Lecture 9: pancreatic islet hormones

Question 1

where does blood glucose come from?

Answer 1

• the food that we eat,

- stimulates the beta cells to release insulin

Question 2

What is insulin?

Answer 2

• fuel storage hormone.

- its primary role is to decrease blood glucose and utilise this to store it.

Question 3

What is the basic effect of insulin?

Answer 3

• increases glucose uptake into muscle and fat cells
• increases the synthesis of glycogen
• prevents the breakdown of glycogen

Question 4

What is glycogen?

Answer 4

-our glucose storage format. This is stored in the liver for long term use

Question 5

When is insulin secreted?

Answer 5

• when blood glucose levels increase.
• the b cells in the pancreas respond by releasing insulin both to absolute glucose levels and changes in blood glucose levels

Question 6

What is the insulin profile of a normal person?

Answer 6

• there is always a baseline level of insulin being secreted (a baso semi state) so the body is never without any insulin release
• at the onset of glucose (due to eating a meal ) causes a very rapid insulin release. This reflects the release of stored insulin hormone in the beta cells and usually lasts 30 minutes.
• there is a secondary phase with a lower level of insulin release which is a bit more sustained. This reduces blood glucose back down to a steady state level

Question 7

What does the second insulin release reflect?

Answer 7

the release of stored insulin and the reduction of release of new inulin

Question 8

How is insulin secreted?

Answer 8

• ATP sensitive potassium channels normally let K+ outside the cell to maintain the resting potential
• glucose enters the B cells via the glut 2 transporter
• within the B cell we have increased glucose which is broken down by glucokinase to form ATP
• increased ATP shuts the ATP sensitive potassium channels by binding to them
• causes cell membrane to depolarise
• other channels present on B cells are also voltage dependent and wait for the B cell membrane to depolarise to allow an influx of calcium
• increased intracellular calcium stimulates the release of insulin from the B cell

Question 9

Which receptors does insulin bind to?

Answer 9

Tyrosine kinase receptors

• these have two homodimer components
• insulin sits in the receptor as an agonist and phosphorylates the tyrosine kinase receptor which activates a number of secondary messenger pathways which in turn activate a number of things

Question 10

What is the pathology of type 1 diabetes”

Answer 10

• type 1 is an autoimmune disease where the body’s immune system attacks and destroys B cells in the pancreas
• destruction can take several years to occur before clinical onset
• clinical onset tends to be very abrupt and sudden over a number of days
• eventually patient has no B cells left

Question 11

What is the result of patients having no B cells?

Answer 11

• they cannot produce insulin so whenever they eat food, they run the risk of hyperglycaemia
• there is no insulin to utilise and store the blood glucose
• insulin is also involved in fatty acid synthesis which cannot occur if insulin is not produced. This results in ketosis or the formation of ketones which is a metabolic crisis

Question 12

What happens if ketosis is not addressed?

Answer 12

patientscan slip into a coma and die

Question 13

How is type I diabetes treated?

Answer 13

• can only provide the patient with insulin the body is not producing
• this is dependent on the administration of exogenous insulin to maintain their blood glucose levels and prevent the formation of ketones

Question 14

Why have we changed from traditional bovine or porcine insulin to biotechnologically engineered inulin?

Answer 14

• the 1 or 2 amino acid difference between bovine or porcine insulin made it very poorly tolerated
• with genetic engineering, we can syntheticalyl form human insulin which looks and acts like the insulin the body would produce

Question 15

How is insulin delivered?

Answer 15

• cannot be done orally as most are destroyed by proteases in the GIT before it is absorbed.
• the only way at the moment is via sub cut injection
• you can also obtain jet injection systems
• some patients have an insulin pump.

Question 16

What are the developments in insulin therapy?

Answer 16

• now we have a range of different types of insulin with different duration of actions and rates of action
• humalog is rapid acting with short duration
• glargine is slow acting with a long duration of action

Question 17

What is the advantage with the variation of insulin products?

Answer 17

-allows patient to mix and match depending on what they are doing in their lifestyle

Question 18

What potential products could be produced using glucose responsive insulin release?

Answer 18

• we can have insulin being released by microgels in a controlled manner in response to glucose
• these injectable microgels contain insulin in nano-particles
• glucose comes in and is synthesised to glucomic acid which activates enzymes and releases insulin out into the capsule
• the amount of insulin release is affected by the amount of glucose entering the body
• this ensures that it is comparable to the blood glucose levels

Question 19

What is Diabecell?

Answer 19

• Living cell technologies in auckland, NZ are conidering islet cell transplantation for type 1 diabetes agents
• porcine islet cells are being transplanted and these have already gone into phase III of clinical trials
• source is a population of pigs isolated on the auckland islands for several 100 years so they do not have diseases, thus we can provide completely pathogen free cells for transplantation into patients

Question 20

What is the limitation with Dibecell porcine islet cell transplant therapy?

Answer 20

-we don’t know what causes type 1 diabetes so even if the transplantation of cells into the body was successful, these cells may also be killed off due to the autoimmune disease process

Question 21

What is the pathology of type II diabetes?

Answer 21

• patient has insulin resistance and the body does not respond to the insulin released
• the baso insulin levels would be much higher
• there is nothing wrong with the B cells

Question 22

What are the original theories regarding type II diabetes?

Answer 22

• insulin receptors deficient

- lack of numbers of insulin receptors

Question 23

What are the recent theories regarding type II diabetes?

Answer 23

• something wrong with secondary messenger pathways in the middle
• body does not respond to insulin so blood glucose is not being taken up properly.

Question 24

What are the classes of oral hypoglycaemic agents used to treat type II diabetes?

Answer 24

• sulfonylureas
• meglitinides
• biguanides
• alpha glycosidase inhibitors
• anti hyperglycaemic agents

Question 25

What are sulfonylureas?

Answer 25

- e.g. Tolbutamide. - in the absence of blood glucose, they bind to ATP sensitive potassium channels and mimicks the ATP to stimulate insulin release - In the presence of glucose, they stimulate even more insulin release - increases the utilisation of blood glucose - they also stimulate activation of GLUT4 receptor to help take up more blood glucose into muscle and fat

Question 26

What are meglitinides?

Answer 26

- e.g. glicazide. - also work on pancreas to activate insulin release - they bind on a different binding site on the ATP sensitive K channel, but achieve the same mechanism as sulfonylureas - i.e. also mimic ATP to release insulin

Question 27

What are biguanides?

Answer 27

- e.g. metformin - this stops the liver from making new glucose - activates the liver enzyme that plays an important role in insulin signalling - normally insulin would activate this enzyme, (AMP activated protein kinase) but it doesnt appear to happen in type 2 diabetes so biguanides do it instead. - also acts on GLUT 4 transporter to stimulate uptake and utilisation of glucose into skeletal muscle - often used in combination with sulfonylureas

Question 28

What are alpha glycosidase inhibitors?

Answer 28

- e.g. acarbose - alpha glyosidase is an enzyme in the intestine which promotes the absorption of carbohydrates - inhibitors prevent this and prevent the absorption of carbs - carb absorption still occurs, but much more slowly - the increase in glucose after a meal is not sudden and takes place over a much more protracted time.

Question 29

What are anti hyperglycaemic agents?

Answer 29

- e.g. Symlin, which is a synthetic version of amylin - this positively regulates B cell release of insulin - produces more insulin to help regulate blood glucose levels - injectable agent predominantly used with type II diabetics but can also be used for type I diabetics who have become slightly insulin resistant.