the early morning hours, circadian rhythms cause a rise in cortisol and growth hormone, which stimulate hepatic glucose production.^[5][6] This can lead to a rise in blood glucose in the early morning, even before eating, and is particularly noticeable in people with diabetes.

• Stress hormones: Adrenaline and cortisol, released during physical or psychological stress, both stimulate hepatic glucose production independently of glucagon. This is part of the body's fight-or-flight response.

• Low insulin levels: Insulin normally suppresses hepatic glucose output. When insulin levels fall, for example between meals or in type 1 diabetes, this suppression is lifted and the liver increases glucose release.

Understanding these triggers helps explain why blood glucose levels fluctuate throughout the day even in the absence of food, and why stress, illness or disrupted sleep can cause unexpected rises in blood glucose in people with diabetes.

How do conditions like type 2 diabetes affect liver glucose production?

In type 2 diabetes, hepatic insulin resistance causes the liver to continue producing glucose at inappropriately high rates despite elevated blood glucose, worsening fasting hyperglycaemia. Dysregulated glucagon secretion and associated fatty liver disease further impair normal glucose regulation.

In type 2 diabetes, the liver produces and releases excessive amounts of glucose into the bloodstream, even when blood glucose levels are already elevated, contributing significantly to fasting hyperglycaemia. This occurs because of hepatic insulin resistance, a state in which liver cells fail to respond normally to insulin's suppressive signal. As a result, gluconeogenesis and glycogenolysis continue at inappropriately high rates despite adequate or even elevated circulating insulin.

Research has shown that increased gluconeogenesis, particularly from amino acid and glycerol precursors, is a major driver of elevated fasting blood glucose in people with type 2 diabetes.^[2][3] This is compounded by the fact that glucagon secretion is often dysregulated in type 2 diabetes, with alpha cells continuing to release glucagon even when blood glucose is high, further stimulating hepatic glucose output.^[7][8]

Non-alcoholic fatty liver disease (NAFLD, also increasingly referred to as metabolic dysfunction-associated steatotic liver disease or MASLD), which is closely associated with obesity and type 2 diabetes, also impairs the liver's ability to regulate glucose metabolism.^[9][10] Excess fat accumulation within hepatocytes worsens insulin resistance and disrupts normal glycogen storage and release.

Several medicines used in the management of type 2 diabetes work, at least in part, by targeting hepatic glucose production. Metformin, for example, reduces gluconeogenesis in the liver and is recommended as a first-line treatment by NICE (NG28).^[11][12] GLP-1 receptor agonists, such as semaglutide (available in the UK as Ozempic, which is licensed for type 2 diabetes, and as Wegovy, which is licensed for chronic weight management), reduce hepatic glucose output in part by stimulating glucose-dependent insulin secretion and suppressing glucagon. Tirzepatide (Mounjaro, which is MHRA-authorised both for type 2 diabetes and for chronic weight management) is a dual GIP and GLP-1 receptor agonist and acts through both receptor pathways to reduce hepatic glucose output. If you have been diagnosed with type 2 diabetes or are concerned about your blood glucose levels, speak to your GP for assessment and guidance on appropriate management.

What can you do to support healthy liver and blood sugar function?

A diet lower in refined carbohydrates, at least 150 minutes of moderate aerobic activity per week, and modest weight loss of 5 to 10 per cent can all improve hepatic insulin sensitivity and lower fasting blood glucose. Persistent symptoms such as thirst, frequent urination or fatigue should be assessed by a GP.

Supporting healthy liver and blood glucose function involves a combination of dietary choices, physical activity, weight management and, where appropriate, medical treatment. No single intervention works in isolation, and the most effective approach is one that is sustained over time.

Diet: A diet lower in refined carbohydrates and added sugars reduces the glucose load delivered to the liver after meals, lessening the demand on hepatic glucose storage and insulin signalling. The NHS Eatwell Guide recommends basing meals on wholegrains, vegetables, lean proteins and healthy fats. Reducing alcohol intake is also important, as alcohol interferes with gluconeogenesis and can contribute to fatty liver disease.

Physical activity: Regular aerobic exercise improves insulin sensitivity in both muscle and liver tissue, reducing the degree of hepatic insulin resistance. The UK Chief Medical Officers' Physical Activity Guidelines recommend at least 150 minutes of moderate-intensity activity per week for adults.^[19][20] Resistance training also improves glucose uptake in skeletal muscle, indirectly reducing the burden on the liver.

Weight management: Even modest weight loss of 5 to 10 per cent of body weight has been shown to reduce liver fat, improve hepatic insulin sensitivity and lower fasting blood glucose (NICE NG49).^[22] For people with obesity and type 2 diabetes or prediabetes, clinically supervised weight management programmes may be appropriate. Bolt Pharmacy is a GPhC-registered UK online pharmacy offering online weight-management consultations, with prescriber review and pharmacist support, where a range of treatment options may be considered if clinically appropriate.

When to seek medical advice: If you experience persistent thirst, frequent urination, unexplained fatigue or unexpected changes in weight, contact your GP. These may be signs of impaired blood glucose regulation that warrant investigation, including fasting plasma glucose or HbA1c testing in line with NICE guidance (NG28). If you or someone with you develops vomiting, abdominal pain, rapid or deep breathing, confusion or signs of severe dehydration alongside high blood glucose or positive ketones, seek urgent medical attention by calling 999 or going to your nearest emergency department, as these may indicate a serious hyperglycaemic emergency such as diabetic ketoacidosis (DKA) or hyperosmolar hyperglycaemic state (HHS).

Frequently Asked Questions