Endocrine Regulation of Blood Glucose

Blood glucose is regulated by the hormones insulin, which lowers it by promoting the storage and use of glucose, and glucagon, which raises it by releasing glucose from stores, both made by the pancreas. In brief: the normal fasting blood glucose is about 4 to 6 mmol/L (roughly 70 to 100 mg/dL). After a meal, beta cells release insulin; between meals, alpha cells release glucagon. If the system fails, diabetes mellitus results, in which blood glucose is persistently high.

The brain depends on a steady glucose supply, so control is critical. This article focuses on the endocrine mechanism in detail, including the liver’s role and diabetes, and complements the general discussion in the article on hormonal control. It explains the stores of glucose, the actions of the two hormones, the types of diabetes and its management, compares the hormones, works through an insulin-dose style calculation and corrects common mistakes.

Why is blood glucose controlled?

Glucose is the main fuel for cell respiration, and the brain uses about 20 percent of the body’s energy, almost all as glucose. If blood glucose falls too low (hypoglycemia), a person feels shaky, sweaty and confused, and may lose consciousness. If it stays too high (hyperglycemia), it damages blood vessels, nerves, kidneys and eyes over the years, and it also draws water into the urine.

The body has stores of glucose in the form of glycogen: about 100 g in the liver and 300 to 500 g in the muscles. Muscle glycogen is used only by the muscle cells, while liver glycogen is released into the blood. The stores last about a day, and then the liver makes glucose from other substances such as amino acids and glycerol (gluconeogenesis). Intake of food, exercise and stress change the glucose level continually, yet the system keeps it within narrow limits.

What does insulin do?

Insulin is a protein hormone of 51 amino acids, made in the beta cells of the islets of Langerhans in the pancreas. Rising blood glucose after a meal is detected directly by the beta cells, which release insulin into the blood. Insulin is carried to target cells, particularly in the liver, muscle and fat tissue, and it binds to receptors on their membranes. Its effects are:

• Muscle and fat cells insert more glucose transporters (GLUT4) into their membranes, so they take up more glucose from the blood.
• The liver and muscles convert glucose to glycogen (glycogenesis).
• Cells use more glucose in respiration.
• The liver converts excess glucose into fat, which is stored in adipose tissue.
• The liver reduces glucose production.

As a result, blood glucose falls, and the beta cells release less insulin, a negative feedback.

What does glucagon do?

Glucagon is a peptide hormone of 29 amino acids, made in the alpha cells of the islets of Langerhans. Low blood glucose, between meals, during fasting or exercise, stimulates its release. It acts mainly on liver cells and has these effects:

• It stimulates the breakdown of glycogen to glucose (glycogenolysis).
• It stimulates gluconeogenesis, the production of glucose from non-carbohydrate sources.
• It reduces glucose use by the liver and stimulates the breakdown of fat for fuel.

The liver releases glucose into the blood, which raises the glucose level. When the level returns to normal, the release of glucagon decreases. The two hormones act in an antagonistic pair, as muscles do, so that the glucose level can be corrected in either direction.

Insulin and glucagon compared

What is diabetes?

Diabetes mellitus is a group of diseases with high blood glucose. About 500 million people live with it worldwide, according to recent estimates.

• Type 1 diabetes: an autoimmune disease in which the beta cells are destroyed, so little or no insulin is made. It usually starts in childhood or youth. Treatment requires insulin injections or an insulin pump, glucose monitoring, and balancing food and exercise.
• Type 2 diabetes: cells become less responsive to insulin (insulin resistance), and the pancreas may later not make enough insulin. It is much more common (around 90 percent of cases) and is associated with overweight, inactivity, age and genetics. It is managed by diet, exercise, weight loss, medicines and sometimes insulin.
• Gestational diabetes: develops during pregnancy and usually disappears after birth, but it raises the later risk of type 2 diabetes.

Symptoms of high glucose are thirst, frequent urination (because glucose in the filtrate exceeds the reabsorption capacity of the kidney tubules and holds water in urine), tiredness and weight loss. Complications include heart disease, kidney failure, blindness and nerve damage. The urine may contain glucose, which can be detected with test strips.

Worked example: carbohydrate and insulin

A person with type 1 diabetes plans to eat a meal with 60 g of carbohydrate. In their case, 1 unit of rapid-acting insulin covers about 10 g of carbohydrate (an insulin-to-carbohydrate ratio of 1:10), and 1 unit lowers blood glucose by about 2.5 mmol/L. Their blood glucose before the meal is 9.0 mmol/L, and the target is 6.0 mmol/L. Calculate the dose. (This is an illustration of the reasoning only. Real doses are set by a diabetes team.)

1. Insulin for the meal: 60 g ÷ 10 g per unit = 6 units.
2. Correction for high glucose: the excess is 9.0 − 6.0 = 3.0 mmol/L; 3.0 ÷ 2.5 = 1.2 units.
3. Total: 6 + 1.2 = 7.2 units, which would normally be rounded to the nearest practical dose, for example 7 units.

The calculation shows why people with diabetes count carbohydrates. Too much insulin causes hypoglycemia, which is treated with fast-acting sugar. Too little leads to hyperglycemia. In a healthy person, the pancreas makes similar adjustments automatically within minutes. Modern systems combine continuous glucose monitors with insulin pumps, and some adjust the doses automatically (an “artificial pancreas”).

Which other hormones affect blood glucose?

Adrenaline raises blood glucose by stimulating glycogen breakdown in the liver, especially in stress or exercise. Cortisol, from the adrenal cortex, raises glucose over a longer term by stimulating gluconeogenesis. Growth hormone and thyroxine also have effects. Insulin is the only hormone that lowers blood glucose in a major way, which explains why diabetes is a common disease.

How was glucose control discovered?

Paul Langerhans described the islets in 1869. Oskar Minkowski and Joseph von Mering showed in 1889 that removing the pancreas from a dog causes diabetes. Frederick Banting and Charles Best, with John Macleod and James Collip, isolated insulin in 1921 in Toronto, and it was first given to a patient, a 14-year-old boy, in January 1922. The Nobel Prize was awarded to Banting and Macleod in 1923. Genetically engineered human insulin, made in bacteria, was approved in 1982.

Which mistakes are common?

Mistake 1: Mixing up insulin and glucagon

Insulin lowers glucose, and glucagon raises it.

Mistake 2: Saying that people with type 2 diabetes make no insulin

In the early stage, they make insulin, but the cells respond poorly.

Mistake 3: Confusing glycogen with glucagon

Glycogen is the storage carbohydrate. Glucagon is the hormone.

Mistake 4: Thinking that insulin can be taken as a pill

Insulin is a protein that would be digested in the stomach, so it is injected.