• The pancreas has two major types of tissue (Fig. 79.1):
  • Acini → secrete digestive juices into the duodenum.
  • Islets of Langerhans → secrete insulin and glucagon directly into the blood.
• The human pancreas contains about 1–2 million islets of Langerhans.
• Each islet is very small, about 0.3 mm in diameter, and is arranged around small capillaries.
• Islet cells release their hormones directly into these capillaries.
• The islets mainly contain alpha, beta, and delta cells.
• Beta cells form about 60% of islet cells and are mainly located in the center.
• Beta cells secrete:
  • Insulin
  • Amylin, also called islet amyloid polypeptide (IAPP)
• Amylin is often secreted together with insulin.
• Alpha cells form about 25% of islet cells and secrete glucagon.
• Delta cells form about 10% of islet cells and secrete somatostatin.
• A small number of PP cells are also present and secrete pancreatic polypeptide.
• These islet cells are closely connected, allowing their hormones to control one another’s secretion.
• Insulin inhibits glucagon secretion.
• Amylin inhibits insulin secretion.
• Somatostatin inhibits both insulin and glucagon secretion.

KEY CONCEPT

• Acini → digestive secretion into duodenum.
• Islets of Langerhans → hormones directly into blood.
• Beta cells 60% → insulin + amylin.
• Alpha cells 25% → glucagon.
• Delta cells 10% → somatostatin.
• PP cells → pancreatic polypeptide.
• Islet hormones can regulate each other’s secretion.

Conceptual Examples

• Beta cell:
  Beta cell → insulin + amylin.
• Alpha cell:
  Alpha cell → glucagon.
• Delta cell:
  Delta cell → somatostatin → inhibits insulin and glucagon.
• Cell-to-cell control:
  Insulin rises → glucagon secretion decreases.

INSULIN AND ITS METABOLIC EFFECTS

• Insulin was first isolated from the pancreas in 1922 by Banting and Best.
• Its discovery rapidly improved survival in patients with severe diabetes mellitus.
• Insulin has major effects on carbohydrate metabolism and therefore strongly influences blood glucose.
• However, insulin also has major effects on fat and protein metabolism.
• In diabetes mellitus, abnormal fat metabolism can contribute to acidosis and arteriosclerosis, causing serious illness and early death.
• Prolonged untreated diabetes also decreases protein synthesis.
• This causes tissue wasting and many disturbances of cellular function.
• Therefore, insulin is important for carbohydrate, fat, and protein metabolism.

INSULIN SECRETION IS ASSOCIATED WITH ENERGY ABUNDANCE

• Insulin secretion increases when the body has an abundant supply of energy, especially after eating excess carbohydrates.
• Insulin then helps store this excess energy.
• Excess carbohydrates are first stored as glycogen, mainly in:
  • Liver
  • Muscles
• Carbohydrates that cannot be stored as glycogen are converted into fat under the influence of insulin.
• This fat is then stored in adipose tissue.
• For protein metabolism, insulin increases amino acid uptake into cells.
• These amino acids are then used to form proteins.
• Insulin also inhibits the breakdown of proteins already present in cells.

KEY CONCEPT

• Insulin = major energy-storage hormone.
• ↑ Energy, especially carbohydrates → ↑ insulin secretion.
• Insulin promotes:
  • Glucose → glycogen
  • Excess carbohydrate → fat
  • Amino acids → protein
• Insulin also reduces protein breakdown.
• Therefore, insulin regulates carbohydrate, fat, and protein metabolism.

Conceptual Examples

• After excess carbohydrate intake:
  ↑ Carbohydrates → ↑ insulin → glycogen storage in liver and muscles.
• When glycogen storage is full:
  Extra carbohydrates → insulin stimulation → converted to fat → stored in adipose tissue.
• Protein metabolism:
  Insulin → ↑ amino acid uptake → ↑ protein formation + ↓ protein breakdown.
• Untreated diabetes:
  Insufficient insulin effects → ↓ protein synthesis → tissue wasting and cellular dysfunction.

INSULIN CHEMISTRY AND SYNTHESIS

• Human insulin has a molecular weight of 5808 and consists of two amino acid chains connected by disulfide bonds (Fig. 79.2).
• If these two chains are separated, insulin loses its biological activity.
• Insulin is synthesized in pancreatic beta cells by normal protein-synthesis machinery.
• The synthesis occurs in sequence: Insulin RNA → Preproinsulin → Proinsulin → Insulin + C peptide
• Ribosomes attached to the endoplasmic reticulum first produce preproinsulin, with a molecular weight of about 11,500.
• Preproinsulin is then cleaved in the endoplasmic reticulum to form proinsulin, with a molecular weight of about 9000.
• Proinsulin contains three peptide chains:
  • A chain
  • B chain
  • C chain
• In the Golgi apparatus, most proinsulin is further split into:
  • Insulin → A and B chains joined by disulfide bonds.
  • C peptide → the connecting peptide.
• Insulin and C peptide are stored in secretory granules and released in equal molar amounts.
• About 5%–10% of the secreted product remains as proinsulin.
• Proinsulin and C peptide have almost no insulin activity.
• C peptide can activate sodium-potassium ATPase and endothelial nitric oxide synthase, although the physiological importance of these effects is still uncertain.
• Measuring C peptide helps determine how much natural insulin a patient is still producing.
• In type 1 diabetes, patients who cannot produce insulin usually also have very low C-peptide levels.
• After secretion, insulin circulates mainly in the blood in an unbound form.
• Its plasma half-life is only about 6 minutes, and most insulin is removed within 10–15 minutes.
• Insulin not bound to target-cell receptors is broken down by insulinase, mainly in the:
  • Liver
  • Kidneys and muscles to a lesser extent
  • Other tissues in small amounts
• This rapid removal allows the body to switch insulin effects off quickly when they are no longer needed.

KEY CONCEPT

• Preproinsulin → Proinsulin → Insulin + C peptide.
• Mature insulin = A chain + B chain connected by disulfide bonds.
• Insulin and C peptide are secreted in equal molar amounts.
• C peptide indicates the body’s own insulin production.
• Insulin has a short half-life of about 6 minutes and is mainly degraded in the liver.

Conceptual Examples

• Insulin synthesis:
  Preproinsulin → proinsulin → insulin + C peptide.
• C-peptide measurement:
  Low natural insulin production → low C peptide.
• Type 1 diabetes:
  Little or no insulin production → markedly decreased C peptide.
• Insulin removal:
  Insulin enters blood → acts on receptors → remaining insulin is rapidly degraded, mainly by the liver.

INSULIN ACTIVATION OF TARGET CELL RECEPTORS AND CELLULAR EFFECTS

• To produce its effects, insulin first binds to and activates its membrane receptor on target cells (Fig. 79.3).
• The insulin receptor has a molecular weight of about 300,000 and contains four subunits joined by disulfide bonds:
  • 2 alpha subunits → completely outside the cell membrane.
  • 2 beta subunits → pass through the membrane and extend into the cytoplasm.
• Insulin binds to the alpha subunits outside the cell.
• This activates the beta subunits inside the cell and causes their autophosphorylation.
• Therefore, the insulin receptor acts as an enzyme-linked receptor.
• Autophosphorylated beta subunits activate tyrosine kinase.
• Tyrosine kinase then phosphorylates several intracellular proteins, especially insulin-receptor substrates (IRS).
• Different tissues contain different IRS types, such as IRS-1, IRS-2, and IRS-3.
• These signals activate some intracellular enzymes and inhibit others.
• In this way, insulin controls cellular metabolism of carbohydrates, fats, and proteins.
• Within seconds, insulin markedly increases glucose uptake in about 80% of body cells.
• This effect is especially important in skeletal muscle and adipose tissue, but not in most brain neurons.
• Insulin causes intracellular vesicles containing glucose transport proteins to move to and join the cell membrane.
• These transport proteins then increase glucose entry into the cell.
• After entering the cell, glucose is rapidly phosphorylated and becomes available for carbohydrate metabolism.
• When insulin disappears, the glucose-transporter vesicles leave the membrane within about 3–5 minutes and return inside the cell for later reuse.
• Insulin also increases cell membrane permeability to:
  • Amino acids
  • Potassium ions
  • Phosphate ions
• Therefore, uptake of these substances into cells increases.
• During the next 10–15 minutes, insulin changes the activity of many intracellular metabolic enzymes.
• These effects mainly occur by changing the phosphorylation state of enzymes.
• Over hours to several days, insulin produces even slower effects.
• It changes:
  • mRNA translation at ribosomes → changes production of new proteins.
  • DNA transcription in the nucleus → changes protein production further.
• Therefore, insulin can gradually remodel the cell’s enzyme machinery to produce longer-lasting metabolic effects.

KEY CONCEPT

• Insulin → alpha receptor binding → beta-subunit autophosphorylation → tyrosine kinase → IRS activation → cellular metabolic effects.
• Seconds: ↑ glucose transport, especially in muscle and adipose tissue.
• Insulin also increases cellular uptake of amino acids, K⁺, and phosphate.
• 10–15 minutes: changes activity of metabolic enzymes.
• Hours to days: changes protein synthesis and gene transcription.

Conceptual Examples

• Glucose uptake:
  Insulin binds receptor → glucose-transporter vesicles move to membrane → more glucose enters the cell.
• When insulin falls:
  Glucose-transporter vesicles leave the membrane within 3–5 minutes → glucose uptake decreases.
• Rapid enzyme effect:
  Insulin receptor activation → phosphorylation changes → metabolic enzyme activity changes within minutes.
• Long-term effect:
  Insulin → altered mRNA translation and DNA transcription → new proteins and enzymes are produced over hours to days.

Insulin Receptor — Figure 79.3

Easiest Concept

Think of insulin as a key that switches on a receptor present in the cell membrane.

• Insulin binds to the α (alpha) subunits outside the cell.
• The receptor contains:
  • 2 α subunits → outside the cell; bind insulin.
  • 2 β subunits → cross the cell membrane and act inside the cell.
• S–S = disulfide bonds holding the receptor parts together.
• Insulin binding activates the β subunits.
• β subunits undergo autophosphorylation.
• This activates tyrosine kinase.
• Tyrosine kinase phosphorylates insulin receptor substrates (IRS) and other enzymes.

What does IRS activation cause?

• ↑ Glucose transport → glucose transporters move to the membrane → glucose enters the cell.
• ↑ Glycogen synthesis → glucose is stored.
• ↑ Fat synthesis
• ↑ Protein synthesis
• ↑ Growth and gene expression

Diagram arrows

• Solid red arrows → show the different cellular effects of insulin.
• Dotted red arrow → shows movement of glucose transporters toward the cell membrane.

🔑 KEY CONCEPT

Insulin → α subunit → β autophosphorylation → tyrosine kinase → IRS → glucose uptake + glycogen, fat & protein synthesis + growth

In one line:
Insulin tells the cell to take in glucose and store/build nutrients.

EFFECTS OF INSULIN ON CARBOHYDRATE METABOLISM

• After a high-carbohydrate meal, absorbed glucose rapidly raises blood glucose.
• This stimulates rapid insulin secretion.
• Insulin then promotes rapid uptake, storage, and use of glucose by most tissues.
• These effects are especially important in:
  • Muscles
  • Adipose tissue
  • Liver

Insulin Promotes Muscle Glucose Uptake and Metabolism

• During most of the day, resting muscle uses mainly fatty acids for energy rather than glucose.
• This is because the resting muscle membrane is normally only slightly permeable to glucose.
• Significant glucose entry into muscle usually requires insulin stimulation.
• Between meals, insulin levels are relatively low, so only small amounts of glucose enter muscle cells.
• Muscles use large amounts of glucose mainly in two conditions:
  • During moderate or heavy exercise:
    • Muscle contraction causes GLUT 4 transporters to move from intracellular storage sites to the cell membrane.
    • GLUT 4 then increases glucose entry into muscle cells.
    • Therefore, exercise can increase muscle glucose uptake without requiring large amounts of insulin.
  • During the few hours after a meal:
    • Blood glucose rises.
    • The pancreas secretes large amounts of insulin.
    • Insulin rapidly increases glucose transport into muscle cells.
    • During this period, muscle uses glucose preferentially instead of fatty acids.

KEY CONCEPT

• High-carbohydrate meal → ↑ blood glucose → ↑ insulin → ↑ glucose uptake, storage, and use.
• Resting muscle normally uses mainly fatty acids because glucose entry is low between meals.
• Muscle uses large amounts of glucose during:
  • Exercise → muscle contraction → GLUT 4 moves to membrane
  • After a meal → ↑ insulin → ↑ glucose entry
• After meals, muscle temporarily prefers glucose over fatty acids.

Conceptual Examples

• Between meals:
  ↓ Insulin → little glucose enters resting muscle → muscle mainly uses fatty acids.
• During exercise:
  Muscle contraction → GLUT 4 moves to cell membrane → more glucose enters muscle even without much insulin.
• After a meal:
  ↑ Blood glucose → ↑ insulin → ↑ muscle glucose uptake → muscle uses glucose instead of fatty acids.

Storage of Glycogen in Muscle

• After a meal, if muscles are not exercising, much of the glucose entering muscle cells is stored as muscle glycogen instead of being used immediately for energy.
• Muscle glycogen can accumulate up to about 2%–3% concentration.
• This stored glycogen can later provide energy for muscle activity.
• Glycogen is especially useful during short periods of very intense exercise.
• It can also provide anaerobic energy for a few minutes.
• During this process: Glycogen → glycolysis → lactic acid + energy
• This energy production can occur even when oxygen is absent.

Quantitative Effect of Insulin to Facilitate Glucose Transport Through the Muscle Cell Membrane

• The effect of insulin on muscle glucose transport is shown in Fig. 79.4.
• Without insulin, intracellular glucose remains almost zero, even when extracellular glucose rises as high as 750 mg/100 mL.
• When insulin is present, intracellular glucose may rise to about 400 mg/100 mL.
• Therefore, insulin can increase glucose transport into resting muscle cells by at least 15-fold.

KEY CONCEPT

• After a meal, unused glucose in muscle is stored as glycogen.
• Muscle glycogen provides rapid energy, especially during intense or anaerobic activity.
• Insulin greatly increases glucose entry into resting muscle cells—at least 15-fold.

Conceptual Examples

• After a meal without exercise:
  ↑ Glucose enters muscle → not immediately needed for energy → stored as glycogen.
• During intense exercise:
  Muscle glycogen → glycolysis → lactic acid + rapid anaerobic energy.
• Insulin effect:
  Without insulin → very little glucose enters resting muscle.
  With insulin → glucose entry increases greatly → up to at least 15 times more transport.

Figure 79.4 — Effect of Insulin on Glucose Entry into Muscle Cells

🧠

Think of insulin as a key that opens the muscle-cell door for glucose.

• Without insulin → door almost closed → very little glucose enters.
• With insulin → door opens → glucose easily enters the muscle cell.

📊 Understanding the graph

X-axis = Extracellular glucose (mg/100 mL)
This means glucose outside the muscle cell. Moving left → right means more glucose is available outside.

Y-axis = Intracellular glucose (mg/100 mL)
This means glucose inside the muscle cell. Moving upward means more glucose has entered the cell.

🔴 Red line = INSULIN present

The red line rises strongly upward.

• At low extracellular glucose → intracellular glucose is low.
• As extracellular glucose rises → intracellular glucose rises greatly.
• At about 250 mg/100 mL outside → ~100 mg/100 mL inside.
• At about 500 mg/100 mL outside → ~300 mg/100 mL inside.
• At still higher extracellular glucose → intracellular glucose becomes >400 mg/100 mL.

Meaning: Insulin greatly increases the ability of muscle cells to take up glucose.

🟢 Green line = CONTROL = No insulin

The green line stays almost flat near zero even when extracellular glucose becomes very high.

So:

Lots of glucose outside + no insulin → almost no glucose gets inside.

This shows that simply increasing blood/extracellular glucose is not enough for efficient glucose entry into muscle cells.

🔴🟢 What do the circles mean?

The circles are actual experimental measurement points.

• 🔴 Red circles = measured intracellular glucose with insulin.
• 🟢 Green circles on the control line = measured values without insulin.
• The lines simply connect these measured points to show the overall trend.
• The isolated green circle beside the word “Control” is mainly a label/legend marker, not another point on the curve.

⭐ KEY CONCEPT

Insulin acts like a key for muscle glucose uptake:

Insulin present → glucose transport into muscle ↑↑ → intracellular glucose ↑↑

Insulin absent → glucose transport remains very low → intracellular glucose stays near zero

So the huge gap between the red and green lines shows the powerful effect of insulin on glucose entry into muscle cells.

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