S2: Control of Blood Glucose and the Endocrine Pancreas Flashcards
What keeps blood glucose kept constant?
Blood glucose is kept within constant limits by insulin, despite periodic intake of sugar and bursts of exercise requiring fuels
What is the liver’s role in glucose control?
The liver sits at the head of the portal vein (taking blood from the gut and feeding it into the liver). The liver has a high capacity to take up glucose and can buffer increases in blood sugar concentration (keep levels constant).
Describe arrangement of cells in islet of Langehans
- Arrangement of cells in islet of Langehans : clusters of endocrine cells surrounded by exocrine pancreas
- The islets form only a small part of the pancreatic mass but receive a very large part of the pancreatic blood supply
Cells in islets:
- Beta cells that release insulin (inside)
- Alpha cells which release glucagon (outside)
- Delta cells release somatostatin (GHIH) which inhibits both glucagon and insulin release
Describe synthesis of insulin
Insulin is a small polypeptide so is encoded for by a gene. The original transcript gives pre-proinsulin.
Pre-proinsulin has the signal sequence cleaved off to give proinsulin (in RER).
Then proinsulin has chain C removed in Golgi apparatus to give insulin
Insulin then packaged into secretory vesicles
One mole of C-peptide is secreted for each mole of insulin
What stimulates insulin release?
- Rising blood glucose levels
- Most amino acids can stimulate insulin release (albeit to different extents).
- As well as non-esterified fatty acids, also called free fatty acids (NEFAs), precise role not clear as of yet.
- Secretion is also regulated by the autonomic nervous system, through sympathetic and parasympathetic mechanism.
However, insulin release is almost entirely locally regulated (i.e. the beta cells respond to the high glucose in the blood) and a neural input isn’t needed, although it can modulate it.
Describe insulin release and glucose concentration graph
Here we can see release of insulin in relation to blood glucose concentration, from low to very high. The threshold for insulin release is around 5mmol/l of glucose. This means once blood glucose drops below this insulin release shuts down, the anabolic actions of insulin stop and catabolic actions of glucagon take over – preventing blood glucose from falling further. Also note that 50% of insulin reaching the liver is removed in its first passage through.
Describe blood supply of pancreas
Pancreas supplied by branches of the coeliac, superior mesenteric, and splenic arteries.
The venous drainage of the pancreas is into the portal system.
Why is insulin in peripheral circulation diluted?
Hepatic portal vein is only a fraction of the cardiac output, so insulin levels in the peripheral circulation (where you can easily sample) are much diluted.
Half of the secreted insulin is metabolized by the liver in it’s first pass; the remainder is diluted in the peripheral circulation
Why is C-peptide a more accurate index of insulin secretion in peripheral circulation?
C-pepitide is not metabolised by the liver
-One mole of C-peptide is secreted for each mole of insulin
How do the beta cells know blood glucose has risen?
- Indirectly via a response to the end-products of glucose oxidation.
- The beta-cell membrane has GLUT-2 transporters, so as blood glucose rises in diffuses into cell down its gradient.
- It enters glycolysis and TCA resulting in increased ATP
- There is an ATP sensitive K+ channel in membrane
- ATP acts as an intracellular messenger and closes the channel so there is depolarisation of the membrane (as K+ cannot diffuse out)
- Voltage gated Ca2+ open which influx and acts as intracellular messengers causing exocytosis of vesicles containing insulin
List factors regulating insulin secretion
Positive:
- Incretin hormones
- Plasma glucose
- Amino acids
- Parasympathetic nervous system
Negative:
- Alpha adrenergic
- Somatostatin
Why does amino acids stimulate both insulin and glucagon?
Not all meals are high carbohydrate, low carb meals and insulin release could lead to hypoglycaemic conditions
Effects of insulin
- Uptake of glucose into adipose tissue, skeletal muscle and cardiac muscle
- Uptake of FFAs and amino acids into adipose and muscle tissue
- Stimulation of glycogen synthesis, inhibition of glycogenolysis
- Inhibition of gluconeogenesis, lipolysis and proteolysis
Describe signalling at insulin receptor (mechanism and result)
- Effects of insulin come about through insulin binding to its receptor.
- The insulin receptor is a tyrosine kinase receptor, so when insulin binds tyrosine kinase (present on inside of membrane) is activated (by phosphorylation)
- This then phosphorylates insulin receptor substrate (IRS) and activation of further downstream cell signalling pathways
- Many metabolic effects of insulin involve phosphorylation cascade activated by PIP3
- Growth factor-like effects involve MAPK signaling
As a result:
- There is insertion of glucose transporter into cell membrane – allowing uptake of glucose down its gradient
- Glycogen synthesis
- Gene transcription so modulates activity of metabolic enzymes
- Activates cascade of protein phosphorylation, which stimulate or inhibit specific metabolic enzymes by modulating enzyme phosphorylation
How does glucose get into cells?
- Sodium glucose cotransporters (SGLTs)
- Secondary AT
- SGLT1: glucose absorption from gut
- SGLT2: glucose reabsorption from kidney (PCT)
- Glucose Transporters (GLUT)
- Affinity of these transporters is the rate glucose can pass through
- GLUT 2 (liver, kidney, pancreas) is a low affinity transporter. This allows a constant rate of glucose flow over a range of concentration = glucose dependent release
- GLUT 4 (muscle and adipose tissue) has medium affinity of glucose important for removal of glucose from blood for storage = insulin dependent uptake of glucose
- Also GLUT 1 (brain, erythrocytes, placenta) and GLUT 3 (brain) – both high affinity for glucose. GLUT 3 has preferential uptake of glucose in hypoglycaemia
