Endocine Pancreas Flashcards
Where is insulin synthesis end
RER of pancreatic β-cells
What is the initial insulin form made in the RER
preproinsulin
How is pro insulin made from preproinsulin
The removal of prrproinsulin’s signalling peptide during insertion into the endoplasmic reticulum generates proinsulin
What is pro-insulin composed of
A chain, B chain & connecting C peptide
How is insulin different compared to proinsulin and how is this clinically relevant
Proinsulin forms insulin by losing the C peptide
C peptide & insulin are secretion together
& so c peptide can be used to measure endogenous insulin production
Describe the structure of insulin
2 polypeptides (A & B) linked by a disulphide bond
What are the effects of insulin in the body
General
- DNA synthesis
- Protein synthesis
- Growth responses
- Increased lipogenesis, decreased lipolysis
- Increased glycogen formation, decreased gluconeogenesis
I.e. increased glucose storage & decreased glucose release
Muscle
- Increased amino acid uptake
- Increased glucose uptake
- Increased glycogen synthesis
Adipose
- Increased glucose uptake
- Increased lipogenesis (lipid synthesis)
Liver
- Increased glycogen synthesis
- Increased lipogenesis
At what level should pancreatic beta cells start producing insulin to decrease glucose
5 mmol/l
What receptor transports glucose into beta cells
GLUT2
What happens to glucose once it enters beta cells
Glucose is phosphorylated by glucokinase
What is the role of glucokinase in the secretion of insulin
It acts as a glucose sensor - a change of glucose concentration leads to a dramatic change in glucokinase activity & hence glucose phosphorylation
What is the effect of increased glucose metabolism/ phosphorylation in the beta cells
Increase in intracellular ATP
What is the effect of increased ATP in the beta cells that eventually results in the secretion of insulin
Inhibition of ATP-sensitive K+ channel KATP =>
Depolarisation =>
opening of voltage gated Ca2+ channels =>
Increased intracellular ca2+ concentration =>
Fusion of secretory vesicles with the cell membrane =>
Insulin release
Summarise the steps that lead to the release of insulin from pancreatic beta cells
Glucose enters beta cells through CLUT2 =>
Glucose is phosphorylated by glucokinase =>
Inhibition of ATP-sensitive K+ channel KATP =>
Depolarisation =>
opening of voltage gated Ca2+ channels =>
Increased intracellular ca2+ concentration =>
Fusion of secretory vesicles with the cell membrane =>
Insulin release
Describe the pattern of release of insulin
Low basal rate (accounts for ~5%)
Post-prandial insulin release in biphasic pattern (~95%)
Describe the post-prandial release of insulin
- Is biphasic
- 5% insulin granules available & released immediately (1st)
- This prevents sharp increase in blood glucose
- Preparation & release of reserve insulin occurs in response to signalling (2nd)
- This means the second phase is more tuned to the insulin requirement/ blood glucose levels
What is the importance of the first phase of post-par dial insulin release
Prevents sharp increase in blood glucose
What is the importance of the second phase of post-par dial insulin release
It is controlled by signalling processes (GLUT2 glucose transport in beta cells) that are related to the amount of glucose exposure.
This allows a more tuned response related to the insulin requirement
Describe the three main cell types of the islets of langerhans. state what they secrete & where they are located within the islet of langerhans
Beta cells - Secrete insulin, located near the blood vessel
Alpha cells - Secreted glucagon, located near the blood vessel
Delta cells - Secrete somatostatin, location on periphery
Two other, less common cell types
- PP cells - secrete pancreatic polypeptide, periphery
- ε cells - secrete ghrelin
Thinking about the cell types in the islets of langerhans, name the hormones produced & what there main roles are
- Insulin - lowers blood glucose, increases glucose storage
- Glucagon - raises blood glucose, breaks down storage
- Somatostatin - inhibits insulin & glucagon secretion (prevents fluctuation) & reduces gastric secretions
- Ghrelin - increases appetite
- Pancreatic polypeptide - regulates pancreatic secretions & food intake
What are the islets of langerhans
Clumps of cells that form the endocrine part of the pancreas
Summarise glucose homeostasis
Hypoglycaemia/lipidaemia =>
Increased glucagon, decreased insulin =>
Gluconeogenesis & lipolysis
*above pathway can also be stimulated by raised adrenaline (in response to fasting or exercise)
Hyperglycaemia/lipidaemia =>
Increased insulin, decreased glucagon =>
Glucose storage (lipogenesis, glycogen formation)
- above pathway can also occur in response to eating
Describe the relationship between insulin sensitivity & release in a normal vs T2 diabetic patient
Increased insulin sensitivity => decreased insulin secretion
Decreased insulin sensitivity => increased insulin secretion
& vice versa
This compensatory mechanism does not occur in T2DM
What changes occur in a T2DM & pre diabetic patients between cells
the number of secretory granules per β-cell is reduced - degranulation
