Lecture 1 -- Glucose Homeostasis

What are the three types of cell signaling in the endocrine system?

1. Endocrine (Distant mediator):
   Require blood vessels
   → Endocrine cells produce hormone → Transfer long distance via bloodstream → Reaches to the target cell and bind to its receptors

2. Paracrine (Local mediator):
   Paracrine cells produce neurotransmitter → Exit from the end of terminal → pass through the neurotransmitter junction and reaches to the cells near by

3. Autocrine (Local mediator):/

   The cells produce signal → The cells respond to the signal and the signal also upregulate the receptors on the cell itself → It also produce inhibitor to prevent ever lasting cycle

Please give one example for autocrine cell?

Macrophage
Macrophage produce ILK-1
→ ILK-1 up regulate the no. of receptors + recruit more macrophage to the area
→ ILK-1 also acts as a cytokine, as well as pyrogen → Increase the ”set temp” of the body → Cause fever as an inflammatory response to infection
→ Production of ILK-1 also downregulate the receptors on the macrophage surface to prevent over activation of immune response

What are the function of Acini?

Exocrine cells in the Acini are responsible for producing digestive enzymes

Exocrine cells are clustered as a group of cell in pancreas. What is the name of the cluster of cells?

Acini

Pancreas are divided into two lobes. What are those two lobes covered by?

→ Left lobe within the deep leaf of greater omentum of stomach
→ Right lobe within mesoduodenum

What is the difference between endocrine and exocrine glands?

Endocrine glands secrete hormones directly into the blood, while exocrine glands use ducts to secrete substances.

Endocrine cells are clustered as a group of cell in pancreas. What is the name of the cluster of cells?

Islet of Langerhans

What do the islets of Langerhans in the pancreas secrete?

Beta cells: Insulin
Alpha cells: Glucagon
Delta cells: Somatostatin (Little amount)
F cells: Pancreatic polypeptide (Little amount)

How is insulin secretion regulated?

Insulin secretion is mainly regulated by blood glucose concentration.
When there is an increase concentration of blood glucose, it goes in to the beta cells via GLUT 2 → Increase cellular respiration →Increase ATP production → Switch off the ATP sensitive potassium channel → Concentration of potassium inside the cell increase → Depolarisation → Calcium influx via voltage-gated calcium channel → Insulin from the vesicle via exocytosis

What is the role of GLUT 2 transporters in the liver?

GLUT 2 transporters allow glucose to move in and out of liver cells.

Which cells in the pancreas secrete insulin?

Beta cells in the islets of Langerhans secrete insulin.

What is the role of GLP-1 and GIP in insulin secretion?

GLP-1 and GIP stimulate the anticipatory release of insulin before glucose enters the bloodstream.

Apart from blood glucose concentration, what are the other controls of insulin

1. Parasympathetic
   → Increase insulin secretion

2. Sympathetic

   → Decrease insulin secretion → Insulin are available in blood

3. Increase amino acid in plasma → Especially for carnivores because their diet are mainly protein → Amino acid can be converted to glucose through gluconeogensis

4. GI hormone e.g. glucose like peptide (GLP-1); gastric inhibitor peptide (GIP)
   → Anticipatory release of insulin
   → It causes 50% of insulin released before the glucose being present in cell → Prevent sudden surge in glucose absorption

What prevents the sudden absorption of glucose after a meal?

-> Anticipatory release of GLP-1 (Glucose like peptide) and GIP (Gastric inhibitor peptide) that allows insulin to start being produced

What is the effect of insulin on glucose uptake?

Insulin increases glucose uptake into cells, especially muscle and fat cells.
→ Since glucose is not lipid soluble, it requires transport proteins like GLUT4 to enter cells.
→ Insulin bind to the insulin receptor on the cell surface → It induces the GLUT 4 translocate from the cytoplasm to the cell membrane → Glucose then can enter the cells via GLUT 4 transporter

What are the metabolic effects of insulin?

1. Protein synthesis

2. Lipogenesis

3. Glucose oxidation

4. Glucogenesis

What cells do not require insulin in order to take glucose into the cell?

CNS and mammary glands
→ No all of the cells in the body have GLUT 4 transporter and not all of them response to insulin or glucose

Is insulin release an example of a negative feedback loop?

Yes

How does the sympathetic nervous system affect insulin secretion?

Sympathetic activity
1. activate the alpha cell to release more glucagon → More glucose can be produced from glycogen
2. inhibits beta cells to secrete insulin to ensure that glucose is available for immediate energy needs.

How does the parasympathetic nervous system affect insulin secretion?

In term of rest and digest, the parasympathetic actvity may have an effect on both alpha and beta cells to produce insulin and glucagon
-> Effect on insulin would be predominant state but still have some effect on glucagon

How does insulin affect GLUT 4 transporters?

Insulin signals cells to increase the expression of GLUT 4 transporters on their membranes to facilitate glucose uptake.

Does hepotocyte use GLUT 4 as a transport for taking up glucose?

No. Hepatocyte use GLUT 2 as a transporter for glucose uptake.

What is the difference between GLUT 2 and GLUT 4?

GLUT2 allows glucose to enter and leave the cells, while GLUT4 only allows glucose to enter, not leave

Which cells have GLUT 4 transporters?

Skeletal cells

Which cells have GLUT 2 transporters?

Liver

Describe how the liver takes up glucose via the GLUT2 transporter

When there is an increase in glucose in plasma e.g. after eating, glucose enter the hepatocyte via GLUT 2 transport
→ Glucose convert into glucose-6-P → Glucose-6-P then convert glycogen for storage
→ The conversation of glucose to glucose-6-P require hexokinase.
→ Insulin stimulates the hexokinase → Maintain low intracellular concentration of glucose

BUT stored glycogen can also be converted back to glucose → When there is a decrease in glucose in plasma → Liver can undergo glycogenolysis or glyconeogenesis to release glucose to the bloodstream via GLUT 2 transporter, maintaining glucose homeostasis.

What triggers glucagon secretion?

→ Hypoglycemia (Primary factor)
→ Increase amino acid after meal
→ Parasynthetic activity
→ Sympathetic activity

What occurs during hypoglycemia in relation to glucagon?

During hypoglycemia, only low level of glucose enter the alpha cells via GLUT1 transporter → Low level of glucose cause low cellular respiration → ATP production drops → Low level of ATP cause closure of ATP-sensitive potassium channels → Increase intracellular potassium level → Calcium influx via voltage-gated channel → Glucagon is released via exocytosis

What is the primary action of glucagon?

Glucagon promotes glucose release from stored glycogen in the liver

What actions glucagon do?

1. Increase glucogenolysis

2. Increase gluconeogenesis

3. Increase ketogenesis

What happens to the nerves if there is excess blood glucose or too little glucose?

→ The level of plasma glucose is directly proportional to the the level of glucose in CSF
→ Excess glucose increase osmolarity of CSF → Draw water out of the neurone → Nerve will be dehydrated overtime → Stop working
→ Too little glucose → Starvation

What is the primary function of somatostatin in the pancreas?

Somatostatin inhibits the release of both insulin and glucagon.

What is the role of pancreatic polypeptide?

It comes from F cells and has complex and not well-understood interactions with other pancreatic hormones.

What differentiates Type 1 from Type 2 diabetes?

→ Type 1 diabetes is due to inadequate insulin secretion
→ Type 2 is due to abnormal target cell responsiveness.

What are some clinical signs of diabetes mellitus in animals?

Hyperglycemia, polydipsia, polyuria, and possible ketoacidosis.

Is Type 1 diabetes more common in dogs?

Yes
→ Type 1 DM is more common in dogs than cats while Type 2 DM is more common in cats than dogs

What are the problems with prolonged hyperglycaemia?

Renal neuropathy
High BP
Production of ketone (Beta oxidation of fatty acid)
Diabetic cataracts + Blindness
Glucose toxicity of nerve
Systemic inflammation