• After a meal, insulin causes much of the absorbed glucose to enter the liver and be stored as glycogen.
• Between meals, blood glucose begins to fall, so insulin secretion decreases.
• Low insulin allows liver glycogen to be broken down into glucose, which is released into the blood to prevent blood glucose from falling too low.
• Insulin promotes liver glycogen storage by three main actions:
  • It inactivates liver phosphorylase, so stored glycogen is not broken down.
  • It increases glucokinase activity, causing glucose entering liver cells to be phosphorylated and trapped inside.
  • It increases glycogen synthase activity, promoting formation of glycogen.
• The liver can store glycogen up to about 5%–6% of its mass, equal to nearly 100 g of glycogen.

Glucose Is Released From the Liver Between Meals

• When blood glucose falls:
  • The pancreas secretes less insulin.
  • Glycogen synthesis and further liver glucose uptake decrease.
  • Low insulin together with increased glucagon activates phosphorylase.
  • Glycogen is broken down to glucose phosphate.
  • Glucose phosphatase removes the phosphate, producing free glucose.
  • Free glucose then leaves the liver and enters the blood.
• Therefore:
  • After meals: liver removes and stores excess glucose.
  • Between meals: liver releases glucose back into blood.
• Normally, about 60% of glucose from a meal is temporarily stored in the liver and released later.

Insulin Promotes Conversion of Excess Glucose Into Fatty Acids and Inhibits Gluconeogenesis in the Liver

• When liver glucose exceeds the amount that can be stored as glycogen or used for energy, insulin promotes its conversion into fatty acids.
• These fatty acids are converted into triglycerides and packaged in very low density lipoproteins.
• They are transported through blood to adipose tissue and stored as fat.
• Insulin also inhibits gluconeogenesis by decreasing the amount and activity of liver enzymes needed for glucose formation.
• Insulin also decreases release of amino acids from muscle and other tissues, reducing the raw materials available for gluconeogenesis.

Lack of Effect of Insulin on Glucose Uptake and Usage By the Brain

• Insulin has several effects on brain-related feeding behavior and body energy balance.
• However, insulin has little effect on glucose uptake by most brain cells.
• Most brain cells can take up and use glucose without insulin.
• The brain normally depends mainly on glucose for energy and uses fats only with difficulty.
• Therefore, maintaining blood glucose above a critical level is essential.
• If blood glucose falls to about 20–50 mg/100 mL, hypoglycemic shock may occur.
• This may cause:
  • Nervous irritability
  • Fainting
  • Seizures
  • Coma

Effect of Insulin on Carbohydrate Metabolism in Other Cells

• Insulin increases glucose transport and use in most body cells, similar to its action in muscle.
• Most brain cells are an important exception.
• In adipose cells, glucose provides material for the glycerol part of triglycerides.
• Therefore, insulin indirectly promotes fat storage in adipose tissue.

EFFECTS OF INSULIN ON FAT METABOLISM

• Insulin has important long-term effects on fat metabolism.
• Severe insulin deficiency can contribute to marked atherosclerosis, which may lead to heart attacks, strokes, and other vascular problems.

Insulin Promotes Fat Synthesis and Storage

• Insulin promotes fat storage in adipose tissue.
• By increasing glucose use, insulin decreases fat use and therefore acts as a fat sparer.
• When carbohydrate intake exceeds immediate energy needs, insulin promotes conversion of the excess carbohydrate into fatty acids.
• Most fatty acid synthesis occurs in the liver.
• Fatty acids are then transported through blood lipoproteins to adipose tissue for storage.
• Fatty acid synthesis occurs through these main steps:
  • Insulin increases glucose entry into liver cells.
  • When liver glycogen reaches about 5%–6%, extra glucose is directed toward fat synthesis.
  • Glucose → pyruvate → acetyl-CoA.
  • Acetyl-CoA provides the substrate for fatty acid synthesis.
  • Excess glucose metabolism produces citrate and isocitrate.
  • These activate acetyl-CoA carboxylase.
  • Acetyl-CoA is then converted to malonyl-CoA, an early step in fatty acid synthesis.
  • Fatty acids form triglycerides in the liver.
  • Triglycerides are transported in blood lipoproteins to adipose tissue.
  • Insulin activates lipoprotein lipase in adipose capillaries.
  • This enzyme releases fatty acids from triglycerides so they can enter adipose cells and be stored again as triglycerides.

Insulin Is Essential for Fat Storage in Adipose Cells

• Insulin inhibits hormone-sensitive lipase.
• Therefore, breakdown of stored triglycerides and release of fatty acids from adipose tissue are reduced.
• Insulin also increases glucose entry into adipose cells.
• Some glucose contributes to fatty acid synthesis.
• More importantly, glucose forms α-glycerol phosphate.
• α-Glycerol phosphate provides glycerol that combines with fatty acids to form triglycerides.
• Therefore, without insulin, storage of fatty acids in adipose tissue becomes greatly reduced.

Insulin Deficiency Increases Use of Fat for Energy

• When insulin is absent, fat breakdown and fat use for energy increase greatly.
• Some fat breakdown normally occurs between meals when insulin is low.
• In diabetes mellitus, when insulin is almost absent, this fat breakdown becomes extreme.

KEY CONCEPT

• After meal: ↑ insulin → liver takes up glucose → stores it as glycogen.
• Between meals: ↓ insulin + ↑ glucagon → liver glycogen breaks down → glucose enters blood.
• Excess glucose → fatty acids → triglycerides → adipose storage.
• Insulin inhibits gluconeogenesis.
• Most brain cells use glucose without insulin.
• Insulin promotes fat storage by:
  • ↑ Fatty acid synthesis
  • ↑ Lipoprotein lipase
  • ↑ Glucose entry into adipose cells
  • ↓ Hormone-sensitive lipase
• Insulin deficiency → marked fat breakdown and increased fat use for energy.

Conceptual Examples

• After a meal:
  ↑ Blood glucose → ↑ insulin → liver stores glucose as glycogen.
• Between meals:
  ↓ Blood glucose → ↓ insulin + ↑ glucagon → glycogen breakdown → glucose released into blood.
• When glycogen stores are full:
  Extra glucose → pyruvate → acetyl-CoA → fatty acids → triglycerides → fat storage.
• In adipose tissue:
  Insulin → ↓ hormone-sensitive lipase → less stored fat is broken down.
• Without insulin:
  ↓ Fat storage + ↑ fat breakdown → much greater use of fat for energy.

Insulin Deficiency Causes Lipolysis of Storage Fat and Release of Free Fatty Acids

• Without insulin, the normal fat-storage effects of insulin are reversed.
• Hormone-sensitive lipase in fat cells becomes strongly activated.
• This breaks stored triglycerides into:
  • Free fatty acids
  • Glycerol
• These products are released into the blood.
• Plasma free fatty acids rise within minutes and become the main energy source for almost all tissues except the brain.
• Fig. 79.5 shows that after removal of the pancreas, plasma free fatty acids rise almost immediately and even faster than blood glucose.

Insulin Deficiency Increases Plasma Cholesterol and Phospholipid Concentrations

• Excess circulating fatty acids reach the liver.
• The liver converts some of them into:
  • Phospholipids
  • Cholesterol
• The liver also forms excess triglycerides.
• These lipids are released into blood in lipoproteins.
• Without insulin, plasma lipoproteins may increase up to 3-fold.
• Total plasma lipids may rise from the normal 0.6% to several percent.
• High plasma lipids, especially cholesterol, promote atherosclerosis in severe diabetes.

Excess Usage of Fats During Insulin Deficiency Causes Ketosis and Acidosis

• Insulin deficiency causes excessive production of acetoacetic acid in the liver.
• Without insulin, large amounts of fatty acids enter liver cells.
• The carnitine transport mechanism becomes more active and carries fatty acids into mitochondria.
• In mitochondria: Fatty acids → β-oxidation → large amounts of acetyl-CoA
• Much of this excess acetyl-CoA is converted into acetoacetic acid.
• Acetoacetic acid enters the blood and normally reaches peripheral tissues, where it can be converted back to acetyl-CoA for energy.
• However, insulin deficiency also decreases the ability of peripheral tissues to use acetoacetic acid.
• Therefore, acetoacetic acid accumulates in the blood.
• Fig. 79.5 shows that its concentration may rise over several days to 10 mEq/L or more, producing severe body-fluid acidosis.
• Some acetoacetic acid is converted into:
  • β-hydroxybutyric acid
  • Acetone
• Acetoacetic acid + β-hydroxybutyric acid + acetone = ketone bodies.
• Large amounts of ketone bodies in body fluids are called ketosis.
• In severe diabetes, acetoacetic acid and β-hydroxybutyric acid can produce severe acidosis → coma → possible death.

KEY CONCEPT

• ↓ Insulin → ↑ hormone-sensitive lipase → ↑ triglyceride breakdown → ↑ free fatty acids.
• ↑ Free fatty acids → liver → ↑ cholesterol, phospholipids, and triglycerides → increased risk of atherosclerosis.
• ↑ Fatty acid oxidation → ↑ acetyl-CoA → ↑ ketone bodies.
• Excess ketone bodies → ketosis + metabolic acidosis → possible coma and death.

Conceptual Examples

• Fat breakdown:
  ↓ Insulin → hormone-sensitive lipase activated → stored triglycerides break down → free fatty acids enter blood.
• High blood lipids:
  ↑ Free fatty acids → liver makes more cholesterol and triglycerides → plasma lipids rise.
• Ketosis:
  ↑ Fatty acids → β-oxidation → ↑ acetyl-CoA → ↑ acetoacetic acid → ketone bodies accumulate.
• Severe diabetes:
  Excess ketone bodies → acidosis → coma → possible death.

Figure 79.5 — What Happens After the Pancreas Is Removed?

🧠 Main idea

The pancreas makes insulin. When the pancreas is removed → insulin suddenly disappears.

Then the body behaves as if it is starving despite having glucose in the blood:

↓ Insulin → ↓ glucose entry into cells + ↑ fat breakdown → ↑ blood glucose + ↑ free fatty acids + ↑ ketone bodies.

📊 First understand the axes

• X-axis = Days after the experiment begins.
• Y-axis = Concentration in blood.
• The graph gives relative changes, so exact concentration numbers are not shown.

⚫ Vertical line = “Removal of pancreas”

Before this line = Control: pancreas is present → insulin is available → concentrations remain fairly stable.

After this line = Depancreatized: pancreas has been removed → severe insulin deficiency begins.

🔴 Red line = Blood glucose

Before pancreas removal, blood glucose is almost stable.

After removal:

Blood glucose rises progressively ↑↑↑

Why?

• ↓ Insulin → muscle and fat cells take up less glucose.
• Liver releases/makes more glucose.
• Therefore glucose accumulates in blood → hyperglycemia.

The curve gradually becomes less steep at very high levels, so the rise begins to level off.

🔵 Blue line = Free fatty acids

This is the fastest immediate response.

Before removal → relatively low and stable.

Immediately after pancreas removal:

Free fatty acids shoot upward very rapidly ↑↑

Then they remain at a high plateau.

Why?

↓ Insulin → hormone-sensitive lipase becomes active → stored triglycerides break down → free fatty acids enter blood.

⭐ Notice that free fatty acids rise even faster than blood glucose.

🟢 Green line = Acetoacetic acid

Before removal → almost zero.

After pancreas removal:

• it initially rises only slightly,
• then progressively rises faster and faster over several days.

Why?

↑ Free fatty acids → liver receives lots of fatty acids → converts them into ketone bodies, including acetoacetic acid.

So:

Insulin deficiency → lipolysis → free fatty acids ↑ → ketone production ↑ → acetoacetic acid ↑↑

This can eventually contribute to diabetic ketoacidosis.

⭕ What about the circles?

There are no separate data-point circles in this particular graph. The figure shows three continuous curves: red, blue, and green.

⭐ KEY CONCEPT

After removal of the pancreas:

↓ Insulin

→ Blood glucose ↑ progressively 🔴
→ Free fatty acids ↑ very rapidly 🔵
→ Acetoacetic acid/ketones ↑ progressively 🟢

Easy sequence to remember

No insulin → glucose stays in blood + fat leaves adipose tissue → liver converts fat into ketones.

EFFECTS OF INSULIN ON PROTEIN METABOLISM AND GROWTH

Insulin Promotes Protein Synthesis and Storage

• After a meal, excess proteins, carbohydrates, and fats are stored in tissues, and insulin is required for this storage.
• Insulin promotes protein storage mainly by increasing protein formation and decreasing protein breakdown.
• Insulin increases transport of several amino acids into cells, especially:
  • Valine
  • Leucine
  • Isoleucine
  • Tyrosine
  • Phenylalanine
• Growth hormone also increases amino acid uptake, although it may act on different amino acids.
• Insulin increases mRNA translation at ribosomes, leading to rapid formation of new proteins.
• Without insulin, ribosomal protein synthesis greatly decreases.
• Over a longer time, insulin increases transcription of selected DNA sequences.
• This produces more RNA and more proteins, including enzymes needed for storage of carbohydrates, fats, and proteins.
• Insulin also inhibits protein catabolism, especially in muscle.
• Therefore, fewer amino acids are released from cells.
• In the liver, insulin decreases gluconeogenesis by reducing the activity of gluconeogenic enzymes.
• Because amino acids are important substrates for gluconeogenesis, this effect helps preserve amino acids in body proteins.
• Overall: Insulin → ↑ protein synthesis + ↓ protein breakdown → protein storage

Insulin Deficiency Causes Protein Depletion and Increased Plasma Amino Acids

• Without insulin, protein storage almost stops.
• Protein breakdown increases while protein synthesis decreases.
• Large amounts of amino acids are released into the blood, causing increased plasma amino acid levels.
• These excess amino acids are then:
  • Used directly for energy, or
  • Used for gluconeogenesis.
• Increased amino acid breakdown also increases urea excretion in urine.
• Severe protein loss in diabetes can cause:
  • Extreme weakness
  • Disturbed function of many organs

Insulin and Growth Hormone Interact Synergistically to Promote Growth

• Insulin is essential for growth because it is required for protein synthesis.
• Growth hormone is also essential for normal growth.
• Fig. 79.6 shows that animals lacking both pancreatic and pituitary hormones show almost no growth.
• Giving only insulin or only growth hormone produces very little growth.
• Giving insulin + growth hormone together produces marked growth.
• Therefore, insulin and growth hormone act synergistically.
• Each hormone has its own role, and both may promote uptake of different amino acids needed for growth.

Insulin’s Brain Actions May Regulate Metabolism

• Insulin has little role in stimulating glucose uptake in most brain neurons.
• However, insulin can act on the brain to regulate:
  • Food intake
  • Liver glucose production
  • Lipolysis
• Insulin stimulates hypothalamic POMC neurons, which helps reduce food intake.
• Insulin action in the brain can also decrease:
  • Hepatic glucose production
  • Systemic lipolysis
• The exact importance of these brain effects in humans, especially in conditions such as insulin-resistant type 2 diabetes, is still not fully understood.

KEY CONCEPT

• Insulin → ↑ amino acid uptake → ↑ protein synthesis.
• Insulin → ↑ mRNA translation + ↑ DNA transcription → more proteins and enzymes.
• Insulin → ↓ protein breakdown + ↓ gluconeogenesis → preserves body protein.
• Insulin deficiency → protein wasting + ↑ plasma amino acids + ↑ urea excretion.
• Insulin + growth hormone work together synergistically for normal growth.
• Brain insulin can help regulate food intake, liver glucose production, and fat breakdown.

Conceptual Examples

• After a protein-rich meal:
  ↑ Insulin → amino acids enter cells → more protein is synthesized and stored.
• Without insulin:
  ↑ Protein breakdown → ↑ amino acids in blood → gluconeogenesis + increased urea formation.
• Growth:
  Insulin alone or growth hormone alone → little growth.
  Insulin + growth hormone → marked growth.
• Brain action:
  Insulin → stimulates POMC neurons → ↓ food intake + ↓ hepatic glucose production + ↓ lipolysis.

Figure 79.6 — Growth Hormone + Insulin Are Needed Together for Normal Growth

🧠Main idea

Think of growth hormone (GH) as the builder and insulin as the hormone that supplies nutrients and helps build protein.

GH alone → little growth
Insulin alone → little growth
GH + insulin together → very large growth 🚀

📊 Understand the graph

• X-axis = Days → time passing.
• Y-axis = Weight (grams) → body growth of the rat.
• Red line = rat’s body weight over time.

🔴 First rising red line: normal growth

From the beginning to about day 35–40:

Weight rises ~10 g → ~70 g

The young rat is growing normally.

⬇️ “Depancreatized and hypophysectomized”

At about day 40, two glands are removed:

• Pancreas removed → insulin ↓↓↓
• Pituitary removed → growth hormone ↓↓↓

After this, the red line becomes almost flat.

➡️ Little/no weight gain = growth almost stops.

⬛ Black arrows

The arrows indicate the start and end of hormone treatment periods.

🟥 Horizontal red bars

Each red bar shows how long that hormone was being given.1️⃣ Growth hormone alone

During the GH bar:

Red line rises only a little:

~70 g → ~78 g

➡️ GH alone cannot produce major growth when insulin is absent.

2️⃣ Insulin alone

During the insulin bar:

Weight again rises only slightly:

~78 g → ~90–95 g

➡️ Insulin alone also cannot produce strong body growth without GH.

3️⃣ Growth hormone + insulin together

Now both hormones are given together.

The red line becomes very steep:

~90 g → >230 g

🚀 This means rapid, powerful growth.

So the effect of the two hormones together is far greater than either hormone alone.

⭐ Why do they work together?

Growth hormone

Promotes:

amino-acid uptake + protein synthesis + tissue growth

Insulin

Provides:

glucose/energy + amino-acid uptake + protein synthesis

Therefore:

GH gives the growth signal
+
Insulin makes nutrients available for building tissue

= Strong growth

⭐ KEY CONCEPT

No GH + no insulin → growth stops

GH alone → slight growth

Insulin alone → slight growth

GH + insulin → massive growth ↑↑↑

One-line memory

Growth hormone tells the body to grow; insulin provides the metabolic support needed to actually grow.

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