Endocrine Pancreas Flashcards
Type 1 diabetes occurs due to…
Autoimmune destruction of beta cells
This leads to insulin deficiency
Type 2 diabetes occurs due to…
Insulin resistance + beta cell dysfunction
This leads to relative insulin deficiency
The endocrine cells of the pancreas are found in clusters known as…
The Islets of Langerhans
What % of pancreatic volume is made up of the islets of langerhans?
1-2%
The rest is exocrine acinar cells which secrete digestive juices
List 5 different islet cell types and what they secrete
Alpha cells -> glucagon
Beta cells -> insulin
Delta cells -> somatostatin
PP cells -> pancreatic polypeptide
Epsilon cells -> ghrelin
Roughly what proportion of the pancreatic islets are alpha, beta, delta and PP cells?
Beta - 55%
Alpha - 38%
Delta - <5%
PP - ~1%
At what blood glucose threshold is insulin released?
When BG >5.5 mmol/L
At what blood glucose threshold is glucagon released?
When BG <4 mmol/L
Describe regulation of glucose homeostasis by insulin
- Hyperglycaemia and hyperlipidaemia occur during feeding
- Pancreatic beta cells release insulin when glucose >5.5 mmol/L
- Glycogen synthesis and lipid storage occur due to uptake of glucose into the liver, muscle and fat
- Blood glucose and lipid levels drop back to normal
Beta cells are switched off at low glucose levels. T/F
True
And alpha cells are switched off at high glucose levels
Describe regulation of glucose homeostasis by glucagon
- Hypoglycaemia and hypolipidaemia occur during fasting/exercise
- Pancreatic alpha cells release glucagon when glucose <4 mmol/L
- Glycogen breakdown and lipolysis occur
- Blood glucose and lipid levels raise back to normal
In T2DM, beta cell mass in the pancreas decreases, suggesting that…
Beta cells are lost or dedifferentiate
When insulin resistance first develops, why does T2DM not immediately occur?
When does T2DM occur?
Beta cells release more insulin to compensate
T2DM occurs when beta cells fail to produce enough insulin to meet demands
Describe how glucose binds to beta cells and causes insulin release
- Glucose taken in by GLUT 2 transporters
- Glucokinase converts it to glucose-6-phosphate which is used in glycolysis, the TCA cycle and oxidative phosphorylation to produce ATP
- ATP binds to ATP sensitive K+ channels, causing them to close
- K+ builds up in the cell, depolarising the membrane
- Ca2+ can enter through voltage gated Ca2+ channels
- Ca2+ triggers insulin granule exocytosis
Insulin secretion often loses its biphasic nature in type 1 diabetes. T/F
False
Insulin secretion often loses its biphasic nature in type 2 diabetes
Insulin is not secreted in type 1 diabetes
Besides glucose, what other molecules do beta cells regulate insulin in response to?
Nutrients e.g., free fatty acids, amino acids
Hormones e.g., leptin, adiponectin, IGF1, glucagon
Neurotransmitters e.g., acetylcholine
Describe how hypoglycaemia causes glucagon release from alpha cells
- Glucose uptake and metabolism is low so KATP channels open
- K+ leaves the cell
- Voltage gated Na+ channels (NaV) open, allowing Na+ to enter the cell
- This triggers action potentials that open P/Q type voltage gated Ca2+ channels (CaV)
- Ca2+ entry triggers glucagon granule exocytosis
Where does glucagon have its biggest effect once it is released? What does it do here?
In the liver
Glucagon stimulates hepatic glucose output by promoting glycogen breakdown
It also stimulates gluconeogenesis
What alpha cell defect may be seen contributing to hyperglycaemia in T2DM?
Glucagon may still be released in the fed state which means that hepatic glucose production is still being stimulated
This contributes to hyperglycaemia
Define an exocrine cell in relation to the pancreas
A cell which secretes digestive juices into the ducts which drain into the gut
Define an endocrine cell in relation to the pancreas
A cell which secretes hormones into the blood stream which then travel to distal target organs
Define a paracrine cell
A cell which releases a soluble factor which then influences adjacent cells
Define an autocrine cell
A cell which releases a soluble factor which binds to a receptor on that same cell
Define a juxtacrine cell
A cell which presents a ligand on its surface which will interact with the cell next to it
Describe the paracrine action of delta cells
Delta cells secrete somatostatin 14 which suppresses beta and alpha cell function in a paracrine manner
Delta cells release SST14 in response to…
Nutrients, hormones and neurotransmitter stimulation
How does somatostatin 14 suppress alpha and beta cells?
It binds to G-protein coupled receptors which are coupled to Gi (inhibitory) proteins
This inhibits cAMP production
Why are delta cells good at suppressing multiple alpha and beta cells at a time?
They have an unusual neuron-like shape that allows them to be in contact with multiple cells
What is meant by the incretin effect?
Insulin secretion is greater in response to oral glucose in comparison with IV glucose infusion
What are incretins?
Hormones released from the gut which stimulate insulin release in response to oral glucose (i.e., glucose dependent)
What is the main incretin hormone?
Glucagon-like peptide 1 (GLP1)
GLP1 incretin hormone is released from ? cells in the small and large intestines
L-cells
Which enzyme is responsible for the breakdown of incretins?
DPP4
When might a DPP4 inhibitor be used?
To increase release of insulin for treatment of hyperglycaemia in T2DM
(as less incretins are being broken down so more are available to stimulate insulin release)
