glucose homeostasis

Question 1

glucose as an energy source

Answer 1

all tissues use glucose as their primary energy source, nut most can use other energy sources as well
- CNS can’t substitute glucose - delivery essential

Question 2

what do we use to store glucose when blood glucose concentration is in excess

Answer 2

we can use glycogen to store glucose and this happens particularly in the liver and muscle
- this happens through a process known as glycogen synthesis .
- when glucose is in excess the glycogen synthase enzymes will become active and will start to make glycogen which will be stored mainly in the muscle and in the liver,

Question 3

what happens when there is a lack of blood glucose concentration in the blood

Answer 3

we can produce glucose in the body and there’s two different ways of doing this.
It’s known as endogenous glucose production and it mainly occurs in the liver but it also happens in other tissues where you’ve got glycogen stored.

Question 4

glycogenolysis

Answer 4

h involves two different enzymes glycogen phosphorylase and glycogen debranching enzyme
- What these enzymes do is break down that storage of glycogen to release glucose back into the blood.

Question 5

gluconeogenesis

Answer 5

this occurs in the liver and the liver produces new molecules of glucose from its constituent parts.

Question 6

normoglycaemia

Answer 6

a healthy person with normal blood glucose concentrations.
- In the fasted State is between four to six millimoles per liter of glucose in the blood.
- but after a meal the normal increase that you would see would be up to around eight or nine millimoles per liter.
○ that’s what we call the postprandial glucose concentration.

Question 7

what happens if the blood glucose concentration gets too low

Answer 7

we develop a condition known as hypoglycemia
- and hypoglycemia is that if your blood glucose concentration goes below 3 millimoles per litre,

Question 8

hyperglycaemia

Answer 8

if our blood glucose concentrations are not well controlled we can develop hyperglycemia
- and this is where the blood glucose concentrations are Sustained above 10 millimoles per litre.
- diagnosis of diabetes occurs once you reach 11 millimoles per liter and that is sustained.

Question 9

where is glucose coming from and where is it going

Answer 9

the inputs to the glucose come from food intake, glucose uptake in the body, glucose production, and glucose reabsorption in the kidney as well (take in around 160g of glucose per day)
- and the things that help us to get rid of it are energy expenditure and glucose utilization by the body
- and then any excess glucose would be lost in the urine (only about 0.3g)

Question 10

hormones which control blood glucose regulation

Answer 10

Insulin and glucagon and these hormones act on three key tissue types which are the liver and muscle and also the adipose tissue

Question 11

why is adipose tissue important for gluconeogenesis

Answer 11

the adipose tissue is important because it’s able to break down to form the two ingredients that the body then uses to form new glucose.

Question 12

too much insulin production

Answer 12

what would happen if you produce too much insulin, is that as well as pushing that person towards Normo glycemic, it could actually continue and mean that the person develops hypoglycemia
- and that is what happens in a rare disease called congenital hyperinsulinism

Question 13

too much glucagon production

Answer 13

• if a person has low blood glucose concentrations glucagon will come along and attempt to raise the blood glucose concentrations, but if that persists for a long time or if you don’t get rid of the glucagon, It’s actually going to push that person from normal glycemia to hyperglycemia.
  
  • And this is something that does occur in diabetes.

Question 14

control of blood glucose - fasted situation

Answer 14

• you get a reduction in insulin secretion because there’s no glucose floating around
• we’ve also got an increase in glucagon secretion.
• the glucagon will act on the liver to increase endogenous glucose production. and that could be through the breakdown of glycogen or it could be through gluconeogenesis.
• And that will increase the blood glucose levels so that the brain tissues will get their glucose requirement.

Question 15

control of blood glucose - fed situation

Answer 15

• in the FED situation the blood glucose concentration is going to increase to 6-8 millimoles per liter,
• trigger production of insulin by beta cells
• at the same time it will reduce the secretion of glucagon
• that insulin will then act on the insulin dependent or insulin sensitive tissues - so the muscle and adipose tissue and it will cause an increase of the uptake of glucose into those tissues, Thereby reducing the blood glucose concentration

Question 16

glucagon-like peptide 1 hormone

Answer 16

• glp-1 is released from entero Endocrine cells in the gut which respond to meals passing through the system.
• glp-1 will go into the bloodstream and travel to the pancreas and hit on those pancreatic beta cells and increase the amount of insulin that’s being secreted.

Question 17

gastric inhibitory peptide

Answer 17

also released from these entero Endocrine cells and will have other effects in the islets
- in particular it will affect the alpha cells to reduce glucagon secretion

Question 18

diabetes mellitus types

Answer 18

• type 1 which is autoimmune destruction of the pancreas beta cells
• and type 2, which results from defects either in insulin release or insulin sensing and signalling
• means that the hyperglycemic person cannot get back to normal glycemia because they haven’t got the insulin.
• glucagon also continues to be secreted

Question 19

what happens if we have an excess of insulin and glucagon not being secreted at all

Answer 19

that will lead to a severe state of hypoglycemia.

And we see this in the disease congenital hyperinsulinism which is a very rare disease that affects young babies.

Question 20

pancreas

Answer 20

• situated transversely across the posterior wall of the abdomen.
• 15 cm in length in the adult and weighs about 60- 100g
• it’s hidden away at the back and it’s also wrapped up in parts of the duodenum.
• pancreas can be divided up nominally into three different parts.
  ○ the head, the body and the tail
• and the pancreatic ducts run all the way through this pancreas

Question 21

islets in the pancreas

Answer 21

• The islets are like islands of Endocrine cells, which are scattered all the way through the pancreatic tissue.
  -The islets of langerhans take up about 1% of the pancreatic Mass and The other 99% is the exocrine tissue - the acinar cells and the ducts.

Question 22

cells in the islets

Answer 22

-pancreatic beta cells - the ones that produce insulin
- the pancreatic alpha cells which are the ones that produce glucagon
- Pancreatic delta cells - produce a hormone called somatostatin
- Epsilon cells which secrete ghrelin
- and the pancreatic peptide cells which secrete pancreatic polypeptide

Question 23

function of delta cells producing somatostatin

Answer 23

These Delta cells will produce somatostatin and that somatostatin probably doesn’t really go into the general circulation but is used within the islets as a mechanism to control the release of insulin and glucagon from the alpha and beta cells

Question 24

why do islets of langerhans need good blood supply

Answer 24

-they are highly vascularised
-they need that really good blood supply in order to be able to respond to very small changes in blood glucose concentration.
- and these vessels are responsible for moving glucose and amino acids and hormones such as adrenaline, glp-1 and Gip throughout the islet and allowing those cells to respond to those chemical Messengers.

Question 25

innervation of islets of langerhans

Answer 25

richly innervated with sympathetic and parasympathetic nerve fibers and the enteric nervous system ○ The enteric nervous system is a direct connection from the islets to the gut and those enteric nerves will also help to control the functions of the islets of langerhans.

Question 26

blood flow in islet

Answer 26

- the blood will pass from the arterioles into the islet and through these islet capillaries and then the movement of water and fluid will pass through into lymphatic vessels and into the tiny veins which then come to the venules. And get led away from the islet - and the reason it that this flow of blood and fluid through the islet is important is because you've got to think about the paracrine and autocrine signaling that can go on in the islet

Question 27

paracrine responses in the islets

Answer 27

- insulin which will reduce glucagon secretion - Gaba which is Co released with insulin and it will reduce glucagon release - another substance that comes from the pancreatic beta cells is zinc and that can also play a role in modulating other islet cells and their hormones released - glucagon will come from the alpha cells and Prime's the pancreatic beta cells to secrete more insulin. - somatostatin from the Delta cells will reduce insulin and reduce glucagon release

Question 28

autocrine responses in the islets

Answer 28

insulin will reduce secretion of insulin from other beta cells and from itself as well

Question 29

difference in structure between human and mouse islets

Answer 29

human islets contain fewer beta cells, but many more alpha cells - humans are much more likely to be avoiding hypoglycemia - rodents have a strong core of insulin-secreting beta cells with just a few glucagon secreting cells around the edge of the islet - The mouse islet looks really tidy - It's got a very clear structure and very clear organization. - But the human islet just looks a mess.

Question 30

insulin

Answer 30

produced by the islet beta cells. - It's a single polypeptide chain, which is synthesized from the pre-pro insulin Gene to produce proinsulin - proinsulin consists of 23 amino acid peptides known as c-peptides that are linked into the two tail ends of The peptide chain which form the insulin molecule -and the two parts of the insulin molecule are connected by disulfide linkages - then the cell needs to cleave the insulin away from c-peptide

Question 31

how does the cell cleave the insulin away from the c-peptide

Answer 31

this is done by enzymes known as Pro convertase enzymes - and in the pancreatic beta cells that enzyme that's key here is pro convertase 1/3 - It will cleave the c-peptide away from the insulin within the secretory granules inside the beta cell

Question 32

c peptide metabolism

Answer 32

- c-peptide will remain in the body for a while and won't get metabolized so you can measure the c-peptide.

Question 33

insulin receptor

Answer 33

- the insulin receptor is a large multi domain tyrosine kinase link receptor. - it actually has an intrinsic tyrosine kinase activity - when insulin binds to that receptor, it goes through a conformational change and that inactive tyrosine kinase then becomes active and will phosphorylate itself. - This insulin receptor is found on many different tissues and it has a whole ton of actions that it will produce - when insulin binds the insulin receptor is going to lead to an increase in the uptake of glucose from the blood to bring the blood glucose concentrations down

Question 34

what happens when insulin binds to its receptor

Answer 34

the activation of the intrinsic tyrosine kinase and this will cause a whole bunch of second signalling to occur in the cell. ○ And this will involve pi3 kinase, pdk and AKT - on one side This is going to cause more general effects like protein synthesis, cell survival and cell proliferation

Question 35

insulin causing the translocation of glut 4 transporter

Answer 35

these are glucose Transporters that are normally held inside the cell - but when that insulin binds and sets up its signalling mechanism, it will cause the translocation of those glut 4 transporters into the cell surface membrane. - And this means that glucose can be transported into the cell through that transporter and then it will undergo metabolism to produce ATP and it will also be converted to glycogen through glycogenolysis or glycogen synthesis.

Question 36

glucagon

Answer 36

produced by the islet's alpha cells. It's synthesized from a pre-pro Glucagon Gene - once that's been produced in the cell it then needs to go through processing - these Pro convertase enzymes are responsible for chopping that peptide up into its Active forms of hormone - this is pro convertase 2 - the PC2 will then cleave the pro glucagon peptide to form glucagon.

Question 37

glp - 1 pro convertase enzyme

Answer 37

glp-1 is produced from the same gene product as glucagon, but it involves the other Pro convertase enzyme - PC 13 - when that Pro glucagon peptide is processed in the L cells (which produce that glp-1), It will lead to the production of glp-1

Question 38

glucagon receptor

Answer 38

gpcr linked to adenylate cyclase. - So when Glucagon binds to its receptor, it will increase cyclic AMP in the cell and that will lead to the activation of protein kinase A

Question 39

what is glucagon secretion stimulated by

Answer 39

- Glucagon secretion is stimulated by low glucose concentration - . There are also a number of other factors which will increase the secretion of glucagon ○ and those include adrenaline ○ amino acids ○ acetyl choline ○ cholecystokinin ○ and Gip

Question 40

what inhibits glucagon secretion

Answer 40

○ raised glucose concentration ○ somatostatin ○ insulin Gaba and zinc, which are all released from pancreatic beta cells will actually inhibit the secretion of glucagon. ○ Raised fatty acids will reduce glucagon ○ glp-1 ○ and Gip when it's at high concentrations will also reduce glucagon secretion.

Question 41

counter regulatory response to hypoglycaemia

Answer 41

glucagon is really critical for this - if we don't have enough glucagon We can't respond properly to hypoglycemia - glucagon binds to its receptors in the liver, cause an increase in cyclic AMP and activation of protein kinase A - this is increasing endogenous glucose production from the liver by either glycogenolysis or through an increase in gluconeogenesis

Question 42

lipolysis - counter regulatory response to hypoglycaemia

Answer 42

○ the way glucagon does This is by increasing lipolysis ○ So when you have a breakdown of the adipose tissue and an increase in lipolysis you increase glycerol and free fatty acids, and those are the constituent ingredients that are then used by the liver to increase gluconeogenesis. - glycogenolysis is more of a short term regulator of glycemia. - you're only got a Limited store of glycogen in the body and at some point that will run out

Question 43

intra islet endocrine events - low glucose

Answer 43

-low glucose is going to stimulate the pancreatic Alpha cell to produce glucagon, but what's actually going to go on in the endocrine islet itself. - that glucagon will also have an effect on pancreatic beta-cell and Prime's the beta cells ○ The beta cell is ready so that if the blood glucose concentration gets too high because of the glucagon - the alpha cells glucagon will also increase the Delta cells to secrete somatostatin ○ somatostatin is then going to have a dampening effect on the alpha cells and the beta cells to reduce the secretion of glucagon and also to hold that beta cell back and stop it from secreting the insulin that it's been preparing in response to that glucagon signal

Question 44

glucose homeostasis disorders

Answer 44

hyperinsulinism in infancy diabetes mellitus