Glucose Homeostasis

What is the exocrine and endocrine function of the pancreas?

Exocrine: Secreting digestive enzymes into ducts

Endocrine: Releasing hormones into the blood

Name the cells in the islets of Langerhans

α-cells
β-cells
δ-cells

What hormone does α-cells in islet of Langerhans secrete?

Glucagon

What hormone does β-cells in islet of Langerhans secrete?

Insulin

What hormone does δ-cells in islet of Langerhans secrete?

Somatostatin

What’s the difference between endocrine signalling and paracrine signalling?

Endocrine signalling acts over long distances, using the bloodstream to transport hormones to distant target cells.

Paracrine signalling acts locally (signaling molecules diffuse through the extracellular matrix to affect nearby neighboring cells)

What are the effects of insulin on plasma metabolite (small molecules circulating in the blood plasma, resulting from metabolic processes like breaking down food, drugs, etc)?

• Insulin decreases plasma glucose, amino acids, and free fatty acids

What are the effects of insulin on metabolism?

• Insulin promotes anabolic processes such as uptake and storage in liver, muscle, and adipose tissue

What are the effects of glucagon on plasma metabolites and metabolism?

• Glucagon increases plasma glucose and ketones

• Glucagon promotes catabolic processes such as the breakdown of energy stores (mainly in the liver)

What is the structure of insulin?

• The B and A chain are biologically active

• The C-peptide is inactive

What degrades insulin?

Insulinase

Is insulin a highly conserved structure across many species or not?

It is highly conserved

Insulin is secreted in response to what?

Changes in glucose/ATP

How is insulin secreted from β-cells?

Via calcium-dependent exocytosis

• Glucose enters β-cells

• Glucose is metabolised to produce ATP

• Increased ATP closes ATP sensitive K⁺ channels, causing depolarisation

• This opens voltage-dependent Ca²⁺ channels, allowing Ca²⁺ influx, triggering insulin release by calcium dependent exocytosis

Sulfonylureas

A class of oral medications used to treat type 2 diabetes by stimulating the pancreas to release more insulin, lowering blood sugar levels

How does sulfonylureas stimulate insulin secretion?

Sulfonylureas closes ATP-sensitive K⁺ channels, leading to depolarisation. This opens voltage-dependent Ca²⁺ channels, allowing Ca²⁺ influx, triggering insulin release by calcium dependent exocytosis

When are we in absorptive state?

After eating

Nutrients absorbed

Insulin level increases

When are we in post-absorptive state?

Fasting (between meals)

Insulin levels decrease

What happens to plasma insulin levels during the day?

Plasma insulin concentrations rise during the absorptive state and fall during the post-absorptive state

When and how is insulin secreted?

Insulin is secreted by β-islet cells via exocytosis in response to high glucose levels. Insulin acts by binding to specific receptors on the plasma membrane of target cells.

What does RTK stand for?

Receptor tyrosine kinase

What is RTK?

A type of cell surface receptor that has built in enzyme activity. It binds a signalling molecule (like insulin) outside the cell and then triggers changes inside the cell.

What’s the mechanism of action with a ligand?

When a ligand binds, the receptor forms a dimer and activates its tyrosine kinase activity. It then autophosphorylates (adds phosphate groups to its own tyrosine residues), which starts intracellular signalling pathways.

Why are RTKs important?

RTKs regulate key processes like cell growth, metabolism, and survival

• The insulin receptor is an RTK and is essential for controlling blood glucose levels

What are the effects of insulin on carbohydrate metabolism?

• Insulin facilitates glucose entry into muscle and adipose tissue via GLUT transporters

• Insulin stimulates the liver to store glucose as glycogen

• Insulin decreases the concentration of glucose in the blood

What are the effects of insulin on carbohydrate metabolism?

• Insulin promotes synthesis of fatty acids in the liver when glycogen stores are saturated, increasing lipoproteins in circulation

• Insulin inhibits breakdown of fat in adipose tissue

• Insulin promotes glycerol synthesis from glucose and increases triglyceride synthesis

How does insulin stimulate glucose uptake in cells?

1. When blood glucose levels rise, insulin is released into the bloodstream

2. Insulin binds to insulin receptor (RTKs) on the cell membrane

3. This activates intracellular signalling pathways.

4. Glucose transporter-containing vesicles move to and fuse with the cell membrane

5. This increases the number of glucose transporters on the cell surface

6. As a result, more glucose enters the cell from the bloodstream

7. Insulin-sensitising drugs enhance this process and increase glucose uptake

What are the effects of insulin on skeletal muscle?

1. Insulin stimulates glucose uptake into muscle cells via GLUT4 transporters

2. Inside the cell, glucose is converted to glucose-6-phosphate

3. It can also be metabolised to produce energy or converted to lactic acid

4. Insulin promotes amino acid uptake into muscle cells

5. This supports protein synthesis and formation of structural proteins

6. Overall, insulin increases glucose utilisation and storage in skeletal muscle

What are the effects of insulin on the liver?

• Insulin increases uptake and phosphorylation in liver cells (via glucokinase), forming glucose-6-phosphate

• It stimulates glycogen synthesis from glucose-6-phosphate (via glycogen synthase)

• It promotes glycolysis, converting glucose-6-phopshate to pyruvate

• Pyruvate is further converted to acetyl-CoA, which is used for fatty acid synthesis

• Fatty acids are packaged into lipoproteins and exported to adipose tissue

• Insulin promotes uptake and use of substrates such as lactic acid and amino acids

• It inhibits gluconeogenesis

• Overall, insulin promotes storage of glucose and reduces glucose production by the liver

How does insulin promote triglyceride storage in adipose tissue?

• Insulin increases glucose uptake, which is converted to glucose-6-phosphate, then pyruvate, then acetyl CoA, then fatty acids

• Insulin increases production of glycerol-3-phosphate from glucose, providing the backbone for triglyceride formation

• Insulin stimulates lipoprotein lipase, releasing fatty acids from circulating lipoproteins for uptake

• Insulin increases amino acid uptake to support metabolic activity

• Overall, insulin increases triglyceride synthesis and fat storage

What is glucagon?

• Glucagon is a peptide hormone made of 29 amino acids.

• It is synthesised and released by α-cells of the pancreatic islets.

When is glucagon released?

When blood glucose levels fall. It acts as a counter-regulatory hormone to insulin.

What are the main actions of glucagon?

• Glucagon stimulates glycogenolysis in the liver, increasing glucose release

• It promotes gluconeogenesis, producing new glucose

• It increases the breakdown of fats (lipolysis)

• Overall, it raises blood sugar

How would you describe insulin and glucagon?

Counter-regulatory hormones

What is hypoglycaemia?

Hypoglycaemia is defined as blood glucose less than 3 mmol/L (normal is 4-6 mmol/L)

Glucose supply becomes insufficient to maintain normal tissue function

What is sensitive to low glucose levels in hypoglycaemia?

• The CNS is particularly sensitive to low glucose levels

• Neuroglycopenic symptoms include:

  • Impaired vision

  • Slurred speech

  • Staggered walk

  • Mood change

  • Confusion

  • Coma

  • Death

• ANS symptoms include:

  • Palpitations

  • Sweating

  • Shakiness

  • Hunger

What is diabetes mellitus characterised by?

Characterised by hyperglycaemia (blood glucose over 7mmol/L)

What is a major risk factor for developing type 2 diabetes?

Obesity