• Glucagon is secreted by the alpha cells of the islets of Langerhans when blood glucose falls.
• Its actions are largely opposite to insulin.
• Its major overall effect is to increase blood glucose concentration.
• Glucagon is a large polypeptide hormone.
• It has a molecular weight of 3485 and contains 29 amino acids.
• Even a very small amount of glucagon can markedly raise blood glucose.
• About 1 μg/kg of glucagon can increase blood glucose by approximately 20 mg/100 mL, or about 25%, within 20 minutes.
• Because of this strong glucose-raising action, glucagon is called the hyperglycemic hormone.

EFFECTS ON GLUCOSE METABOLISM

• Glucagon raises blood glucose mainly by two major actions in the liver:
  • Glycogenolysis → breakdown of liver glycogen into glucose.
  • Gluconeogenesis → formation of new glucose in the liver.
• Both actions increase the amount of glucose available to other organs.

KEY CONCEPT

• ↓ Blood glucose → ↑ glucagon from alpha cells → ↑ blood glucose.
• Glucagon acts mainly through:
  • ↑ Glycogenolysis
  • ↑ Gluconeogenesis
• Therefore, glucagon is called the hyperglycemic hormone and generally acts opposite to insulin.

Conceptual Examples

• Between meals:
  ↓ Blood glucose → ↑ glucagon → liver glycogen breaks down → glucose enters blood.
• When liver needs to make new glucose:
  ↑ Glucagon → ↑ gluconeogenesis → new glucose is released into blood.
• Easy comparison:
  Insulin → lowers blood glucose.
  Glucagon → raises blood glucose.

Glucagon Causes Glycogenolysis and Increased Blood Glucose Concentration

• The most dramatic action of glucagon is to cause rapid glycogen breakdown in the liver.
• This releases glucose and can raise blood glucose within minutes.
• The sequence is: Glucagon → G protein–coupled receptor → adenylyl cyclase → cAMP → protein kinase regulator protein → protein kinase → phosphorylase b kinase → phosphorylase b → phosphorylase a → glycogen breakdown → glucose-1-phosphate → free glucose → blood
• Step by step:
  • Glucagon binds its G protein–coupled receptor on the liver cell membrane.
  • This activates adenylyl cyclase.
  • Adenylyl cyclase increases cyclic AMP (cAMP).
  • cAMP activates the protein kinase regulator protein.
  • This activates protein kinase.
  • Protein kinase activates phosphorylase b kinase.
  • Phosphorylase b kinase converts phosphorylase b → phosphorylase a.
  • Phosphorylase a breaks glycogen → glucose-1-phosphate.
  • Glucose-1-phosphate is then dephosphorylated.
  • Free glucose leaves the liver and enters the blood.
• This pathway is an important example of cAMP acting as a second messenger.
• It is also a cascade amplification system.
• At each step, a small signal produces a larger response at the next step.
• Such amplification can reach as much as one-million-fold.
• Therefore, only a few micrograms of glucagon can cause blood glucose to double or rise even more within minutes.
• Continuous glucagon infusion for about 4 hours can cause such intense glycogenolysis that liver glycogen stores become depleted.

KEY CONCEPT

• Glucagon → cAMP cascade → phosphorylase activation → liver glycogen breakdown → ↑ blood glucose.
• The pathway produces strong signal amplification.
• Therefore, a very small amount of glucagon can produce a very large rise in blood glucose.
• Prolonged glucagon action can eventually empty liver glycogen stores.

Conceptual Examples

• During low blood glucose:
  ↑ Glucagon → liver glycogen breaks down → glucose rapidly enters blood.
• Amplification:
  Small glucagon signal → many activated enzymes at each step → huge final glucose response.
• Prolonged glucagon:
  Continuous glycogen breakdown for hours → liver glycogen stores become depleted.

Glucagon Increases Gluconeogenesis

• Even after liver glycogen is completely depleted, glucagon can continue to raise blood glucose.
• This continued hyperglycemia occurs because glucagon stimulates gluconeogenesis in the liver.
• Glucagon increases amino acid uptake by liver cells.
• These amino acids are then converted into glucose.
• Glucagon activates several enzymes needed for:
  • Amino acid transport
  • Gluconeogenesis
• An especially important effect is activation of the pathway: Pyruvate → phosphoenolpyruvate
• This is an important rate-limiting step in gluconeogenesis.

Other Effects of Glucagon

• Most other glucagon effects occur only when glucagon levels rise well above normal.
• Glucagon activates adipose cell lipase.
• This increases release of fatty acids, making more fat available for energy.
• Glucagon also inhibits triglyceride storage in the liver.
• Therefore, the liver removes fewer fatty acids from blood, leaving more fatty acids available for other tissues.
• At high concentrations, glucagon also:
  • Increases the strength of heart contraction
  • Increases blood flow in some tissues, especially the kidneys
  • Increases bile secretion
  • Decreases gastric acid secretion
• These effects are much less important than glucagon’s major effects on blood glucose regulation.

KEY CONCEPT

• Glucagon can raise blood glucose even after liver glycogen is exhausted.
• It does this by: ↑ Amino acid uptake → ↑ gluconeogenesis → ↑ glucose
• Glucagon also promotes fatty acid availability by increasing lipolysis and decreasing liver triglyceride storage.
• Its most important physiological role remains increasing blood glucose.

Conceptual Examples

• After liver glycogen is gone:
  ↑ Glucagon → amino acids enter liver → gluconeogenesis → new glucose enters blood.
• Gluconeogenesis pathway:
  Glucagon → promotes pyruvate → phosphoenolpyruvate → ↑ glucose formation.
• Fat metabolism:
  ↑ Glucagon → adipose lipase activation → ↑ fatty acids available for energy.
• Overall:
  Glycogen exhausted but glucagon remains high → blood glucose can still stay elevated through gluconeogenesis.

REGULATION OF GLUCAGON SECRETION

Increased Blood Glucose Inhibits Glucagon Secretion

• Blood glucose concentration is the strongest regulator of glucagon secretion.
• Its effect on glucagon is opposite to its effect on insulin:
  • ↑ Blood glucose → ↓ glucagon
  • ↓ Blood glucose → ↑ glucagon
• Fig. 79.10 shows that when blood glucose falls from the normal fasting level of about 90 mg/100 mL into the hypoglycemic range, plasma glucagon rises severalfold.
• Conversely, hyperglycemia causes glucagon secretion to decrease.
• During hypoglycemia, increased glucagon stimulates the liver to release more glucose and therefore helps correct low blood glucose.

Increased Blood Amino Acids Stimulate Secretion of Glucagon

• After a protein-containing meal, increased blood amino acids stimulate glucagon secretion.
• Alanine and arginine are especially effective.
• Amino acids also stimulate insulin secretion, so in this situation insulin and glucagon are both increased.
• Increased glucagon promotes conversion of amino acids into glucose.
• This makes additional glucose available to the tissues.

Exercise Stimulates Secretion of Glucagon

• During exhaustive exercise, blood glucagon may increase about 4–5 times.
• Increased glucagon helps prevent blood glucose from falling too low during exercise.
• Possible causes of increased glucagon during exercise include:
  • Increased circulating amino acids
  • β-adrenergic stimulation of the islets of Langerhans

KEY CONCEPT

• ↓ Blood glucose → ↑ glucagon → ↑ liver glucose output → correction of hypoglycemia.
• ↑ Blood glucose → ↓ glucagon.
• Amino acids, especially alanine and arginine → ↑ glucagon.
• Exercise → ↑ glucagon → helps maintain blood glucose.

Conceptual Examples

• Hypoglycemia:
  ↓ Blood glucose → ↑ glucagon → liver releases glucose → blood glucose rises toward normal.
• Protein meal:
  ↑ Alanine/arginine → ↑ glucagon → amino acids converted to glucose → more glucose becomes available.
• Heavy exercise:
  ↑ Glucagon 4–5 fold → ↑ liver glucose output → prevents excessive fall in blood glucose.

Figure 79.10 — Effect of Blood Glucose on Glucagon Secretion

🧠 Main idea

Glucagon works opposite to insulin.

When blood glucose falls, the pancreas releases more glucagon to bring glucose back up.

Blood glucose ↓ → glucagon ↑↑
Blood glucose ↑ → glucagon ↓

Think of glucagon as the body’s “low-glucose rescue hormone.”

📊 Understand the axes

X-axis = Blood glucose (mg/100 mL)

• Moving left → right = blood glucose increases.
• 100 mg/100 mL = 100 mg/dL.

Y-axis = Plasma glucagon (× normal)
This tells how much glucagon is present compared with normal.

• 1× = normal glucagon level
• 2× = twice normal
• 4× = four times normal

🔴 Red curve = glucagon concentration

The red curve slopes downward.

➡️ This means blood glucose and glucagon have an inverse relationship:

Glucose ↓ → glucagon ↑
Glucose ↑ → glucagon ↓

1️⃣ Very low glucose → glucagon becomes very high

At about 50 mg/dL glucose:

Glucagon ≈ 4× normal

Why?

The body detects dangerous hypoglycemia.

Pancreatic α-cells release large amounts of glucagon.

Glucagon tells the liver:

“Put glucose into the blood!”

The liver responds mainly by:

• Glycogenolysis → breaking glycogen into glucose
• Gluconeogenesis → making new glucose

➡️ Blood glucose rises toward normal.

2️⃣ Around normal glucose → glucagon near normal

At approximately 80–90 mg/dL:

Glucagon ≈ 1× normal

➡️ This is around the normal fasting range, so only normal basal glucagon secretion is needed.

3️⃣ High glucose → glucagon is suppressed

As glucose rises above about 100 mg/dL:

Glucagon falls below normal.

At about 120–125 mg/dL, it is only around 0.4× normal.

Why?

There is already plenty of glucose in blood, so the body does not need glucagon to produce more.

📉 Why does the curve flatten at high glucose?

At higher glucose concentrations, glucagon secretion is already strongly suppressed.

So further increases in glucose cause only a small additional decrease.

⭐ KEY CONCEPT

Glucagon responds strongly to LOW blood glucose:

Hypoglycemia
→ pancreatic α-cells stimulated
→ glucagon ↑↑
→ liver releases glucose
→ blood glucose ↑

Easy memory:

Insulin = high glucose hormone
Glucagon = low glucose hormone

Or simply:

Glucose ↓ = Glucagon GOES UP
Glucose ↑ = Glucagon GOES DOWN

Somatostatin Inhibits Glucagon and Insulin Secretion

• Somatostatin is secreted by the delta cells of the islets of Langerhans.
• It is a 14–amino acid polypeptide.
• Its blood half-life is very short, about 3 minutes.
• Food intake stimulates somatostatin secretion.
• Important stimulators include:
  • ↑ Blood glucose
  • ↑ Amino acids
  • ↑ Fatty acids
  • ↑ Gastrointestinal hormones released after eating
• Somatostatin has several important inhibitory effects:
  • It acts locally in pancreatic islets to decrease insulin secretion.
  • It also decreases glucagon secretion.
  • It decreases movement of the stomach, duodenum, and gallbladder.
  • It decreases gastrointestinal secretion and absorption.
• The main suggested role of somatostatin is to slow the entry and use of nutrients after a meal.
• By slowing gastrointestinal movement, secretion, and absorption, nutrients enter the blood over a longer period.
• By decreasing insulin and glucagon secretion, somatostatin also slows the use of absorbed nutrients by tissues.
• Therefore, nutrients are not rapidly exhausted and remain available for a longer time.
• Somatostatin is chemically the same as growth hormone inhibitory hormone.
• In the hypothalamus, it inhibits growth hormone secretion from the anterior pituitary.

KEY CONCEPT

• Delta cells → somatostatin.
• Food nutrients → ↑ somatostatin.
• Somatostatin causes:
  • ↓ Insulin
  • ↓ Glucagon
  • ↓ GI motility
  • ↓ GI secretion and absorption
• Overall effect → slower absorption and slower utilization of nutrients.
• Hypothalamic somatostatin also causes ↓ growth hormone secretion.

Conceptual Examples

• After a meal:
  ↑ Glucose + ↑ amino acids + ↑ fatty acids → ↑ somatostatin → nutrient absorption is slowed and prolonged.
• Inside pancreatic islets:
  ↑ Somatostatin → ↓ insulin + ↓ glucagon.
• Gastrointestinal tract:
  ↑ Somatostatin → ↓ motility + ↓ secretion + ↓ absorption → food nutrients enter blood more slowly.
• Hypothalamus:
  Somatostatin → anterior pituitary → ↓ growth hormone secretion.

SUMMARY OF BLOOD GLUCOSE REGULATION

• In a fasting person, blood glucose is normally maintained around 80–90 mg/100 mL.
• After a meal, it may rise to about 120–140 mg/100 mL during the first hour.
• Feedback mechanisms usually return blood glucose toward normal within about 2 hours after carbohydrate absorption ends.
• During starvation, the liver maintains blood glucose mainly by gluconeogenesis.
• The liver acts as a blood glucose buffer:
  • After a meal → ↑ blood glucose + ↑ insulin.
  • Up to about two-thirds of absorbed glucose is rapidly stored in the liver as glycogen.
  • Later, when blood glucose and insulin fall, the liver releases glucose back into the blood.
  • This reduces blood glucose fluctuations to about one-third of what they would otherwise be.
  • Therefore, severe liver disease makes stable blood glucose control difficult.
• Insulin and glucagon form major feedback systems:
  • ↑ Blood glucose → ↑ insulin → ↓ blood glucose toward normal.
  • ↓ Blood glucose → ↑ glucagon → ↑ blood glucose toward normal.
• Under normal conditions, the insulin mechanism is more important.
• During starvation, exercise, or other stress, glucagon becomes especially important.
• In severe hypoglycemia:
  • Low blood glucose stimulates the hypothalamus.
  • The hypothalamus activates the sympathetic nervous system.
  • The adrenal glands release epinephrine.
  • Epinephrine increases glucose release from the liver and helps protect against severe hypoglycemia.
• During prolonged hypoglycemia over hours to days:
  • Growth hormone and cortisol increase.
  • They decrease glucose use by many body cells.
  • Cells shift more toward fat utilization.
  • This helps preserve glucose and return blood glucose toward normal.

Importance of Blood Glucose Regulation

• Blood glucose must be maintained because glucose is the main nutrient normally used in sufficient amounts by the brain, retina, and germinal epithelium of the gonads.
• During the period between meals, much of the glucose produced by gluconeogenesis is used by the brain.
• Insulin secretion should remain low during this period so limited glucose is not excessively taken up by muscle and other peripheral tissues, leaving too little for the brain.
• Blood glucose must also not become excessively high because:
  • High glucose increases extracellular osmotic pressure → water leaves cells → cellular dehydration.
  • Very high blood glucose causes glucose loss in urine.
  • Glucose in urine causes osmotic diuresis → excessive loss of water and electrolytes.
  • Long-term hyperglycemia damages tissues, especially blood vessels.
  • This vascular damage increases the risk of:
    • Heart attack
    • Stroke
    • End-stage renal disease
    • Blindness

KEY CONCEPT

• Normal fasting glucose ≈ 80–90 mg/100 mL.
• After meal → ↑ insulin → liver stores glucose → blood glucose falls toward normal.
• Low glucose → ↑ glucagon → liver releases/makes glucose.
• Severe hypoglycemia → epinephrine helps rapidly raise blood glucose.
• Prolonged hypoglycemia → growth hormone + cortisol → ↓ glucose use + ↑ fat use.
• Blood glucose must stay within a narrow range to protect the brain and other glucose-dependent tissues and to prevent damage from hyperglycemia.

Conceptual Examples

• After a meal:
  ↑ Glucose → ↑ insulin → liver stores glucose as glycogen → blood glucose returns toward normal.
• Between meals:
  ↓ Glucose → ↓ insulin + ↑ glucagon → liver releases glucose → brain continues receiving glucose.
• Severe hypoglycemia:
  ↓ Glucose → hypothalamus → sympathetic activation → ↑ epinephrine → rapid liver glucose release.
• Prolonged fasting:
  ↑ Growth hormone + ↑ cortisol → ↓ tissue glucose use + ↑ fat use → glucose is preserved.
• Severe hyperglycemia:
  ↑ Blood glucose → glucose enters urine → osmotic diuresis → loss of water and electrolytes.

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