MEH - The Endocrine Pancreas

Question 1

What two functions does the panccreas have?

Answer 1

Exocrine (lipase amylase/alkaline secretions etc) and Endocrine (insulin glucagon)

Question 2

What part of the pancreas produces hormones? How much of the pancreas does this take up?

Answer 2

Islets of langerhans

1%

Question 3

What are islets of langerhans made up of?

Answer 3

75% beta cells - insulin
20% alpha cells - glucagon
some others

Question 4

How are alpha/beta cells suited to hormone production (5)?

Answer 4

• Rough ER for protein synthesis (peptide hormones)
• Many vesicles (granules) to store hormone in ready for secretion when needed (15,000)
• Well defined golgi (post translational modification)
• Many mitochondria
• Tubules/microfilaments for transporting

Question 5

What is the structure of insulin?

Answer 5

2 polypeptide chains (alpha and beta) linked by disulphide bonds (2 for stability, 1 to create a coil), and a C-peptide that detaches

Question 6

What foods do insulin and glucagon regulate the metabolism of?

Answer 6

Carbs
Fat
Protein (Only insulin)

Question 7

What are the target tissues for insulin?

Answer 7

Liver, skeletal muscle, adipose

Question 8

What are the target tissues for glucagon?

Answer 8

Liver and adipose

Question 9

Why is plasma glucose kept within a tight range?

Answer 9

1) Brain sensitive to changes in blood glucose - glucose is an osmolite so can lead to cerebral swelling/shrinking among other things - bad

Question 10

Normal glucose range? How about immediately after a meal? What is the renal threshold for glucose? What happens after this?

Answer 10

3.3-6mmol/L (UHL)
7-8mmol/L
10mmol/L - after this glycosuria - gets excreted as kidney reaches max reabsorption rate

Question 11

Which organ uses glucose at the fastest rate?

Answer 11

Brain

Question 12

What happens to the renal threshold for glucose in pregnancy and age?

Answer 12

Age the threshold goes up

Pregnancy the threshold goes down

Question 13

Are insulin and glucagon water-soluble? How are they carried in the blood?

Answer 13

Water soluble and don’t need carrier proteins

Question 14

What is the half-life of insulin and glucagon?

Answer 14

Short - 5mins

Question 15

What kind of receptors recognise insulin and glucagon? How does the hormone become inactivated?

Answer 15

Insulin - Tyrosine kinase - on cell surface receptor - that goes on to phosphorylate things when insulin bound. Insulin+receptor can be internalised and this will inactivate

Glucagon - GPCR

Question 16

Name some enzymes that insulin activates/inhibits in carb/fat metabolism

Answer 16

Insulin activates glycogen synthesise PFK and pyruvate dehydrogenase, and inactivates and hormone-sensitive lipase.

Question 17

How is pre-pro-insulin modified to mature insulin?

Answer 17

Pre pro insulin enters ER –> becomes pro insulin (signal peptide cleaved off)
Pro insulin folds to ensure correct disulphide bonds are formed
Pro insulin goes to golgi to be packaged into vesicles
In the vesicles the C peptide is cleaved off
= mature insulin + C peptide

Question 18

How can C peptide be used in monitoring of insulin dependent diabetic patients?

Answer 18

As it is released in the vesicles with insulin in equimolar amounts can be used to compare to insulin to see whether there is any endogenous insulin being secreted.

Question 19

What is insulin stored as in the vesicle?

Answer 19

crystalline zinc- insulin complex hexer

6 insulin around 2 zinc molecules

Question 20

How can insulin have both immediate and long term effects on target cells?

Answer 20

Immediate anabolic effects due to its action on already formed proteins e.g. enzymes.

Long term effects due to its ability to stimulate synthesis of new proteins and to stimulate DNA replication (Insulin is friends with growth hormone)

Question 21

10 Major actions of insulin on carb, lipid and protein metabolism?

Answer 21

Increase glucose transport into adipose tissue & skeletal muscle.
 Increase glycogenesis and decrease glycogenolysis in liver &
muscle.
 Decrease gluconeogenesis in liver.
 Increase glycolysis in liver & adipose tissue.
 Decrease lipolysis in adipose tissue.
 Increase lipogenesis and esterification of fatty acids in liver & adipose tissue.
 Decrease ketogenesis in liver.
 Increase lipoprotein lipase activity in the capillary bed of tissues
such as adipose tissue.
 Increase amino acid uptake and protein synthesis in liver, muscle & adipose tissue.
 Decrease proteolysis in liver, skeletal muscle & heart muscle.

Question 22

Is there a big store of insulin in the pancreas?

Answer 22

Yes daily secretion is just 15% of that stored per day

Question 23

What three groups of substances have an effect on insulin secretion?

Answer 23

Hormones - cortisol inhibits
Metabolites - glucose, AA, FAs
Neurotransmitters - NA inhibits

Question 24

Does glucagon have disulphide bonds? How is it synthesised/secreted roughly?

Answer 24

No

Pre pro glucagon –> then post translational modification to glucagon

Question 25

4 main actions of glucagon? Which organ does it have its main effect?

Answer 25

 Increase glycogenolysis and decrease glycogenesis in liver.  Increase gluconeogenesis in liver.  Increase ketogenesis in liver.  Increase lipolysis in adipose tissue. Main effect liver.

Question 26

What is the receptor for glucagon and how does it work?

Answer 26

GPCR - G alpha S ---> cAMP ---> PKA phosphorylates important enzymes in target cells Glucagon recognises low glucose in alpha-cells

Question 27

Can insulin inhibit glucagon?

Answer 27

Yes

Question 28

What are the kATP channels? How are the kATP channels regulated by metabolism?

Answer 28

K channels gated by ATP/ADP and control insulin secretion Inhibited by ATP (high energy signal) - ATP is high due to glucose being high so ATP is made. K channels shut means membrane is depolarised --> Ca channels open ---> cause insulin vesicles to fuse with membrane and release insulin Low glucose --> glucagon --> low ATP --> disinhibition of kATP channel ---> K out of beta cell = hyperpolarises cell --> no Ca in so no insulin released

Question 29

How does insulin lead to uptake and metabolism of glucose?

Answer 29

Stimulates GLUT4 transporter to translocate to cell membrane of target cell so glucose can go from plasma to cell

Question 30

Which metabolite when increased alone (e.g. just this in diet) stimulates both insulin and glucagon

Answer 30

Amino Acids - maybe survival mechanism

Question 31

What takes longer lipogenesis or gluconeogenesis?

Answer 31

Lipogenesis

Question 32

Is glucose uptake to muscle and adipose fast or slow?

Answer 32

Fast

Question 33

Is protein synthesis fast/slow/intermediate?

Answer 33

Intermediate

Question 34

What level of blood sugar indicates diabetes?

Answer 34

Random >11mmol/L | Fasting >7mmol/L

Question 35

What two reasons for Type 1 diabetes are there?

Answer 35

Its autoimmune 1) Destruction of pancreatic beta cells 2) secretory response of beta cell is abnormally slow or small = insulin deficiency

Question 36

How can a gain of function kATP mutation lead to decreased insulin secretion?

Answer 36

As less sensitive to ATP so not inhibited at high levels of glucose so insulin not released. (not autoimmune more population/mutation problem)

Question 37

How can type 2 diabetes occur? Which is the most common?

Answer 37

Normal insulin Peripheral resistance 1) Defective insulin receptor mechanism - change in receptor number or affinity 2) Defective post receptor events 3) Excessive or inappropriate glucagon secretion Insulin resistance is most common 92% of people with type 2 diabetes

Question 38

What can lead to type 2 diabetes (3)?

Answer 38

Genetics | Environment - Sedentary lifestyle/obestiy

Question 39

What happens in young (before 12 years) insulin resistance onset?

Answer 39

Initially: beta cells compensate by increasing insulin production Then: beta cells unable to maintain increased insulin --> impaired glucose tolerance Then: beta cell dysfunction leads to relative insulin deficiency --> overt type 2 diabetes

Question 40

What is the role of C peptide?

Answer 40

Protective role against vascular damage in patients with diabetes. Research into whether C peptide should added to insulin therapy due to its protective functions