The Endocrine Pancreas Flashcards
What tissue does the pancreas come from?
It is a foregut stucture (coeliac truck).
The pancreas is a large gland
What are the two functions of the pancreas?
Exocrine: Produces digestive enzymes secreted directly into duodenum
- Exocrine function form the bulk of the gland. - Alkaline secretion via pancretic duct into duodenum
Endocrine: Hormone production and secretion
- From islets of langerhans
Only 1% of the pancreas is endocrine tissue, the other 99% is exocrine tissue.
Exocrine v endocrine tissue in pancreas
Exocrine - ducts
Endocrine - diffuse into blood
What polypeptide hormones are secreted by pancreas?
- Insulin - B-cells
- Glucagon - A-cells
- Somatostatin - delta-cells
- Panreatic polypeptide (PP) - PP cells
- Ghrelin - e cells
- Gastrin - G cells
- Vasoactive intestinal peptide - VIP cells
All of these hormones are associated with a particular type of cell in the pancreas.
How is plasma glucose controlled?
Using a feedback system.
Insulin: Lowers blood glucose. - Cells to take up glucose and liver to produce glycogen.
Glucagon: Raises blood glucose.
What are the actions of Insulin and Glucagon?
(signal, target tissue, affects on metabolism, actions)
Why is it important that blood glucose remains constant?
- Brain uses glucose at fastest rate in the body
- Relies on blood
- Sensitive to falls in glucose
- or rise = increased osmolarity
- Circulation glucose needs to be controlled
- Relies on blood
- Normally 3.3-6 mmol/L (UHL reference range)
- After a mean 7-8 mmol/L
- Renal threshold = 10mmol/L (threshold at which glucose gets into the urine)
- Glucosuria
- Pregancy, the renal threshold decreases
- Elderly, the renal threshold increases
- Glucosuria
What are the properties of insulin and glucagon?
- Water soluble hormones:
- Carried dissolved in plasma - no special transport proteins
- Short half life - 5 mins
- Interact with cell surface receptors on target cells
- Receptor with hormone bound can be internalised - inactivation
Properties of insulin
- Action (favours storage) it is the hormone of energy storage
- Is anti-gluconeogenic - At high dose, it lowers incorporation of pyruvate - into blood glucose, but also stimulated its incorporation into liver glycogen.
- Insulin is anabolic
- Anti-gluconeogenic
- Anto-lipolytic and anti-ketogenic
What is the structure of insulin?
- Insulin is a big peptide with an alpha structure - 3 bits
- Consists of two un-branched peptide chains which are connected by 2 disulphide bridges. This ensures stability (hold chains together)
- 51 amino acids
- 2 polypeptide chains
- A = 21, B = 30
- 2 disulphide bridges = rigid structure
How is insulin synthesised?
- Pre-pro insulin translation signal cleavage, proinsulin folding
- Proinsulin is transported to golgi
- Proinsulin is cleaved to produce insulin and C-peptide
- Both Insulin and C-peptide in vesicle. They marginate to surface of pancreasic B cell where all cuddle together
- Only when there is a signal from Ca2+ will these vesicles fuse with the cell membrane and secrete contents.
What are KATP channels?
These are channels that are regulated by ATP / ADP
- Glucose closes KATP channels in pancreatic beta-cells
- Metabolic inhibition reopens KATP channels
- Cell attached patch recordings, high external K, -60mV
How are KATP channels and insulin secretion linked?
What does insulin do?
Increases glucose uptake into target cells and glycogen synthesis (insertion of GLUT4 channel)
- In the liver, it increases glycgen synthesis by stimulating glycogen formating and by inhibiting breakdown
- In muscles it increases uptake of AA promoting protein synthesis
- In liver inhibits breakdown of AA
- In adipose tissue increases storage of triglycerides
Inhibits breakdown of fatty acids.
What is glucagon?
Hormone that opposes insulin
- Acts to raise blood glucose levels
- It is glycogenolytic
- Gluconeogenic
- Lipolytic
- Ketogenic
It mobilises energy release
How do a cells synthesises and secrete glucagon?
- Glucagon is secreted by a-cells
- Secreted due to low glucose levels in a-cells
- Synthesized in rough ER transported to Golgi
- Packed in granules
- Effect mainly in the liver
- Granules move to cell surface
- Margination - movement of storage vesicles to cell surface
- Exocytosis - fusion of vesicel membrane with palsma membrane with the release of vesicle contents
What is the structure of glucagon?
- 29 AA in one polyppetide chain
- No disulphide bridges = Flexible structure
- Simpler synthesis
What effect does glucagon have?
- In the liver, it increases the rate of glycogen breakdown (glycogenolysis)
- Stimulates the pathway for synthesis of glucose from AA (glucoseneogenesis)
- Net effect is a rise in blood glucose levels
- Stimulates lipolysis to increase plasma fatty acid
Why is glucagon clinically important?
Glucagon in emergency medicine is used when a person with diabetes is experiencing hypoglycaemia and cannot take sugar orally
In what stages of carbohydrate metabolism are insulin and glucagon stimulated?
In what stages of lipid metabolism are insulin and glucagon produced?
In what stages of amino acid metabolism are insulin and glucagon secreted?
What is it called if Insulin is high / low?
High insulin = Hypoglycaemia
Low insulin = Hyperglycaemia -Diabetes mellitus
What happens if glucagon levels are high / low?
High glucagon = Makes diabetes worse
Low glucagon = May contribute to hypoglycaemia
How do you know if you have disorders of blood glucose?
- Diabetes mellitis
- Mellitus (L) = honeysweet
- Group of metabolic diseases
- Affect over 2% of population in UK
- Characteried by:
- Chronic hyperglycaemia (prolonged elevation of blood glucose)
- Leading to long-term clinical complications
- Associated with elevated glucose levels in urine.
How do you diagnose diabetes mellitus?
Diagnosis basis of venous plasma glucose concentration:
- Normal range is 3.3-6mmol/L plasma glucose
- Fasting: over 7mM
- Random: Over 11.1 mM
Causes of type 1 diabetes?
Asolute insulin deficiency (Autoimmune destruction of pancreatic b-cells)
- Absolute - pancreatic b-cells destroyed
- Relative - secretory response of b-cells is abnormaly slow or small (insulin -deficiency - failure to secrete adequate amounts of insulin from b-cells or b-cell loss)
- Explaied by a gain of function mutation in Kir6.2 - this mutations makes the KATP channels less ATP sensitve
What causes type 2 diabetes?
Normal (?) secretion by relative peripheral insulin resistance
- Defective insulin receptor mechanism - change in receptor number and/or affinity
- Defective post-receptor events
- Insulin resistance - tissues become insensitive to insulin
- Or excessive or inapproproate glucagon secretion.
Insulin resistance
Main site of glucose utilisation (adipose, liver and skeletal muscle) show decreased response to normal circulating concentrations of insulin
Affects:
- 25% og general population
- 92% of patients wiht type 2 diabetes
Results from combination of:
- Genetic factors
- Environmental factors including:
- Obesity
- Sedentary lifestyle
What happens if there is insulin resistance in the young?
- Insulin resistance present before (12+years) onset of hyperglycaemia and development of overt type 2 diabetes
- Initially:
- B cells compensate by increasing insulin production - maintain normal blood glucose
- Eventually:
- B-cells unable to maintain increased insulin production - impaired glucose tolerance
- Finally:
- B-cell dysfunction leads to relative insulin deficiency - overy type 2 diabetes
