Acute Regulation of Glucose Flashcards
What is normal plasma glucose concentration?
Between 3 and 10 mM
What is plasma glucose concentration after eating and between meals?
Portal vein glucose conc can reach 20 mM after eating
Between meals it could decline to 0 mM without replenishment
What are the passive transporters of glucose?
What is their role?
GLUT
They transport glucose out of the cells and into the circulation, down a concentration gradient
What is the role of Na+ symporters for glucose transport?
SGLT-1 and SGLT-2
These are secondary active transporters that take up glucose from the gut lumen into cells
Where is GLUT-1 found and why?
Brain and red blood cells
There always needs to be some uptake of glucose as the brain and RBCs only use glucose
What passive porters are involved in regulating blood glucose level?
The balance between GLUT-4 and GLUT-2
What happens to GLUT-4 when insulin levels are high?
More GLUT-4 passive porters are placed into the membrane, allowing cells to take up more glucose
Where is GLUT-4 found?
How would it be described?
skeletal muscle, heart, adipocytes
It is insulin-responsive
What is significant about GLUT-5?
It is a fructose transporter
What are the types of cells in the islets of Langerhans and what do they secrete?
Alpha cells secrete glucagon
Beta cells secrete insulin
The beta cells are in the middle of the gland, and the alpha cells are scattered around the outside
What other cells are found in the islets of Langerhans?
delta cells that secrete somatostatin
F cells that produce pancreatic polypeptide
How are cells in the islets of Langerhans distributed?
beta cells are mainly central and most abundant
alpha cells are at the periphery
the blood will pick up insulin, followed by glucagon, before passing into the circulation
What do beta cells sense?
They sense glucose (and amino acids) in the blood, by using it to make ATP
What is the role of the ATP-gated K+ channel in the membrane of the beta cell?
It closes when there is lots of ATP present (produced from glucose)
The cell depolarises
What happens when the K+ channels on the B cells shut?
Depolarisation triggers voltage-gated Ca2+ to open, leading to calcium influx
This leads to secretion of insulin by exocytosis
What is the role of GLUT-2 transporters in beta cells?
As glucose conc starts to rise, the GLUT-2 transports more glucose into the cell
They are insulin-insensitive and low-affinity
What is the difference between insulin concentrations after oral and IV glucose is given?
There is a rapid and large increase in insulin production after oral glucose is taken
If there is a slow IV infusion of glucose, there is a much smaller rise in insulin concentration
Why does insulin concentration rise higher when oral glucose is taken?
There are other aspects to eating that enhance the insulin response
How do CCK and parasympathetic input influence insulin release?
ACh (parasympatheti NS) and CCK are activated once a meal has been eaten
They signal through Ca2+ cascade to enhance insulin release
What are incretins?
a group of metabolic hormones that stimulate a decrease in blood glucose level
What is the role of an incretin?
They will act via cAMP or PLC pathways to increase exocytosis of insulin
How does the autonomic nervous system influence insulin secretion?
The PNS will drive insulin secretion
The SNS will inhibit insulin secretion
How does action of a-adrenergic agonists affect insulin release?
This involves sympathetic stimulation
This suppresses insulin release
Where is insulin produced?
What type of hormone is it initially?
It is a preprohormone produces in the ER
It is one long chain containing lots of cysteine residues that cross-link by disulphide bonds
What forms the folded structure of insulin after it is cleaved?
It is cleaved to a prohormone which is folded up by internal disulphide bonds
What happens to insulin during processing in the Golgi and secretory granules?
It is cleaved to give A and B chains (held together by disulphide links) and a free C peptide
What is the role of C peptide?
It is inactive
It is used clinically as a marker of endogenous insulin production
(how much insulin the patient is producing)
What type of receptor is the insulin receptor?
It is a receptor tyrosine kinase
The receptor dimerises through disulphide bonds
What happens when insulin binds to its receptor?
It activates the tyrosine kinase domains, which phosphorylate each other and nearby proteins
What, in particular, do the receptor tyrosine kinases phosphorylate?
Insulin receptor substrates
These are inactive proteins within the cell that act as signalling molecules after phosphorylation
What are the two main pathways of insulin receptor signalling?
What do they control?
The fast pathway controls metabolism
The slow (MAPK) pathway alters gene expression
What enzymes are involved in the fast pathway?
What is the result of this pathway being activated?
PI3K and PKB will phosphorylate proteins to alter their activity
They phosphorylate GLUT-4 and traffic it to the membrane, allowing the cell to pick up more glucose
What is the role of the slow pathway?
What type of responses is it involved in?
It causes changes in transcription
It is involved in longer-term responses, such as growth
What type of glucose transporters are found in the liver?
What does this mean?
Hepatocytes have GLUT-2 but not GLUT-4
This means all responses are in terms of metabolic changes
What happens in the liver as glucose levels rise?
Pathways which favour storage of glycogen are switched on
There is movement of glucose down the glycolysis pathway and into the mitochondria where acetyl CoA is made
The acetyl CoA is converted into fatty acids and triacylglycerols
What happens to the fatty acids that are produced by the liver when glucose concentrations are high?
They are packaged as VLDL and used elsewhere
What processes are decreased in the liver when glucose concentration is high?
- gluconeogenesis
2. ketone body formation
What happens in muscle cells when glucose concentration is high?
Insulin receptors trigger the insertion of GLUT-4 into the membrane
Lots of ATP is made and less fatty acids are used in energy
What processes increase in muscle cells when insulin levels rise?
Glycogen, triglyceride and protein synthesis increase
Fatty acid storage is favoured as glucose is used to produce energy
What happens to the amount of triglyceride storage when glucose levels are high?
Triglyceride storage is increased and export of fatty acids and glycerol is reduced
What is the action of lipoprotein lipase when glucose levels are high?
Lipoprotein lipase is exported to the endothelium, where it extracts free fatty acids from VLDL
What will drive and antagonise glucagon release by alpha cells?
Glucagon release is driven by amino acids and antagonised by glucose
Where is proglucagon produced?
What can it be cleaved to?
It is produced by L cells in the small intestine
It can be cleaved differently to produce glucagon or GLP1
What is the role of GLP1?
It is a potent incretin
Glucagon itself is an incretin
At high levels, what will glucagon cause?
- lipolysis in adipocytes
2. proteolysis in muscle (releasing AA for gluconeogenesis)
Why is there never much change in peripheral glucagon concentration?
First-pass metabolism in the liver means that glucagon is largely cleared in the liver
High levels are only found pathologically
Where are the effects of glucagon targeted?
Liver
How does somatostatin affect insulin and glucagon release?
If it can get to the cells, it will inhibit BOTH insulin and glucagon release
During exercise, what will adrenaline signal for?
It signals via cAMP to enhance:
- glucose production in liver
- glycogen breakdown in muscle
- fatty acid release from adipocytes
What happens in a type 2 muscle fibre during exercise?
They use glucose to make pyruvate and lactate which are released into the circulation
What is significant about type 2 muscle fibres?
The cells can only use glucose
what happens to the pyruvate and lactate released from the type 2 cells?
What process is this part of?
They are made back into glucose in the liver
This is released back into the circulation to be used for energy
This is the Cori cycle
How will Type 1 muscle fibres use the lactate from the type 2 fibres?
They convert it to pyruvate and use it in the TCA cycle
Why is diabetes mellitus called “sweet urine”?
Failure of insulin action leads to high plasma glucose
The glucose is lost in urine, taking water with it osmotically
What are the main symptoms of diabetes mellitus?
- polyuria
- polydipsia
- weight loss
- blurred vision
- ketoacidosis
What is polyuria?
Loss of large amounts of urine due to glucose osmotically trapping the water
What is polydipsia?
The tendency for diabetics to drink lots of fluid to make up for the loss of water
Why does diabetes (type 1) cause weight loss?
A lot of energy is lost through excretion of sugar
When there is no insulin, ketone body production begins
This worsens weight loss as fats are burnt as well as sugar
What is the underlying mechanism of type 1 diabetes?
There is an inability to produce (enough) insulin
What causes type 1 diabetes?
It is an autoimmune disease in which beta cells are destroyed
What does excess glucagon in type 1 diabetes lead to?
- lipolysis
- proteolysis
- gluconeogenesis and ketogenesis in the liver
Why is type 1 diabetes referred to as “starving in the midst of plenty”?
There are lots of foodstuffs in the circulation, but the cells cannot use them due to the lack of insulin
What is the primary defect of type 2 diabetes?
Impaired cellular response to insulin
This is due to receptor down-regulation or reduced signalling
How do plasma insulin levels vary in type 2 diabetes?
There are initially high plasma insulin levels
Eventually the cells become exhausted and insulin levels fall
How is type 1 diabetes treated?
What are the issues with this?
They are injected with insulin
There are timing issues with balancing diet and insulin
There is a risk of hypoglycaemia which can be fatal
How is type 2 diabetes treated?
- diet and exercise
- drugs to enhance insulin secretion
- drugs to enhance insulin sensitivity
- drugs to inhibit gluconeogenesis
What is the role of sulphonylureas and incretins in type 2 diabetes treatment?
They enhance insulin secretion
Sulphonylureas block the K+ channel to depolarise the cell
What type 2 diabetes drug can no longer be used?
Pioglitazone (enhances insulin sensitivity)
What is the only type 2 diabetes medication that does not cause weight gain?
How does it work?
Metformin
It tells cells they are dying of starvation as there is lots of AMP present
Why do type 2 diabetes treatments often cause weight gain?
Increasing insulin leads to increased fat storage
