# Controlling Blood Glucose Concentration ## Factors Affecting Blood Glucose Concentration - There are **three main ways** glucose can enter the bloodstream: - **Absorption** in the gut following carbohydrate digestion - **Hydrolysis of glycogen** stores - **Non-carbohydrates** such as lipids, lactate and amino acids that have been converted to glucose - The amount of glucose absorbed into the blood from digested food can **vary substantially** - A pasta-heavy meal will result in very different blood glucose levels compared to a salad - Some meals may be much more carbohydrate-rich than others - Control systems within the body help to **manage the concentration of glucose** in the blood via the hormones **insulin** and **glucagon** - When there is **excess glucose** in the blood from a carbohydrate-dense meal it is removed - This occurs through increased glucose uptake into muscle, fat and liver cells and **glycogenesis** - When there is **insufficient glucose** in the blood for metabolic needs it is rapidly released from storage molecules - This occurs through **glycogenolysis** and **gluconeogenesis** - The levels of insulin and glucagon present in the blood are **constantly regulated and adjusted** in order to maintain the blood glucose concentration at a mostly constant level ## The Control of Blood Glucose Concentration

If blood glucose concentration falls too low, cells may not have enough glucose for respiration and may not be able to function normally

If blood glucose concentration rises too high, this can disrupt normal cell function, potentially causing major problems

- The control of blood glucose concentration is a **key part of homeostasis** - Blood glucose concentration is controlled by **two hormones** secreted by endocrine tissue in the pancreas - This tissue is made up of groups of cells known as the **islets of Langerhans** - The islets of Langerhans contain **two cell types**: - **α (alpha) cells** that secrete the hormone **glucagon** - **β (beta) cells** that secrete the hormone **insulin** - These α and β cells act as the **receptors** and initiate the response for controlling blood glucose concentration - The control of blood glucose concentration by glucagon can be used to demonstrate the **principles of cell signalling** ## Decrease in Blood Glucose Concentration - If a **decrease** in blood glucose concentration occurs, it is detected by the **α and β cells** in the pancreas: - The **α cells** respond by **secreting glucagon** - The **β cells** respond by **stopping the secretion of insulin** - The decrease in blood insulin concentration **reduces the use of glucose** by liver and muscle cells ### Glucagon mechanism of action - **Glucagon** binds to **receptors** in the cell surface membranes of **liver cells** - This binding causes a **conformational change** in the receptor protein that activates a **G protein** - This activated G protein activates the enzyme **adenylyl cyclase** - Active adenylyl cyclase catalyses the conversion of **ATP** to the second messenger, **cyclic AMP (cAMP)**

Cyclic AMP (cAMP) is a second messenger molecule that relays signals from hormones inside cells

- **cAMP** binds to **protein kinase A enzymes**, activating them - Active protein kinase A enzymes activate **phosphorylase kinase enzymes** by adding **phosphate groups** to them - Active phosphorylase kinase enzymes activate **glycogen phosphorylase enzymes** - Active glycogen phosphorylase enzymes **catalyse the breakdown of glycogen to glucose** - This process is known as **glycogenolysis**

The enzyme cascade amplifies the original signal from glucagon and results in the release of extra glucose by the liver to increase blood glucose concentration back to normal

### Summary of glucagon action | Step | Process | |------|---------| | 1 | Glucagon binds to liver cell membrane receptor | | 2 | G protein is activated | | 3 | Adenylyl cyclase converts ATP to cAMP | | 4 | cAMP initiates enzyme cascade | | 5 | Protein kinase A → Phosphorylase kinase → Glycogen phosphorylase | | 6 | Glycogen broken down to glucose | | 7 | Glucose released into bloodstream | ### Adrenaline's role - The hormone **adrenaline** also **increases the concentration of blood glucose** - It does this by binding to **different receptors** on the surface of liver cells that activate the **same enzyme cascade** and lead to the same end result – the breakdown of glycogen by glycogen phosphorylase - Adrenaline also stimulates the **breakdown of glycogen stores in muscle** during exercise - The glucose produced remains in the muscle cells where it is needed for respiration ## Increase in Blood Glucose Concentration - When the blood glucose concentration **increases** to above the normal range it is detected by the **β cells** in the pancreas ### How β cells detect glucose - When the concentration of glucose is high, glucose molecules enter the **β cells** by **facilitated diffusion** - The cells **respire this glucose** and produce **ATP** - High concentrations of ATP causes the **potassium channels in the β cells to close**, producing a change in the **membrane potential** - This change in the membrane potential causes the **voltage-gated calcium channels** to open - In response to the **influx of calcium ions**, the β cells secrete the hormone **insulin** - Insulin-containing vesicles move towards the cell-surface membrane where they release insulin into the capillaries - Once in the bloodstream, insulin circulates around the body - It **stimulates the uptake of glucose** by muscles cells, fat cells and the liver ## Action of Insulin - Muscle cells, fat storage cells, adipose tissue and liver cells possess **glucose transporter proteins** in their surface membranes - They are the **target cells** of insulin - These membrane proteins allow for the uptake of glucose molecules via **facilitated diffusion** - The rate of glucose uptake for these cells is **limited by the number** of glucose transporter proteins present

The glucose transporter proteins on target cells are insulin-sensitive

### Insulin mechanism of action - **Insulin** binds to **specific receptors** on the membranes of target cells - This stimulates them to **activate/add more glucose transporter proteins** to their cell surface membrane which **increases the permeability** of the cells to glucose - As a result, the **rate of facilitated diffusion increases** ### How insulin affects the liver - Insulin also helps to **increase the uptake of glucose in the liver** by stimulating **glycogenesis** - Once glucose has entered a liver cell an enzyme rapidly converts it to **glucose phosphate** - Different enzymes then convert glucose phosphate into **glycogen** - This helps to **lower glucose concentration within the liver cell** - A **steep diffusion gradient is maintained** between the blood in the capillaries and the liver cells | Process | Effect | |---------|--------| | Insulin binds to receptor | Chemical signal sent | | Vesicles move to membrane | Fuse and add more glucose transporter proteins | | Increased permeability | More glucose enters cell by facilitated diffusion | | Glycogenesis stimulated | Glucose converted to glycogen for storage | ## Negative Feedback Control

Blood glucose concentration is regulated by negative feedback control mechanisms

### How negative feedback works - In negative feedback systems: - **Receptors** detect whether a specific level is too low or too high - This information is communicated through the **hormonal or nervous system** to effectors - **Effectors** react to counteract the change by bringing the level back to normal ### Application to blood glucose control - In the control of blood glucose concentration: - **α and β cells** in the pancreas act as the **receptors** - They release the hormones **glucagon** (secreted by α cells) and **insulin** (secreted by β cells) - **Liver cells** act as the effectors in response to glucagon - **Liver, muscle and fat cells** act as the effectors in response to insulin ### Visualizing negative feedback in action The chart below shows how blood glucose concentration changes over time in response to meals and hormonal regulation:

- At **time 30 minutes**: A carbohydrate-rich meal causes blood glucose to spike above normal - **β cells** detect this increase and secrete **insulin** - Insulin promotes glucose uptake and glycogenesis - Blood glucose returns to normal range by time 90 minutes - At **time 150 minutes**: Between meals, blood glucose drops below normal - **α cells** detect this decrease and secrete **glucagon** - Glucagon promotes glycogenolysis and gluconeogenesis - Blood glucose returns to normal range by time 240 minutes ### Negative feedback loops | Scenario | Detection | Hormonal response | Effector response | Outcome | |----------|-----------|-------------------|-------------------|---------| | **High blood glucose** | β cells detect increase | Less glucagon and more insulin secreted | Less glucagon results in decreased glucose production in liver cells; More insulin results in increased uptake and use of glucose by liver and muscle cells | Blood glucose concentration **decreases** | | **Low blood glucose** | α cells detect decrease | More glucagon and less insulin secreted | More glucagon results in increased glucose production in liver cells; Less insulin results in decreased uptake and use of glucose by liver and muscle cells | Blood glucose concentration **increases** | ## The Role of the Liver - The liver plays a **vital role** in the conversion between glycogen and glucose - The conversion between these molecules helps to **regulate blood glucose concentration** - Both insulin and glucagon have **specific receptors** on the membranes of liver cells - When these hormones bind to their receptors they trigger **several processes** within the liver ### Glycogenesis

Glycogenesis is the synthesis of glycogen from glucose molecules

- **Insulin** triggers this process after it detects an increased blood glucose concentration - The synthesis of glycogen **removes glucose molecules from the bloodstream** and decreases the blood glucose concentration to within a normal range - Glycogen acts as a **compact and efficient carbohydrate storage molecule** ### Glycogenolysis

Glycogenolysis is the breakdown of glycogen to produce glucose molecules

- **Glucagon** triggers this process after it detects a decreased blood glucose concentration - It activates enzymes within the liver that breakdown glycogen molecules into glucose - The breakdown of glycogen **releases more glucose molecules to the bloodstream** and increases the blood glucose concentration to within the normal range ### Gluconeogenesis

Gluconeogenesis is the synthesis of glucose molecules from non-carbohydrate molecules

- **Glucagon** also triggers this by activating enzymes within the liver - These enzymes convert other molecules, such as **fatty acids** and **amino acids**, into glucose molecules - Glucose molecules are released into the bloodstream which **increases the blood glucose concentration** to within the normal range ### Summary of liver processes ```text High Blood Glucose → Insulin → GLYCOGENESIS (Glucose → Glycogen) ↓ Storage Low Blood Glucose → Glucagon → GLYCOGENOLYSIS (Glycogen → Glucose) ↓ Release to bloodstream → GLUCONEOGENESIS (Non-carbs → Glucose) ↓ Release to bloodstream ```

The enzyme cascade triggered by glucagon only occurs in liver cells; there are no glucagon receptors on muscle cells

## Key Comparison: Glucagon vs Insulin | Feature | Glucagon | Insulin | |---------|----------|---------| | **Secreted by** | α cells of pancreas | β cells of pancreas | | **Triggered by** | Low blood glucose | High blood glucose | | **Target cells** | Liver cells | Liver, muscle, and fat cells | | **Mechanism** | Activates enzyme cascade via cAMP (second messenger) | Stimulates addition of glucose transporter proteins to cell membranes | | **Effect on liver** | Stimulates glycogenolysis and gluconeogenesis | Stimulates glycogenesis | | **Net effect** | Increases blood glucose | Decreases blood glucose | | **Type of feedback** | Negative feedback | Negative feedback |