8 - Insulin

Question 1

Fasting glucose level

Answer 1

3.5-5 mmol/L

Question 2

Glucose level after meals

Answer 2

<8mmol/L

Question 3

What can the brain not do

Answer 3

Synthesise or store glucose

Extract glucose at low concentrations

Question 4

What percent of pancreas cells are endocrine and exocrine

Answer 4

Endocrine - 2%

Exocrine - 98%

Question 5

What do alpha cells produce

Answer 5

Glucagon

Question 6

What do beta cells produce

Answer 6

Insulin

in islets of langerhans

Question 7

Delta cells

Answer 7

Somatostatin

Question 8

PP cells

Answer 8

Pancreatic polypeptide

Question 9

Epsilon cells

Answer 9

Ghrelin

Question 10

Structure of insulin

Answer 10

2 chains linked by 3 disulphide bonds

Question 11

Which form of insulin is active

Answer 11

Monomer

Dimers when insulin increases

Question 12

What is the stored form of insulin

Answer 12

Hexamer

Question 13

What causes a dimer to hexamer

Answer 13

Zinc and pH

Question 14

How is insulin synthesised

Answer 14

Pancreatic B cells –> preproinsulin in ER (110) –> proinsulin (86) –> indergoes maturation into active insulin via cellular endopeptidases in golgi A
o Endopeptidases cleave off C peptide from insulin by breaking the bonds between lysine 64 and arginine 55 + arginine 31 and 32 (21+30).

Question 15

How long is preproinsulin

Answer 15

110

Question 16

How long is proinsulin

Answer 16

86

Question 17

What controls production of insulin

Answer 17

Transcription from insulin gene
mRNA stability
mRNA translation
post-translational modifications

Question 18

How does glucose enter B cells

Answer 18

via GLUT 1 (humans) 
GLUT 2 (rats)

Question 19

What is the function of glucokinase

Answer 19

Acts as the glucose sensor for insulin secretion

Question 20

When is insulin secreted

Answer 20

When the levels exceed 5mm

Question 21

What is the process of insulin being secreted

Answer 21

Glucose –> G6P –> Pyruvate (glycolysis) –> Krebs cycle –> generates ATP –> increases ATP:ADP ration in the cell –> at sub-stimulatory glucose concentrations, Katp channels open –> resting potential is maintained at hyperpolarised level –> increase in Katp closing and membrane depolarisation –> voltage gated calcium channels open –> insulin secretion

Question 22

What are the 2 phases of insulin secretion

Answer 22

1) Rapid release in response to raised BG

2) Sustained, slow release of newly formed vesicles

Question 23

What other signals can potentiate insulin release

Answer 23

Arginine
Leucine
GLP-1
Fatty Acids
Ach release via phospholipase C
CCK

Question 24

How does arginine potentiate insulin release

Answer 24

Directly depolarises the membrane

Question 25

How does leucine potentiate insulin release

Answer 25

Act through allosteric activation of glutamate dehydrogenase can be transaminated --> KIC --> Acetyl CoA

Question 26

How does GLP-1 enhance insulin secretion

Answer 26

Inhibits glucagon Promotes satiety promotes B cell differentiation and can restore their function

Question 27

How can you amplify insulin secretion with amino acids

Answer 27

Intracellular catabolism of amino acids increase ATP/ADP ratio

Question 28

Incretins

Answer 28

GLP-1 secretion | GLP-1 (7-36)/exendin-4 administration stimulates insulin secretion through GPCR-1 using glucose.

Question 29

Role of phosphorylated inositol

Answer 29

Phospholipase C cleaves PIP2 to IP3 + diacylglycerol IP3 binds to receptor protein in ER allowing for the release of calcium from ER (increases Ca --> increase insulin release)

Question 30

What activates the insulin receptor

Answer 30

Insulin IGF-1 IGF-II

Question 31

What type of receptor is insulin receptor

Answer 31

transmembrane tyrosine kinase receptor

Question 32

Activation of insulin receptor

Answer 32

Insulin binds to extracellular alpha subunit on IR Conformational change Activates tyrosine kinase within the cell Activated kinase domain autophosphorylates tyrosine residues on C-terminus of the receptor + tyrosine residues in the adaptor protein (IRS) Relocation of IRS then phosphorylation of P13K P13K activates and reloactes PIP2 to PIP3 causes change in Akt phosphorylation of downstream effectors

Question 33

What does insulin do in muscles

Answer 33

Stimulate glycogen synthesis via glycogenesis | Stimulates translocation of GLUT4 to muscles

Question 34

Function of Akt

Answer 34

increases glucose transport and glycogen synthesis - induces translocation of GLUT4 to plasma membranes - phosphorylates and inactivates glycogen synthase kinase (GSK)

Question 35

How does insulin stimulate glucose uptake into adipocytes and lipogenesis

Answer 35

Glucose used for alpha glycerol phosphate that supplies glycerol to triglycerides Insulin inhibits lipolysis - Inhibits HSL - Inhibits hydrolysis of triglycerides and FA release into blood

Question 36

Insulin function in the liver

Answer 36

``` Enhances glucose uptake increases glucokinase activity Increases glycogen synthesis (100g stored glycogen) Lipids exported as lipoproteins Insulin inhibits gluconeogenesis ```

Question 37

Other insulin function

Answer 37

``` Protein synthesis Transports AA into cells Increases translation of mRNA to new proteins Inhibits catabolism of proteins Promotes K+ uptake ```

Question 38

What occurs during a fast

Answer 38

Glycogen is broken down via glycogen phosphorylase Increase in gluconeogenesis and glycogenolysis (AA and glycerol used) Fatty acids go through B-oxidation to produce acetyl coA from acyl CoA acetyl CoA converted into ketone bodies Lactate to pyruvate via cori cycle

Question 39

what converts acetyl coa to ketone bodies

Answer 39

Thiolase | HMG CoA synthase

Question 40

How to turn off insulin

Answer 40

- 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 (acts on IRS)

Question 41

Insulin resistance

Answer 41

- Reduced response in target tissue due to the IRS phosphorylating the threonine/serine instead of the tyrosine. o Downstream activation of PI3K does not occur