Insulin

Question 1

Normal glucose before meals

Answer 1

3.5-5.5 mmol/L

Question 2

Normal glucose 2 hours after meals

Answer 2

Less than 8mmol/L

Question 3

Pancreas in Glucose Homeostasis

Answer 3

Regulation of insulin secretion to promote glucose storage after meals
Regulation of glucose output from liver during fasting

Question 4

Where is insulin synthesised

Answer 4

Islets of Langerhans

Question 5

Endocrine part of pancreas

Answer 5

2% of total pancreas mass

1-3 million islets of Langerhans

Question 6

Pancreas is primarily a

Answer 6

Exocrine gland

Question 7

PP cell

Answer 7

Produces pancreatic polypeptide

Question 8

Acinar cells

Answer 8

Exocrine

Question 9

Alpha cell

Answer 9

Glucagon producing

Question 10

Delta cell

Answer 10

Somatostatin producing

Question 11

Epsilon cells

Answer 11

Produce ghrelin

Question 12

Insulin

Answer 12

Two chain linked by 3 disulphide linkings

Monomer is its active form

Question 13

Insulin conc. increases

Answer 13

Monomers tend to form Dimers

Question 14

Presence of zinc + specific pH

Answer 14

Dimers form hexamers (storage form of insulin)

Question 15

Insulin synthesis step 1

Answer 15

Initially synthesised as Preproinsulin in pancreatic Beta cells

Question 16

Insulin synthesis step 2

Answer 16

After 5 mins of assembly in endoplasmic reticulum, preproinsulin –> proinsulin

Question 17

Insulin synthesis step 3

Answer 17

Proinsulin matures into insulin

Through action of cellular endopeptidases within Golgi apparatus

Question 18

Endopeptidases function

Answer 18

Cleave off C peptide from insulin

Break bonds between lysine 64 + arginine 65, and between arginine 31 + 32

Question 19

Mechanism of insulin secretion

Answer 19

Glucose enters Beta cell through glucose transporter GLUT1
Initiation of insulin secretion by glucose occurs only when glucose >5mM
Glucose –> G6P –> pyruvate
Pyruvate, through Krebs cycle + ETC, generates ATP
–> ATP:ADP ratio in cell rises
Results in closure of KATP channels + membrane depolarisation
Voltage gated Ca2+ channels open
–> intracellular Ca2+ rises
–> insulin secretion

Question 20

Insulin release first phase

Answer 20

Release is rapidly triggered in response to increased blood glucose levels

Question 21

Insulin release second phase

Answer 21

Sustained, slow release of newly formed vesicles

Question 22

Amino acids + insulin release

Answer 22

Mainly leucine + arginine

Intracellular catabolism of amino acids increases intracellular ATP/ADP ratio

Question 23

Leucine

Answer 23

Acts through allosteric activation of glutamate dehydrogenase (GDH)
Can also be transaminated to alpha-ketoisocaproate (KIC) that is converted into acetyl-CoA

Question 24

Arginine

Answer 24

Can directly depolarise plasma membrane

Question 25

Other molecules that stimulate insulin release

Answer 25

``` GLP1 Glucose-dependent insulinotropic peptide (GIP) FAs Parasympathetic release of acetylcholine Cholecystokinin ```

Question 26

Insulin-responsive cells

Answer 26

Express a specific receptor at plasma membrane

Question 27

Insulin receptor

Answer 27

Transmembrane receptor Belongs to large class of TKIs Activated by insulin, IGF-I, IGF-II

Question 28

Insulin receptor activation

Answer 28

Insulin binds to extracellular portion of Alpha subunits - -> conformational change - -> activates tyrosine kinase domain, residing on intracellular portion of beta subunit

Question 29

Signalling pathway activated by insulin- when NO INSULIN

Answer 29

IRS, PI3K and Akt are inactive Glucose cannot enter cell Glucose cannot be converted into glycogen

Question 30

Signalling pathway activated by insulin- when INSULIN PRESENT

Answer 30

IRS, PI3K and Akt are active (phosphorylated) Glucose can enter cell Glucose can be converted into glycogen

Question 31

Insulin + muscles and adipocytes

Answer 31

Stimulates glucose uptake GLUT4 contained in intracellular vesicles in absence of insulin Insulin-induced Akt activation stimulates GLUT4 translocation to plasma membrane

Question 32

Insulin stimulates glycogen synthesis in muscles

Answer 32

Akt activated by insulin Akt phosphorylates + therefore inactivates glycogen synthase kinase (GSK) --> allows activation of glycogen synthase --> GLYCOGENESIS

Question 33

Insulin + lipogenesis

Answer 33

Stimulates lipogenesis in adipocytes

Question 34

Insulin + lipolysis

Answer 34

Insulin inhibits hormone sensitive lipase | --> inhibits hydrolysis of triglycerides + release of FFAs into circulating blood

Question 35

Malonyl-CoA

Answer 35

Inhibits transport of FFAs into mitochondria via CPT-1 | --> inhibits Beta Oxidation

Question 36

Beta oxidation

Answer 36

FAs broken down to produce acetyl-CoA

Question 37

Insulin + liver

Answer 37

Enhances glucose uptake (increases glucokinase activity) Increases glycogen synthesis Increase lipogenesis Inhibits gluconeogenesis

Question 38

Other insulin functions

Answer 38

Promotes protein synthesis + storage Stimulates AA transport into cells Increases translation of mRNAs (synthesis new proteins) Inhibits catabolism of proteins (decreases aa release from cells) Promotes K+ intracellular uptake

Question 39

During fasting

Answer 39

No insulin secretion Glycogenolysis- breaking down of glycogen Hormone sensitive lipase no longer inhibited, so fat --> glycerol + FAs No malonyl-CoA --> FAs into cell, allows Beta oxidation

Question 40

Fasting

Answer 40

Liver releases glucose into bloodstream AAs and glycerol can be used as precursors for gluconeogenesis Lactate can be used for gluconeogenesis

Question 41

Accumulation Acetyl-CoA that can't enter TCA

Answer 41

Converted into Ketone bodies

Question 42

Ketone bodies

Answer 42

Main source of energy during prolonged fasting

Question 43

Mechanisms that can switch insulin signalling off

Answer 43

Endocytosis + degradation of receptor bound to insulin Dephosphorylation of tyrosine residues by tyrosine phosphatases Decrease in number of receptors Serine/Threonine kinases reduce insulin receptor activity

Question 44

Insulin resistance

Answer 44

Reduced response to insulin in target tissues --> hyperglycaemia + dyslipidaemia Due to tyrosine residues not phosphorylated