Insulin

Question 1

What is the normal fasting blood glucose concentration?

Answer 1

3.5–5.5 mmol/L

Question 2

List 2 functions of the pancreas in glucose homeostasis

Answer 2

1. It regulates insulin secretion to promote glucose storage after meals
2. Regulates glucose output from the liver during fasting

Question 3

Where is insulin and glucagon synthesised?

Answer 3

In the pancreas within the islets of Langerhans

Question 4

Which cells form the endocrine part of the pancreas? What percentage of the pancreas is composed of the endocrine portion?

Answer 4

Islets of Langerhans

2%

Question 5

There are 5 main types of islets of langerhans cells. List them and state what they produce.

Answer 5

Alpha cells producing glucagon
Beta cells producing insulin

Delta cells producing somatostatin

PP cells producing pancreatic
polypeptide

Epsilon cells producing ghrelin

Question 6

Describe the structure of insulin

Answer 6

Two chains (A and B) are linked by three disulfide linkages. Two disulfide bonds, and an additional disulfide is formed within the A chain.

Question 7

Describe how the structure of insulin changes under different conditions

Answer 7

1- when insulin concentration increases monomers forms dimers

2. In the presence zinc and at specific PH dimers form hexomers

Question 8

What is the structural storage form of insulin? What happens to this structure when insulin is secreted?

Answer 8

Stored as hexamers

When secreted insulin dissociates into its monomeric form

Question 9

Which enzyme produces mature insulin? Where can it be found?

Answer 9

Carboxypeptidase E

Golgi apparatus

Question 10

Describe the steps in the synthesis of insulin

Answer 10

1. Insulin is synthesised as pre-proinsulin in Pancreatic B cells
2. After being assembled in endoplasmic reticulum pre-proinsulin is processed into proinsulin
3. Proinsulin matures into active insulin using endopeptidases within the Golgi apparatus
4. Endopeptidases remove a C peptide from insulin via breaking the bonds between lysine 64 and arginine 65 and arginine 31 and 32
5. Insulin and C-peptide is stored for secretion

Question 11

Describe the mechanism of insulin secretions

Answer 11

1. Glucose enters the pancreatic β-cells through the glucose transporter (GLUT1/2)
2. Glucokinase acts as the glucose sensor for insulin secretion
3. The Km of the glucose carrier and of glucokinase ensures that initiation of insulin secretion by glucose occurs only when glucose levels exceed ~5 mM
4. Glucose is used to produce ATP leading to a rise in the ATP:ADP ratio within the cell
5. Increased ATP/ADP ratio results in closure of the K-ATP channels and membrane depolarisation
6. Voltage gated calcium channels open. intracellular concentration of Ca2+ increases and this triggers insulin secretion

Question 12

Which molecule acts as the glucose sensor for insulin secretion?

Answer 12

Glucokinase

Question 13

Which concentration of glucose will trigger insulin secretion?

Answer 13

~5 mM

Question 14

Describe the machanism of the K- ATp channel in pancreatic B cells

Answer 14

At sub-stimulatory glucose concentrations, KATP channels are open. The resting membrane potential is maintained at a hyperpolarised level (~ −70 mV)

Increased ATP/ADP ratio results in closure of the KATP channels and membrane depolarisation

Question 15

Describe the 2 mechanisms used by pancreatic B cells to release insulin

Answer 15

Phase 1- release is rapidly triggered in response to increased blood glucose levels

Phase 2- sustained, slow release of newly formed vesicles

Question 16

Describe the effect of amino acids on insulin release

Answer 16

Intracellular catabolism of amino acids increases the intracellular ATP/ADP ratio

Leucine allostericly activates of glutamate dehydrogenase (GDH) and it can also be transaminated to α-ketoisocaproate (KIC) that is converted into acetyl-CoA

Amino acids such as arginine can directly depolarise the plasma membrane

All of this leads to increased insulin production

Question 17

List the 2 amino acids which have the most effect on insulin secetion

Answer 17

leucine and argenine

Question 18

List 5 other molecules apart from amino acids which can encourage insukin secretion

Answer 18

Gastrointestinally-derived incretins glucagon-like peptide-1 (GLP-1)

Glucose-dependent insulinotropic
peptide (GIP)

Fatty acids

Parasympathetic release 
     of acetylcholine (via phospholipase C)

Cholecystokinin
(CCK, via phospholipase C)

Question 19

Which receptor do insulin responsive cells express on there plasma membrane? What type a receptor is it?

Answer 19

IGF-I, IGF-II (insulin receptor)

Type of tyrosine kinase receptors

Question 20

What happens when insulin binds to its receptor?

Answer 20

1. Insulin binds to the extracellualr alpha portion of the reptor
2. This causes a conformational change which that activates the tyrosine kinase domain on the intracellular portion of the β subunits
3. activated kinase domain autophosphorylates Tyrosine residues on the C-terminus of the receptor as well as Tyrosine residues within the adaptor protein IRS

Question 21

Which proteins in the cytoplasm are inactive when insulin is absent? What effect does this inactivation have?

Answer 21

IRS, PI3K, Akt are inactive

Effect:
Glucose cannot enter the cell

Glucose cannot be converted into glycogen

Question 22

What type of protein are IRS, PI3K, Akt?

Answer 22

IRS- Adaptor protein
PI3K- Lipid kinase
Akt- Protein kinase

Question 23

What effect does insulin have on GLUT4?

Answer 23

GLUT4 is contained in intracellular vesicles when insulin is absent

When present insulin activtes Akt which stimulates GLUT4 translocation and insertion into the plasma membrane

Question 24

What effect does insulin have on the muscles?

Answer 24

Stimulates glycogen synthesis. Atk activated by insulin phosphorylates and inactivates glycogen synthase kinase (GSK):
this allows activation of glycogen synthase (GS)

Question 25

What effect does insulin have in adipocytes?

Answer 25

stimulates lipogenesis and inhibits lipolysis.

Insulin inhibits
hormone sensitive lipase

Question 26

List the effects insulin has on the liver

Answer 26

1. Insulin enhances glucose uptake-
   It increases glucokinase activity
2. Insulin increases glycogen synthesis
3. Insulin increases lipogenesis
4. INSULIN INHIBITS
   GLUCONEOGENESIS

Insulin increases lipogenesis
Lipids are exported as lipoproteins

Question 27

List 3 effects insulin has on proteins

Answer 27

1. promotes protein synthesis and storage
2. stimulates transport of aminoacids
   into the cells
3. It increases translation of mRNAs for new proteins
4. It inhibits catabolism of proteins

Question 28

Can the brain use fatty acids to make ATP?

Answer 28

NO

Question 29

List 4 mechanisms which can switch insulin signalling off

Answer 29

Endocytosis and degradation of the receptor bound to insulin

Dephosphorylation of the tyrosine residues by tyrosine phosphatases

Decrease in the number of receptors also leads to reduced insulin signalling

Serine/Threonine kinases reduce the activity of insulin receptor