Blood Glucose Control

Spec Mapping — OCR H420 Module 5.1.4 — Hormonal communication, content statements covering the control of blood glucose concentration, including the roles of insulin and glucagon, the mechanism of insulin secretion in pancreatic β cells (GLUT2 / KATP / Ca²⁺ exocytosis), the cellular actions of insulin and glucagon on the liver, glycogenesis / glycogenolysis / gluconeogenesis (refer to the official OCR H420 specification document for exact wording). This is the most heavily tested topic in the hormonal-communication module and the conceptual prerequisite for the diabetes lesson that follows.

Blood glucose is one of the most tightly regulated variables in the body. A typical healthy adult maintains a fasting blood glucose of about 4–5.5 mmol dm⁻³, rising to around 7–8 mmol dm⁻³ after a carbohydrate meal. Too low and the brain fails (hypoglycaemia, unconsciousness, death). Too high and tissues are damaged by glycation (hyperglycaemia, diabetes complications). This lesson follows the cellular and molecular events that keep glucose in range.

The discovery of the hormones controlling blood glucose has a clear scientific lineage already touched on in the preceding lesson: Banting and Best (1921, paraphrase) isolated insulin from canine pancreatic islets and showed its glucose-lowering effect. Sutherland (Nobel 1971, paraphrase) discovered cAMP as a second messenger by studying how adrenaline and glucagon mobilise glycogen — work that founded modern signal transduction. Earl Sutherland's insight was specifically that adrenaline binds outside the cell yet causes intracellular changes in glycogen metabolism; this implied a second messenger inside the cell, which he identified as cyclic AMP. Edmond Fischer and Edwin Krebs (Nobel 1992, paraphrase) characterised the reversible protein phosphorylation cascade — glycogen phosphorylase kinase activates glycogen phosphorylase by phosphorylation — that links cAMP to glycogen breakdown. Frederick Sanger (Nobel 1958, paraphrase) determined the complete amino acid sequence of bovine insulin, the first protein ever fully sequenced — a landmark in protein chemistry that opened the way to recombinant DNA technology for insulin manufacture.

Key Definitions:

• Glycogenesis — the synthesis of glycogen from glucose (stimulated by insulin).
• Glycogenolysis — the breakdown of glycogen to glucose (stimulated by glucagon and adrenaline).
• Gluconeogenesis — the synthesis of glucose from non-carbohydrate sources (e.g. amino acids, glycerol, lactate), also stimulated by glucagon and cortisol.
• Insulin — protein hormone from β cells of the pancreas; lowers blood glucose.
• Glucagon — peptide hormone from α cells of the pancreas; raises blood glucose.

---

The Big Picture — Negative Feedback

Blood glucose control is a classic example of negative feedback: a deviation from the set point triggers a response that opposes the deviation.

• If blood glucose rises, β cells release insulin → cells take up glucose, glycogenesis occurs, blood glucose falls back.
• If blood glucose falls, α cells release glucagon → glycogenolysis and gluconeogenesis in the liver, blood glucose rises back.

flowchart TB
    NORM[Normal blood glucose 4-5.5 mmol/dm3]
    NORM -->|Rises after meal| HIGH[High blood glucose]
    HIGH --> BC[β cells release insulin]
    BC --> G1["Cells take up glucose<br/>Glycogenesis in liver and muscle"]
    G1 --> NORM
    NORM -->|Falls during fasting/exercise| LOW[Low blood glucose]
    LOW --> AC[α cells release glucagon]
    AC --> G2["Glycogenolysis<br/>Gluconeogenesis in liver"]
    G2 --> NORM

Two hormones, acting in opposite directions, give very precise control. This is better than a single hormone because the body can adjust glucose both up and down.

---

What Happens When Blood Glucose Rises

After a meal, glucose is absorbed from the ileum into the hepatic portal vein and flows straight to the liver and pancreas.

1. β Cells Detect the Rise

β cells in the islets of Langerhans have a beautiful molecular mechanism for glucose sensing — OCR expects you to know it in detail.

1. Glucose enters the β cell via a GLUT2 transporter (facilitated diffusion).
2. Inside, glucose is metabolised by glycolysis and the Krebs cycle, generating ATP.
3. Rising ATP/ADP ratio closes ATP-sensitive K⁺ channels on the β cell membrane.
4. K⁺ stops leaving the cell, so the membrane depolarises.
5. Depolarisation opens voltage-gated Ca²⁺ channels.
6. Ca²⁺ enters the β cell, triggering vesicles containing insulin to fuse with the membrane.
7. Insulin is released by exocytosis into the blood.

This mechanism is a perfect example of how hormones and cell biology overlap: it is essentially the same as synaptic transmission, with K⁺ channels closing instead of voltage-gated channels opening. You should be able to describe every step for full exam marks.

2. Insulin Acts on Target Cells

Insulin binds to insulin receptors (tyrosine kinase receptors) on the surface of liver, muscle and adipose cells. This triggers several effects:

• Increases glucose uptake — in muscle and fat, insulin causes GLUT4 transporter vesicles to fuse with the plasma membrane, dramatically increasing the number of glucose channels. The liver already has GLUT2 transporters so does not need this, but glucose uptake increases anyway because insulin activates glucokinase, trapping glucose inside the cell.
• Stimulates glycogenesis — glucose molecules are joined into glycogen for storage by glycogen synthase.
• Inhibits glycogenolysis — glycogen breakdown stops.
• Inhibits gluconeogenesis — the liver stops making new glucose.
• Stimulates lipogenesis — in adipose tissue, excess glucose is converted to triglycerides.
• Stimulates protein synthesis — insulin is an anabolic hormone.

The net result: glucose leaves the blood and enters cells, where it is either used (respiration) or stored (glycogen, fat). Blood glucose returns to normal.

3. Negative Feedback Completes the Loop

As blood glucose falls, less glucose enters the β cells, ATP levels fall, K⁺ channels reopen, the membrane repolarises and insulin secretion decreases.

---

What Happens When Blood Glucose Falls

During fasting, exercise or overnight, glucose demand exceeds supply and blood glucose begins to fall.

1. α Cells Detect the Fall

α cells are less well characterised than β cells, but they release glucagon in response to low glucose. (Somewhat counterintuitively, α cells also depolarise when glucose is low — the opposite of β cells.)

2. Glucagon Acts on the Liver

Glucagon binds to glucagon receptors (G-protein coupled receptors) on the liver cell surface. The receptor activates adenylyl cyclase, which makes cAMP as a second messenger. cAMP activates protein kinase A, which phosphorylates two key enzymes:

• Glycogen phosphorylase — activated, catalysing glycogen breakdown to glucose (glycogenolysis).
• Glycogen synthase — deactivated, preventing glucose from being stored as glycogen again.

The net result: glycogen in the liver is broken down and glucose is released into the blood.

Glucagon also stimulates gluconeogenesis, the synthesis of glucose from non-carbohydrate precursors. The liver can make glucose from:

• Amino acids (e.g. alanine) — via pyruvate
• Glycerol — from triglyceride breakdown in adipose tissue
• Lactate — from muscle (Cori cycle)

Gluconeogenesis is slower than glycogenolysis but becomes important during prolonged fasting once glycogen stores are depleted.

3. Adrenaline Backs Up the Response

During acute stress or severe hypoglycaemia, the adrenal medulla also releases adrenaline, which acts on the same cAMP pathway in the liver to trigger glycogenolysis. Adrenaline works faster than glucagon and is particularly important in exercise and the fight-or-flight response.

---

Comparison: Insulin and Glucagon Signalling

Feature	Insulin (on liver cell)	Glucagon / adrenaline (on liver cell)
Receptor type	Tyrosine kinase	G-protein coupled
Second messenger	Not cAMP; uses phosphatidylinositol pathway	cAMP
Key enzyme activated	Glycogen synthase	Glycogen phosphorylase
Effect on glycogen	Synthesised	Broken down
Effect on blood glucose	Lowered	Raised

---

The Liver as the Central Player

The liver is uniquely placed for blood glucose control. It:

• Receives absorbed nutrients directly from the gut via the hepatic portal vein.
• Is freely permeable to glucose (via GLUT2), regardless of insulin.
• Stores up to 100 g of glycogen (about 500 kcal of energy).
• Performs glycogenolysis and gluconeogenesis as needed.
• Uniquely expresses glucose-6-phosphatase, allowing it to release free glucose into the blood.

Muscle also stores glycogen — up to 400 g — but muscle glycogen cannot be released as blood glucose because muscle lacks the enzyme glucose-6-phosphatase. Muscle glycogen is used locally during exercise. This is why the liver is the key organ for maintaining blood glucose.

---

Glycogenesis and Glycogenolysis in Detail

OCR expects you to know that:

• Glycogenesis joins glucose molecules together to form glycogen using the enzyme glycogen synthase. Insulin activates this enzyme (by dephosphorylation via PP1).
• Glycogenolysis breaks glycogen back down to glucose-1-phosphate using the enzyme glycogen phosphorylase. Glucagon and adrenaline activate this enzyme (by phosphorylation via PKA → phosphorylase kinase). Glucose-1-phosphate is then converted to glucose-6-phosphate by phosphoglucomutase, and in liver only, hydrolysed to free glucose by glucose-6-phosphatase.
• Gluconeogenesis makes glucose from non-carbohydrate precursors using enzymes such as pyruvate carboxylase, phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase, and glucose-6-phosphatase. Glucagon and cortisol stimulate this pathway (cortisol acts transcriptionally via glucocorticoid receptors, increasing the expression of gluconeogenic enzymes).

---

Exercise as a Test of the System

During exercise, muscle glucose demand rockets. The response involves:

• Sympathetic nervous system activation → adrenaline release within seconds.
• Adrenaline triggers glycogenolysis in liver (raising blood glucose) and in muscle (providing fuel locally).
• Glucagon also rises within minutes as blood glucose starts to fall.
• Insulin is suppressed — you do not want glucose to stay in storage during exercise.
• Cortisol rises over tens of minutes to hours, supporting gluconeogenesis for sustained exercise.
• Muscle GLUT4 transporters insert into the plasma membrane in response to contraction-induced signals (AMPK activation) independent of insulin — which is why exercise is such an effective treatment for type 2 diabetes (it bypasses the insulin-resistance lesion at the GLUT4 level).

Together these coordinate to provide glucose to the working muscles while maintaining enough in the blood for the brain. The interplay between sympathetic nervous activation, adrenal medulla (adrenaline), pancreatic α cells (glucagon), adrenal cortex (cortisol), and contracting muscle (AMPK) illustrates how nervous, endocrine and metabolic signals weave together to maintain whole-body glucose homeostasis under stress.

---

Exam Tip

For full marks, you must describe the mechanism of insulin secretion in detail: glucose entering via GLUT2, ATP rise, K⁺ channels closing, depolarisation, Ca²⁺ entry, vesicle fusion, insulin release. Memorise the seven steps. The same goes for how insulin acts: GLUT4 vesicles fuse with the membrane in muscle and fat; the liver uses a slightly different mechanism involving glucokinase activation.

---

Common Exam Mistakes

• Saying insulin is released when blood glucose is low. It is released when glucose is high.
• Confusing glycogenesis and glycogenolysis. The "-olysis" ending means breakdown (like hydrolysis); the "-genesis" ending means formation.
• Forgetting the intracellular mechanism of β cell insulin release. It is a high-value topic.
• Saying muscle releases glucose into the blood. Muscle glycogen stays in muscle — glucose-6-phosphatase is absent.
• Saying glucagon acts on muscle. It primarily acts on the liver.
• Claiming blood glucose is controlled at exactly one value. It is maintained within a range, and rises temporarily after meals.

---

Insulin / Glucagon Negative-Feedback Loop — Diagram