The Endocrine Pancreas Flashcards
What is the pancreas?
A large gland
Where is the head of the pancreas?
Nestled in the curvature of duodenum
How does the pancreas develop embryologically?
As an outgrowth of the foregut
What are the functions of the pancreas?
- Produces digestive enzymes secreted directly into duodenum
- Hormone production
What forms the bulk of the pancreas?
Exocrine function
Of what nature are the pancreas’ exocrine secretions?
Alkaline
Where do the pancreas’ exocrine secretions go?
Into the duodenum
How do the pancreas’ exocrine secretions get into the duodenum?
Through the pancreatic duct
Where does the pancreas produce hormones?
From Islets of Langerhans
How much of the pancreas is endocrine function?
~1%
How to the areas responsible for endocrine secretion appear on a micrograph of the pancreas?
As paler pink regions
What kind of hormones does the pancreas secrete?
Polypeptide
What hormones does the pancreas secrete?
- Insulin
- Glucagon
- Somatostatin
- Pancreatic polypeptide (PP)
- Ghrelin
What cells secrete insulin?
ß-cells
What cells secrete glucagon?
α-cells
What cells secrete somatostatin?
Delta cells
What cells secrete PP?
F cells
What are insulin and glucagon used in the regulation of?
Metabolism of carbohydrates, proteins and fats
What is somatostatin used in?
Islet cell secretion regulation
What is PP used in?
GI function
What does insulin do to blood glucose?
Lowers it
What detects high blood glucose?
The pancreas
What happens when the pancreas releases insulin?
Fat cells taken in glucose from the blood, achieving normal blood glucose levels
What effect does glucagon have on blood glucose?
Raises it
How does glucagon raise blood glucose?
Causes liver to release glucose into the blood, achieving normal blood glucose levels
What is insulin signalled by?
Feeding
What are the target tissues for insulin?
- Liver
- Adipose
- Skeletal muscle
What kind of action does insulin cause?
Anabolic- building
What is glucagon signalled by?
Fasting
What are the target tissues for glucagon?
NAME?
What kind of actions does glucagon have?
Catabolic
What uses glucose at the fastest rate in the body?
Brain
What does the brain rely on for its glucose?
Blood
What is the brain sensitive to?
Rises or falls in plasma glucose level
What does a rise in plasma glucose level cause that the brain is sensitive to?
Increased osmolarity
Why does the circulation of glucose in the blood need to be controlled?
The brain doesn’t have it’s own supply of glucose, and so relies on the circulatory system to supply and steady and regular amount
What are the normal plasma glucose concentrations?
- Normally 3.3-6mmol/L
- After a meal 7-8mmol/L
What is the plasma glucose renal threshold?
10mmol/L
What is glucosuria?
When glucose is excreted in urine
When is the renal threshold decreased?
In pregnancy
When is the renal threshold increased?
In the elderly
Are insulin and glucagon water or lipid soluble?
Water
How are insulin and glucagon carried?
Dissolved in the plasma
Do insulin and glucagon require special transport proteins?
No
How long is the half life of insulin and glucagon?
5 mins
What happens to insulin and glucagon at target cells?
They interact with cell surface receptors
How can a receptor with a hormone bound be inactivated?
It can be internalised
What is insulin important in the storage of?
- Carbohydrates
- Protein
- Fat
What does insulin act against?
- Gluconeogenesis
- Lipolysis
- Ketone formation
Is insulin glycogenic?
Yes
What does insulin consist of?
Two unbranched polypeptide chains, connected by 2 disulphide bridges
What do the disulphide bridges in insulin ensure?
Stability
How many amino acids are there in insulin?
51; 21 α, 30 ß
What does insulin start as?
Preproinsulin
Why does insulin start as preproinsulin?
Because insulin mRNA is translated as a single chain precursor
How is proinsulin generated?
Removal of it’s signal peptide during insertion into the ER
What happens to proinsulin within the Golgi?
It is exposed to several specific endopeptidases, which excise the C peptide
What does the excision of the C peptide from insulin generate?
Mature form of insulin, and a C peptide
What happens to the newly generated insulin and C peptide?
It’s packaged in the Golgi into secretory granules, which accumulate in the cytoplasm. They are now packaged ready for exocytosis
What is margination?
When granules move to the cell surface
What is the purpose of margination?
The granules are held in preparation within pancreatic ß-cells ready for need of secretion
What happens in exocytosis?
Fusion of vesicle membrane with plasma membrane to release the vesicle contents
How much of the insulin stored in the pancreas is secreted in a day?
15%
Why is the half life of insulin only 5 minutes?
Because there is no carrier
What is the stimulus for insulin release?
Increase in glucose in the extracellular fluid
How is glucose transported into the ß-cell?
Facilitated diffusion through GLUT2
What does an increase in [glucose ecf ] mean?
Increased concentrations of glucose within the ß-cell
What happens to glucose once it’s inside the pancreatic ß-cell?
It is phosphorylated by glucokinase
What happens once glucose has been phosphorylated?
It goes through glycolysis respiration
What is the result of the phosphorylated glucose going through glycolysis respiration?
Increase in ATP:ADP ratio
What does the increase in ATP:ADP ratio in the pancreatic ß-cell lead to?
Depolarisation the membrane
Why does an increase in ATP:ADP ratio lead to depolarisation of the membrane?
As ATP-sensitive potassium channel (K ATP channels) open, allowing influx of K +
What does the K + influx lead to?
Influx of extracellular calcium
Why does K + influx lead to an influx of extracellular calcium?
Voltage-gated calcium channels open
What does an increase in ECF calcium in the ß-cell trigger?
Exocytosis of insulin-containg secretory granules
What are the metabolic insulin effects?
- Increases glucose uptake in target cells and glycogen synthesis
- Inhibits breakdown of fatty acids
How does insulin increase glucose uptake?
Insertion of GLUT4 channel
What is the effect of insulin in the liver?
- Increases glycogen synthesis by stimulating glycogen formation and by inhibiting breakdown
- Inhibits breakdown of amino acids
What is the effect of insulin in muscles?
It increases uptake of amino acids, promoting protein synthesis
What is the effect of insulin in adipose tissue?
Increases storage of triglycerides
Where does insulin bind?
To the insulin receptor on the cell surface
What kind of molecule is the insulin receptor?
A dimer
What is the structure of the insulin receptor?
Two identical sub-units spanning the cell membrane
What are the insulin receptor sub units made up of?
1 α chain and one ß chain, connected by a single disulphide bond
Where is the α chain of the insulin receptor?
On the exterior of the cell membrane
Where is the ß chain of the insulin receptor?
Spans the cell membrane in a single segment
How is the insulin receptor activated?
- α chains move together when insulin is detected, and fold around the insulin
- Moves the ß chains together
- This makes the ß chains an active tyrosine kinase
- Initiates a phosphorylation cascade, resulting in increase in GLUT4 expression
What does the increase in GLUT4 expression mean?
Means cell can take up more glucose
What does glucagon do?
Acts to raise blood glucose
How does glucagon act to raise blood glucose?
- Glycogenolytic
- Gluconeogenesis
- Lipolytic
- Ketogenic
What does glucagon mobalise?
Energy release
What secretes glucagon?
α cells
What is glucagon secreted in response to?
Low glucagon levels in α cells
Where is glucagon synthesised?
Rough ER
What happens to glucagon once it has been synthesised?
It’s transported to Golgi
How is glucagon packaged?
In granules
Where does glucagon have its main effect?
In the liver
What happens following margination of glucagon granules?
They are held at the cell surface until stimulus of low blood glucose is detected by pancreatic α cells
What happens once the pancreatic α cells have detected the stimulus of low blood glucose?
The vesicle membrane fuses with the plasma membrane with the release of the vesicle contents, in a process called exocytosis
How many amino acids does glucagon have?
29
How many polypeptide chains does glucagon have?
1
Does glucagon have disulphide bonds?
No
What is the result of glucagon having no disulphide bonds?
It’s flexible
How does the synthesis of glucagon differ from that of insulin?
It’s simpler
What are the effects of glucagon?
- In the liver, it increases the rate of glycogen breakdown
- Stimulates gluconeogenesis pathways
- Stimulates lipolysis
What is the result of glucagon stimulating lipolysis?
Increases plasma fatty acids
What is the net effect of glucagon?
Rise in blood glucose levels
What effect does an increase in amino acids have?
Increase in insulin and glucagon
What effect does an increase in fatty acids have?
Increases insulin
What is the effect of an increase in GI tract hormones?
Increase in insulin
What is the effect of an increase in adrenaline and noradrenaline?
Decrease in insulin, increase in glucagon
How quickly does insulin and glucagon affect glucose uptake in muscle and adipose tissue?
Rapidly
How quickly do hormones affect gluconeogenesis and glycogenesis?
Intermediate- in minutes
What effect do insulin and glucagon have on lipogenesis?
NAME?
What effect do insulin and glucagon have on ketogenesis?
NAME?
How quickly do hormones affect lipogenesis?
Delayed- takes hours
What effect does insulin and glucagon have on amino acid uptake?
NAME?
How quickly do hormones affect amino acid uptake?
Rapidly- seconds
What effect does insulin and glucagon have on protein synthesis?
- Increased by insulin
- Decreased by glucagon
How quickly do hormones affect rates of protein synthesis?
Intermediate- minutes
What happens if insulin is excessively high?
Hypoglycaemia
What happens if insulin is deficient?
Hyperglycaemia
What happens if glucagon is excessively high?
Makes diabetes worse
What happens if glucagon is deficient?
May contribute to hypoglycaemia
What is type 1 diabetes caused by?
An absolute insulin deficiency caused by autoimmune destruction of pancreatic ß-cells
What is a relative insulin deficiency?
When the secretory response of ß-cells abnormally slow/small
What are the potential aetiologies of type 2 diabetes?
NAME?
How could the insulin receptor mechanism be defective?
Change in receptor number and/or affinity
What is meant by defective post-receptor events?
Insulin resistance
What happens in insulin resistance?
The tissues become de-sensitive to insulin
What is diabetes insipidus?
An uncommon condition that occurs when the kidneys are unable to conserve water as they perform their function of filtering blood
What are the main sites of glucose utilisation?
NAME?
What do the main sites of glucose utilisation show in insulin resistance?
Decreased response to normal circulating concentrations of insulin
What % of the population does insulin resistance affect?
- ~25% of general population
- ~92% of patients with type 2 diabetes
What does insulin result from?
NAME?
What environmental factors can cause diabetes?
- Obesity
- Sedentary lifestyle
Relative to hyperglycaemia and development of type 2 diabetes, when is insulin resistance present?
12+ years before
How does insulin resistance develop?
- Initially, ß-cells compensate by increasing insulin production, maintaining normal blood glucose
- Eventually, ß-cells are unable to maintain increased insulin production, leading to impaired glucose tolerance
- Finally, ß-cell dysfunction leads to relative insulin deficiency, using overt type 2 diabetes
Why does insulin deficiency/resistance cause chronic hyperglycaemia?
- In the muscles, insulin decreases the uptake of glucose and glycogenesis
- In the adipose tissue, insulin decreases uptake of glucose and decreases lipogenesis and esterification
- In the liver, insulin decreases glycogenesis and glycolysis, and increases gluconeogenesis
If there is no insulin, these things do not happen, causing hyperglycaemia
What are the long term complications of hyperglycaemia in the muscle?
The decreased uptake of amino acids and protein synthesis causes an increase in proteolysis, causing muscle wastage
What are the long term complications of hyperglycaemia in the adipose?
Decreased esterification leads to increased lipolysis, leading to weight loss
What are the long term complications of hyperglycaemia in the liver?
Gluconeogenesis from muscle amino acids, leading to muscle wastage.
Ketogenesis from adipose tissue fatty acids, leading to ketosis
What are the acute metabolic consequences of hyperglycaemia?
- Glucosuria
- Polyuria
- Polydipsia
What are the chronic consequences of diabetes?
NAME?
What are the microvascular diseases caused by chronic hyperglycaemia?
- Eye disease, including retinopathy
- Nephropathy in kidneys)
- Neuropathy in peripheral nervous system
What macrovascular disease is caused by chronic hyperglycaemia?
- Coronary artery disease
- Stroke
- Poor peripheral circulation
