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Membrane Transport And Cell Signalling > Insulin Action And Signalling > Flashcards

Insulin Action And Signalling Flashcards

1
Q

What is the purpose of blood glucose homeostasis

A

To maintain blood glucose at approx 90mg/dl

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2
Q

What are the 2 main functions of the pancreas

A

Exocrine function
Endocrine function

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3
Q

Describe the exocrine function of the pancreas

A

Release digestive enzymes through ducal structures directly into the gut to help digestion

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4
Q

What is the endocrine function of the pancreas

A

Maintain blood glucose levels via the pancreatic islets

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5
Q

What are the 3 type of cells in the islets

A

Beta cells; release insulin
Alpha cells; release glucagon
Delta cells; release somatostatin

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6
Q

Why is important that the pancreatic islets have a good capillary network

A

So that they can sense changes in blood glucose rapidly and can release hormones directly into the blood stream

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7
Q

What inhibits insulin release

A

Adrenaline and somatostatin

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8
Q

What stimulates the release of insulin

A

Glucose (major regulator)
Gut hormones
Amino acids

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9
Q

What inhibits glucagon release

A

Insulin
Gut hormones
Glucose

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10
Q

What stimulates the release of glucagon

A

Cortisol
Adrenaline
Amino acids

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11
Q

Describe the process that insulin is formed

A

Pre-pro insulin -> pro insulin -> insulin + c peptide

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12
Q

How is insulin stored prior to release

A

Within secretory granules and stored as a hexatrimeric complex

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13
Q

Describe the structure of pro insulin

A

Folded in the ER to form the A chain and D chain
Disulphide binds between the A and D chains and within the A chain

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14
Q

Describe the cleavage of pro insulin to insulin

A

Cleaved at position 31 and 65 to end up with insulin (A and B chain connected via disulphide bonds) and C peptide

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15
Q

Why is C peptide a better diagnostic tool than insulin

A

Is a stable molecule with a longer half life than insulin
Will indicate if a patient can produce their own insulin

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16
Q

What happens when glucose enters a beta cell

A

Glucose converted to glucose-6-phosphate via glucokinase
Glucose 6-p undergo glycolysis -> pyruvate
Pyruvate undergoes Krebs cycle
= Production of ATP

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17
Q

What happens if the blood glucose is at a normal level

A

Not much glucose 6-p = low ATP levels
K-ATP channels channel remain open = no depolarisation = no release of insulin

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18
Q

What happens if there’s an increase in blood glucose levels

A

More glucose enters cell = more glucose 6-p
More pyruvate = higher ATP:ADP
K-ATP channel closes to the membrane potential depolarises
Ca2+ channel opens allowing an influx of Ca+ into cell
= release of insulin

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19
Q

Describe the structure of glycogen

A

Branched polymer of glucose w 14 and 1-6 glycosidic bonds

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20
Q

What is the first line of defence for declining blood glucose levels

A

Hepatic glycogen is degraded between meals

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21
Q

Why can’t muscle cells maintain blood glucose levels

A

It can’t release glucose back into the bloodstream
Only acts a store for its own tissue

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22
Q

How does the brain respond to glucose and insulin in the post prandial state

A

Doesn’t respond to insulin but has a high demand for glucose

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23
Q

How do muscle cells respond to insulin and glucose in the post prandial state

A

Wont respond to glucose unless insulin present
Will then take glucose -> glycogen via glycolysis and oxidation

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24
Q

How do adipose tissues respond to insulin and glucose in the post prandial state

A

Take in glucose and convert into triglycerides and it also signals for the tissue to take any fat in from circulation

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25
Q

How does the liver respond to insulin and glucose in the post prandial state

A

Converts glucose -> glycogen and convert surplus glucose/mono acids to lipids
Fat translocates out in lipoproteins which are taken up by adipocytes

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26
Q

What happens to excess glucose after the glycogen stores have been used up during the postprandial state

A

Glucose > pyruvate -> Krebs cycle -> citrate -> fatty acids
Modulated by insulin and is dependent on excess glucose conc

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27
Q

Why does insulin modulate the conversion of glucose -> fatty acids

A

Increases the activity of pyruvate dehydrogenase and increases the txn of a fatty acid synthase and acetyl CoA carboxylase
Drives the pathway to fatty acids

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28
Q

How does the muscles respond to insulin and glucose in the post absorptive state

A

Convert proteins into amino acids and release them into the blood stream

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29
Q

How does adipose tissues respond to insulin and glucose in the post absorptive state

A

Convert triglycerides -> fatty acids and glycerol and release fatty acids are released into the blood
Muscle cells take up fatty acids and metabolise them for fuel instead of glucose

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30
Q

How does the liver respond to insulin and glucose in the post absorptive state

A

Converts glycogen -> glucose and releases into blood
Amino acids -> glucose via gluconeogenesis
Fatty acids -> energy for its own metabolism
Fatty acids -> ketone bodies for the brain

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31
Q

Why can glucose not be taken into the cell in the absence cells of insulin

A

GLUT4 is associated w vesicles in the cytoplasm not at the plasma membrane in the absence of insulin

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32
Q

Describe what happens when insulin binds to the membrane of a muscle cell

A

GLUT4 translocation to the plasma membrane to bring glucose into the cel

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33
Q

How does insulin increase the formation of glycogen

A

Activating glycogen synthase = dephosphorylation

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34
Q

Why do muscle cells express hexakinase 1/2

A

Rapid metabolism of glucose in the cell

35
Q

Why does high glucose levels activate pyruvate dehydrogenase

A

More conversion of pyruvate -> acetyl CoA

36
Q

How does the glucose -> triglycerides in the adipose tissues

A

Glucose metabolised to pyruvate
Insulin increases the txn of fatty acids cid synthase and acetyl CoA carboxylase
Forms triglycerides

37
Q

Why do the adipose tissues convert glucose -> triglycerides

A

There is no glycogen storage only fat

38
Q

Why does insulin switch of hormone sensitive lip abase when glucose levels are high

A

Inhibit the degradation of triglycerides -> fatty acids acids that could be converted into energy

39
Q

What do the adipose tissues do with triglycerides when glucose is high

A

Lipoprotein lipase converts triglycerides -> monacylglycerol hitch Cana be taken up into adipose tissues
Can be converted into triglycerides when needed

40
Q

Why does the liver express GLUT2 instead of GLUT4

A

Has a higher affinity for glucose

41
Q

Why does the liver express glucokinase

A

Conversion of glucose -> glucose 6-P when glucose levels are high

42
Q

What effects does insulin have on the liver

A

Increases translation on glucokinase
Stimulates activity of glycogen synthase
Decreases activity of glycogen phosphorylase
Increases the txn of acetyl CoA carboxylase

43
Q

What is property of RTK receptors

A

Has tyrosine kinase activity -> it can phosphorylate tyrosine residues to evoke a cascade of effects

44
Q

Describe the PH domain

A

Pleckstrin homologous domain
Binds to phosphorylated inositol phospholipid in the plasma membrane

45
Q

Why is the PH domain important

A

Locates signal proteins to the plasma membrane

46
Q

Describe the PTB domain

A

Binds to phosphotyrosine P-Y residues

47
Q

Describe the SH2 domain

A

SRC homologous 2 domains binds P-Y readies surrounded by unique protein sequences

48
Q

Describe the SH3 domain

A

Src homology 3 domain
Binds specifically to proline rich regions

49
Q

Describe the insulin receptor

A

Tyrosine kinase receptor and part of the insulin-IGF1R
Has 2xalpha and 2xbeta subunits

50
Q

Describe the function of the IR alpha subunits

A

Sit on the membrane and bind insulin

51
Q

Describe the function of IR beta subunits

A

Transmembrane and has tyrosine kinase activity

52
Q

How do the 2 isoforms of IR happen

A

Alternative splicing

53
Q

What happens when insulin binds to the alpha subunit of IR

A

Causes transphosphorylation and activation of beta subunits and its tyrosine activity

54
Q

What happens when the beta subunit on the IR becomes phosphorylates

A

Phosphorylation of other tyrosine residues on the subunit
Exposes binding site for proteins w PTB and SH domains

55
Q

What site is phosphorylated on the beta subunit in the IR

A

Activation loop

56
Q

What happens at the juxtamembrane domain in the beta subunit on the IR

A

Phosphorylation of tyrosine residues creates binding site for PTB domain

57
Q

What happens at the C-terminal domain in the beta subunit on the IR

A

Phosphorylation of tyrosine residues creates binding site for SH2 domain

58
Q

What happens at the Ser/Thr sites on the beta subunit on the IR

A

Inhibition of receptor kinase activity when the sites have been phosphorylated

59
Q

What are the 2 adapter proteins that sit below the IR

A

She and IRS1-4

60
Q

Describe Shc

A

SH2 containing adapter proteins
Has 3 different domains; PTB, SH2 and CH1 domains
Binds to IR via PTB and SH2 domains

61
Q

What is the purpose of CH1 domain on Shc

A

Phosphorylation of tyrosine kinase uncovers binding site for proteins w an SH3 domain e.g Grb2

62
Q

What happens once Grb2 is bound to CH1

A

Conveys signal to sos which links to the MAP-kinase signalling pathway

63
Q

What is the purpose of the insulin receptor substrate IRS

A

Essential for most of insulins biological actions in the liver muscles at adipose tissues

64
Q

Describe the structure of IRS and their functions

A

PH domain; binds to a phospholipid in the plasma membrane
PTB; binds directly to PTB binding site on IR

65
Q

Why doe the IRS have a lot of tyrosine residues

A

Leads to phosphorylation of many downstream sites once bound to IR

66
Q

What sites act as positive regulators on the IRS

A

Y - phosphorylation sites
Docking protein w SH2 domain
Can bind GRB2, PI3K and SHP2

67
Q

What sites act as negative regulators on IRS

A

S/T phosphorylation sits
Phosphorylated by stress kinases activated by lipids, inflammation or components of insulin signalling a

68
Q

What happens after the IRS binds to the IR

A

Becomes phosphorylated by IR tyrosine kinase activity

69
Q

Describe the insulin signalling pathways that lead to MAP-kinase pathway activation

A

IR -> IRS -> Grb2 -> SOS -> MAPK
IR -> Shc -> Grb2 -> SOS -> MAPK

70
Q

How does Grb2 interact w SOS

A

Activated by binding to IRS or Shc allowing it to bind to SOS via SH3 domain

71
Q

How does SOS act as a GDP/GTP exchange factor (GEE)

A

Exchanges GDP for GTP on RAS to activate it

72
Q

Describe how RAS is activated and then activates ERK

A

RAS activated when its bound GTP is exchanged for GDP
RAS-GTP activates Raf
Raf activates MEK
MEK activates ERK

73
Q

How does PI-3 kinase pathway lead to activation of AKT

A

Recruitment of IRS to IR beta
Recruitment of PI3K to IRS via SH2 domains and formation of PIP3
Recruitment of AKT and PDK1 by PIP3 to plasma membrane
Phosphorylation of AKT

74
Q

How is PIP3 formed by recruitment of PIK3K

A

Activation of catalytic activity of PIP3K adds aa phosphate to inositol phospholipid in the plasma membrane

75
Q

Describe the structure of PI3K

A

Regulatory subunit p85
Catalytic subunit p110

76
Q

Describe the regulatory unit p85 on PI3K

A

Contains;
2 SH2 domains allowing it to bind to IRS
1 SH3 domain that allows it to bind to p110 subunit

77
Q

Describe the catalytic subunit p110 on the PI3K

A

Activated by interaction w the p85 subunit
When active it allows the addition of the phosphate group to the inositol rings
Allows it to localise to the plasma membrane

78
Q

What mediates the degradation of PIP3 signal

A

Phosphate and tension homologous deleted on chromosome 10 (PTEN)
Removes phosphate group from position 10

79
Q

How does PIP3 dual phosphorylate AKT

A

PIP3 activates mTORC2 and PDK1
PDK1 phosphorylates AKT on Thr308
mTORC1 phosphorylates AKT on Ser473

80
Q

What is the function of AKT once it has ben phosphorylated

A

Regulates proteins and and glycogen synthesis as well as GLUT4 translocation

81
Q

What regulates the movement of storage vesicles containing GLUT4

A

AS160

82
Q

How does AS160 regulate GLUT4 translocation

A

Maintains Rab in its GDP form
Rab requires to be bound to GTP to facilitate movement

83
Q

How does the AS160 complex become inactive

A

Phosphorylation ok AKT -> phosphorylation of AS160 complex

Membrane Transport And Cell Signalling (4 decks)

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