Control of Blood Glucose and The Endocrine Pancreas Flashcards
What maintains constant blood glucose?
What blood glucose level does it usually stay around?
Insulin maintains constant blood glucose:
Blood glucose is kept within constant limits by insulin, despite periodic intake of sugar and bursts of exercise requiring fuels
Here we can see on the glucose line, although there are fluctuations with meal, the fluctuations are not by that much, staying around 5mmol/l
Insulin (secreted from the pancreas) follows the line in a similar fashion, to bring glucose down and regulate it.
Anatomy
Where does the liver sit in relation to the portal vein?
How does liver buffer increase in blood sugar concentration?
Is pancreas more an endocrine or exocrine organ?
What constitue the endocrine part? What about the exocrine parts?
How much of the islet is beta cells? which one releases insulin and which one release glucagon?
What other hormone released from pancreas?
The liver sits at the head of the portal vein which takes 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.
The pancreas is both an endocrine and exocrine organ, with most of it being exocrine tissue which secretes digestive enzymes forming pancreatic juices into the gut.
Below we can see the arrangement of cells in the islets of Langerhans which constitute the endocrine part of the pancreas. The exocrine parts just all join up to form the pancreatic duct.
The islets form only a small part of the pancreatic mass but receive a very large part of the pancreatic blood supply.
There are a variety of cell types in the islets, but the main ones are the beta cells which release insulin and the alpha cells which release glucagon. Beta cells make up about 60% of each islet.
δ-cells: somatostatin
Synthesis of Insulin
What does the original transcript give?
What happens to it after that?
what is cleaved off to give insulin?
What stimulates the secretion of insulin?
What happens to half of the secreted insulin?
What is the more accurate index of insulin secretion? why?
Blood supplies to pancreas and venous drainage?
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
Then proinsulin has chain C removed in Golgi apparatus to give insulin -> then packaged into secretory vesicles
Insulin secretion is then stimulated by rising blood glucose levels
Half of the secreted insulin is metabolised by the liver in its first pass; the remainder is diluted in the peripheral circulation
C-peptide is more accurate index of insulin secretion in peripheral circulation (not metabolised by liver)
Pancreas supplied by branches of the coeliac, superior mesenteric, and splenic arteries.
The venous drainage of the pancreas is into the portal system.
Release of Insulin into the circulation
what is release of insulin in relation to? (threshold)
what happens once it is below threshold?
What happens to 50% of the insulin?
what else can stimulate insulin release to a certain extent?
what can modulate insulin release?
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.
To a certain extent most amino acids can stimulate insulin release (albeit to different extents). As well as non-esterified fatty acids, also called free fatty acids (NEFAs).
Secretion is also regulated by the autonomic nervous system, through sympathetic and parasympathetic mechanism.
But do remember importantly that it 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.
Factors regulating insulin secretion
stimulators and inhibitors
Insulin is secreted from B cells in the islets of Langerhans of the pancreas.
Insulin secretion is stimulated by:
• High levels of plasma glucose
• High levels of amino acids in the plasma
• Parasympathetic stimulation
Insulin secretion is inhibited by:
• Somatostatin
• Alpha adrenergic stimulation
Factors regulating glucagon secretion
stimulators and inhibitors
Glucagon is secreted from A cells in the islets of Langerhans in the pancreas.
Glucagon secretion is stimulated by:
• Amino acids
• Alpha adrenergic stimulation
• Parasympathetic stimulation
Glucagon secretion is inhibited by:
• Insulin
• High plasma glucose
• Somatostatin
How do the beta cells know blood glucose has risen?
What transporters is used?
What acts as an intracellular messenger? what does it do?
What else is needed for the release of insulin?
So as explained above, the release of insulin is a direct response by the beta cells upon high blood glucose.
As of yet no glucose receptors have been found, so how does the cell know blood glucose has risen?
The answer appears to be it is indirectly via a response to the end-products of glucose oxidation.
The beta-cell membrane has GLUT-2 transporters, so as blood glucose rises it will diffuse into the cell down its gradient.
It will enter into glycolysis and TCA cycle ultimately resulting in increased ATP (or more specifically ratio of ATP:ADP)
There is a channel in the membrane which is an ATP-sensitive K+ channel.
Then ATP acts as an intracellular messenger and closes the channel, as a result there will be depolarisation of the membrane (as K+ cannot diffuse out), membrane will become more positive
This depolarisation will result in opening of voltage-gated Ca2+ channels, which influx and act as an intra-cellular messenger causing exocytosis of vesicles containing Insulin
Effects of Insulin
- Uptake of glucose into adipose tissue, skeletal muscle and cardiac muscle
- Uptake of FFAs and amino acids in adipose and muscle tissue
- Stimulation of glycogen synthesis, inhibition of glycogenolysis
- Inhibition of gluconeogenesis, lipolysis and proteolysis
Signalling at the Insulin Receptor
Why kind of receptor is the insulin receptor? what happens when insulin binds? what is phosphorylated?
What activates many of the phosphorykation pathways?
What needs to be involved for the growth-factor like effects?
What is the overal effect? (3)
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 signalling, but the pathways are complex and intersecting.
As a result:
- There is insertion of glucose transporter into cell membrane – allowing uptake of glucose down its gradient
- Glycogen synthesis
- Gene transcription
Insulin binds to its receptor , which starts many protein activation cascades .
These include: • translocation of Glut-4 transporter to the plasma membrane and influx of glucose • glycogen synthesis • glycolysis • fatty acid synthesis
Insulin binding to its receptor activates cascades of protein phosphorylation, which stimulate or inhibit specific metabolic enzymes by phosphorylation and modulates activity of metabolic enzymes by regulating gene transcription.
How does Glucose get into cells?
GLut 2 where? affinity? dependent on what?
glut 4 where? affinity? dependent on what?
Glut 1?
Glut 3?
There are a family of glucose transporters (GLUTs)
GLUT 2 in liver, kidney, pancreas:
o Remember allows movement of glucose into pancreatic beta cells stimulating insulin release
o It is a low affinity transporter, which is good for its job as constant rate of glucose flow over a range of conc. -> so glucose dependent release
GLUT 4 in muscle and adipose tissue:
Has a medium affinity for glucose, important for removal of glucose from blood for storage -> insulin dependent uptake of glucose
GLUT 1: brain and GLUT 3 (brain) – both high affinity
Glucagon
What does it directly effect?
Why is the ratio important?
What does glucagon stimulate?
What happens if hypoglycaemia persists?
what other hormone can stimulae these processes?
How does glucagon start off and where is it cleaved? where is the gene processed differently?
Name one important one and its function.
What peptide slows the rate of gastric emptying? how does it act when you have a fatty/sugary meal?
What is another name for these gut peptides?
Glucagon’s direct effects are typically on the liver and stimulates the processes inhibited by insulin/glucose.
What does tend to be important is the ratio of insulin: glucagon, the ratio falls during the fasting state. So, there is a drop-in insulin causing a drop in the ratio,
Once you drop below 5mmol/l glucose, insulin release will stop so all the processes aiming to store glucose/remove it from the blood will stop and the reverse processes will be favoured, this prevents/limits hypoglycemia. Glucagon release will then also limit hypoglycemia.
It will stimulate:
o Glycogenolysis
o Gluconeogenesis
o Ketogenesis
If hypoglycemia persists (moving into starvation state) the sympathetic nervous system could directly cause more release of glucagon in liver and stimulation of catabolic processes in liver and other tissues -> Release of fatty acids.
Adrenaline also will be stimulating these processes.
- Glucagon release is suppressed by a rise in blood glucose concentration, while it is stimulated by amino acids
- Raised blood glucose concentrations increase the insulin: glucagon ratio. The reverse occurs when blood glucose concentrations fall
- Only direct effects of glucagon are on the liver, stimulating processes for the production of glucose: Gluconeogenesis, glycogenolysis and also ketogenesis in starvation
Glucagon is a peptide, so it starts of as pro-glucagon which gets cleaved into glucagon in the alpha cells in the pancreas.
However, the pro-glucagon gene (that in pancreas leads to glucagon), can be processed differently. In the small intestine it is processed differently to give us a range of different products.
An important one is GLP-1 (glucagon like peptide 1), it increases insulin secretion
There is another important peptide (this time not part of pro-glucagon gene) called GIP (pro-gastrointestinal polypeptide).
GIPs major effect is to slow the rate of gastric emptying, but it also potentiates insulin’s response to glucose especially when there is very fatty/sugary meal.
Another name for these gut peptides is incretins.
There are three important signalling molecules
When are they released? why does this aid the pancreas?
Where do GLP-1 and GIP bind and what is the effect of this?
why is understanding incretin action important?
what is released in response to glucose and fats in the intestine?
what degrades these peptides? what problem does this give us?
What are the two strategies for drug use?
o Glucagon
o GLP-1 is also synthesised from the pro-glucagon gene, released from gut cells having an agonistic effect on insulin release
o GIP also having an agonistic effect on insulin release
These act synergistically, their release is stimulated especially in digestion. So, they immediately prime the pancreas to be ready to deal with the increase in blood sugar.
GLP-1 and GIP bind to cell surface receptors on the beta cells of the pancreas. Their receptors have AC activity on the inside, leading to increased cAMP which then has a similar effect to ATP, in that it leads to closure of the potassium channels, causing membrane depolarisation, activation of vgCa2+ channels and hence exocytosis of vesicles.
So GLP-1 and GIP amplify insulin secretion!
Understanding of incretin action has led to new drugs in treating diabetes mellitus type II.
In response to glucose and fats in the intestine we get release of GLP-1 and GIP. These travel via the circulation to the pancreas where they potentiate insulin secretion, allowing blood glucose to swiftly be brought down.
However, these peptides are rapidly degraded by the enzyme DPP-4, so they aren’t in the plasma for long. For this reason, we cannot use the peptides themselves for drugs in order to increase insulin release.
So, the two strategies are to either:
o Find a long acting analogue (synthetic version) of GLP-1
o Or an inhibitor of DPP-4
Both of these strategies work and drugs to this have been developed. Remember this is treatment only for type II diabetes.
Diabetes
what is type 1? why won’t the incretin treatment be effective?
What is type 2? why is incretin treatment effective?
In type I diabetes mellitus is an absolute insulin deficiency due to the beta cells of the islets of Langerhans no longer work and there is no insulin secreted. Possibly due to genetic susceptibility, environmental factors (virus, dietary) resulting in/or immune (autoimmunity).
Therefore, treatment described above, which promotes insulin secretion, wouldn’t be much of use because there is no insulin released anyway nothing for them to potentiate.
Type II diabetes mellitus is an insulin insufficiency, so there is a lack of insulin and a decrease in sensitivity of tissues to insulin.
Possibly due to genetic susceptibility interacting with environmental factors (obesity, poor foetal development) or loss of receptors. So, it can be treated by potentiating insulin’s actions.
The flow of fuels depends on metabolic state
what happens after overnight fast?
what happens after brekafast?
other hromones that affect blood sugar?
After an overnight fast
o Glucose released into the circulation
o Release of free (non-esterfied) fatty acids from adipose tissue, uptake into muscle and formation of ketone bodies in liver and formation of TAG for recirculation as VLDLs
o Gluconeogenesis
Actions of glycogen prevail, needed to maintain blood sugars especially for the brain
After breakfast
o Glucose taken up into liver, muscle and adipose tissue with formation of glycogen or TAG
o Amino acids taken up into liver and muscle
o Lipolysis and proteolysis inhibited
o Ketogenesis inhibited
Actions of insulin prevail
Other hormones influencing blood sugar include o Adrenaline: mobilises o Growth hormone: mobilises o Cortisol: mobilises o Thyroid hormone *All these have glucagon like actions
Diabetic ketoacidosis
Normally ketones (acids) are buffered by the blood
In insulin deficiency (i.e. type 1 diabetes mellitus) the buffering capacity is overwhelmed
decreased serum bicarbonate
diabetic ketoacidosis
deep sighing (Kussmaul) respiration
