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FTIB > systems to cells > Flashcards

systems to cells Flashcards

1
Q

what is the main energy source of the body

A

glucose

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2
Q

what is the first law of thermodynamics

A

energy cannot be created or destroyed, only transformed from one form to another

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3
Q

what does “energy needs to be balanced” mean

A

there needs to be a balance between energy usage and energy storage

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4
Q

give 3 examples of what energy is needed for

A

cell growth and division
building new molecules and replacing old ones
movement (e.g. muscle contraction is ATP dependent)

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5
Q

what is the currency of energy

A

ATP

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6
Q

in which two ways can ATP be formed

A

substrate level and oxidative phosphorylation

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7
Q

where is the energy of ATP stored

A

in the bond of the gamma phosphate - in the bond between the second and last phosphate

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8
Q

how much ATP does the average human body have

A

100-250g

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9
Q

what is the human daily requirement of ATP

A

50-75kg

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10
Q

approximately how many times a day is ATP reformed from ADP

A

1000

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11
Q

what is glucose broken down to during glycolysis under aerobic conditions

A

pyruvate

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12
Q

what is pyruvate converted to in order to enter the krebs cycle under aerobic conditions

A

acetyl coA

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13
Q

under anaerobic conditions what is pyruvate from glycolysis converted into

A

lactate

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14
Q

give two examples of how glucose is stored in the body

A

starch

glycogen

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15
Q

which tissues have an absolute requirement for glucose

A 
brain
nerves
erythrocytes 
testes 
kidney medulla
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16
Q

blood sugar levels are kept constant by a range of ……….. mechanisms

A

homeostatic

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17
Q

what happens very basically to glucose after a meal

A

glucose gets stored as glycogen in the liver and muscle cells or triglycerides in adipose tissue

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18
Q

in what form is glucose stored in liver and muscle cells

A

glycogen

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19
Q

in what form is glucose stored in fat cells/adipose tissue

A

triglycerides

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20
Q

what happens to liver, muscle and fat cells when blood glucose levels are low

A

these tissues become net exporters of glucose

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21
Q

what is hyperglycaemia

A

high blood glucose

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22
Q

what is hypoglycaemia

A

low blood glucose

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23
Q

what are the different levels of organisation involved in glucose metabolism

A

system
tissue/organ
cellular
subcellular

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24
Q

are mitochondria static

A

no they can move around the cell

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25
Q

………. can rapidly increase and decrease in size

A

lipid droplets

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26
Q

……..…. can increase in number

A

mitochondria

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27
Q

…… .…… needs to be regulated for a steady supply of glucose

A

food intake

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28
Q

what is signal transduction

A

when an extracellular signal is transformed into and intracellular response

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29
Q

what is insulin

A

a hormone released for the pancreatic B cells in response to increased blood glucose. Insulin stimulates glucose uptake from the blood and promotes storage of glucose as glycogen

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30
Q

what is glucagon

A

a hormone released from pancreatic alpha cells in response to decreased blood sugar levels. Glucagon promotes the breakdown of glycogen into glucose when it is needed

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31
Q

insulin increases glucose up take into ……. and ……… cells

A

fat and muscle

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32
Q

insulin increases ………… ………… in the liver

A

glycogen synthesis

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33
Q

insulin inhibits ………….. in the liver

A

gluconeogenesis

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34
Q

insulin signals the fed/fasted state and the removal/addition of glucose from/to the blood

A

fed

removal

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35
Q

glucagon/insulin stimulates gluconeogenesis

A

glucagon

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36
Q

glucagon inhibits …… ……. in the liver

A

glycogen synthesis

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37
Q

glucagon/insulin triggers lipid breakdown

A

glucagon

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38
Q

glucagon/insulin stimulates the release of glucose into the blood

A

glucagon

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39
Q

when someone is the starved/fed state they undergo gluconeogenesis

A

starved

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40
Q

what is gluconeogenesis

A

a metabolic pathway that results in the generation of glucose from non carbohydrate substances such as lactate or amino acids

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41
Q

what is the normal blood glucose concentration

A

90mg/100ml

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42
Q

what are the steps in the homeostatic control of blood glucose, starting with eating a meal

A
  1. stimulus - rising blood glucose - e.g. after eating a meal
  2. insulin is released from the B cells of the pancreas
  3. the liver and body cells (fat and muscle) take up glucose and store it as glycogen
  4. blood glucose level declines to a set point and the stimulus for insulin diminishes
  5. homeostasis is reached
  6. stimulus - dropping blood glucose level (e.g. after skipping a meal
  7. alpha cells of the pancreas are stimulated to release glucagon into the blood
  8. the liver breaks down glycogen and stimulates the release of glucose into the blood
  9. blood glucose level rises to a set point and the stimulus for glucagon is diminished
  10. homeostasis is reached
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43
Q

where is glycogen mainly stored within the body

A

liver and muscle cells

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44
Q

around which cellular organelle are lots of glucose granules found

A

mitochondria - they are right next to the muscle fibres to provide ATP for muscle contraction

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45
Q

what is the fed state

A

high circulating glucose - after a meal

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46
Q

what is the fasted state

A

low circulating glucose - the middle of the night

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47
Q

what does glucokinase convert glucose into

A

glucose-6-phosphate

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48
Q

what converts glucose-6-phophate back into glucose

A

glucose-6-phosphatase

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49
Q

what converts glycogen into glucose-1-phosphate

A

glycogen phosphorylase

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50
Q

what does glycogen synthase do

A

converts glucose-1-phosphate to glycogen

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51
Q

what enzyme converts between glucose-6-phosphate and glucose-1-phosphate

A

phosphoglucomutase

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52
Q

which two pathways are reciprocally regulated and what does this mean

A

glycogen –> glucose-1-phosphate
glucose-1-phosphate –> glycogen
reciprocal regulation means that when one pathway is active, the other is not and vice versa

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53
Q

what is hexokinase

A

a class of enzymes that phosphorylate 6 C sugars - glucokinase in particular phosphorylates glucose, a 6 C sugar

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54
Q

what is flux through a metabolic pathway controlled by

A

regulatory enzymes

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55
Q

what mechanisms can mammalian enzymes be regulated by

A

changing the rate of biosynthesis/degradation levels
changes in activity
changes in location
reversible covalent modification

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56
Q

what effect does insulin have on the glucose-1-phosphate and glycogen conversion

A

insulin promotes glycogen synthase to convert glucose-1-phosphate to glycogen and inhibits glycogen phosphorylase which inhibits the reverse step

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57
Q

what effect does glucagon have on the glucose-1-phosphate and glycogen conversion

A

insulin promotes glycogen phosphorylase to convert glycogen to glucose-1-phosphate and inhibits glycogen synthase which inhibits the reverse step

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58
Q

give examples of types of reversible covalent modification

A

prenylation - addition of hydrophobic molecules e.g. lipids
ubiquination - addition of ubiquitin molecules
glycosylation - adding carbohydrate groups
phosphorylation - adding phosphate groups

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59
Q

what is a phosphatase

A

an enzyme that removes a phosphate from a molecule

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60
Q

what is a kinase

A

an enzyme that adds a phosphate to a molecule

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61
Q

what is phosphorylation

A

the covalent addition of a phosphate transferred from ATP by the action of a class of enzymes called kinases

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62
Q

is phosphorylation reversible or irreversible

A

reversible

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63
Q

what is the charge on a phosphate at physiological pH

A

-2

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64
Q

how can phosphorylation affect a enzyme

A

it can turn it on or off by changing its conformation because of the high charge density of the protein bound phosphoryl group

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65
Q

what do negatively charged protein bound phosphoryl groups often bind to

A

they make salt bridges with nearby positively charged arginine or lysine residues

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66
Q

what are the 2 main classes of kinase

A
  1. those that phosphorylate tyrosine residues

2. those that phosphorylate serine/threonine residues

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67
Q

what form of reversible covalent modification is a key metabolic control process in glucose metabolism

A

phosphorylation

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68
Q

what does a kinase do

A

adds phosphates

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69
Q

what does a phosphatase do

A

removes phosphates

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70
Q

glycogen synthase is turned on/off by phosphorylation by PKA

A

off - glucagon stimuli results in PKA phosphorylation and inactivation of the glycogen synesis pathway

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71
Q

what stimulates phosphorylation of glycogen synthase and glycogen phosphorylase by PKA

A

signals from glucagon

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72
Q

glycogen phosphorylase is turned on/off by phosphorylation by PKA

A

on - glucagon stimuli results in PKA phosphorylation and breakdown of glycogen to release glucose

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73
Q

although glycogen synthase is turned off by PKA phosphorylation and glycogen phosphorylase is turned on by PKA phosphorylation what is important to note about the rate that these processes are occurring at

A

glycogen synthase and glycogen phosphorylase are being phosphorylated equally, just one enzyme (glycogen phosphorylase) is turned on and the other enzyme (glycogen synthase) is turned off

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74
Q

are glycogen synthesis and glycogen degradation ever occurring at the same time

A

no - the would provide no net benefit as glycogen would be getting broken down at the same rate as it was getting made

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75
Q

glycogen synthase is turned on/off by dephosphorylation by protein phosphatase 1

A

on - insulin stimuli results in dephosphorylation by protein phosphatase 1 and activation of the glycogen synthesis pathway

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76
Q

glycogen phosphorylase is turned on/off by dephosphorylation by protein phosphatase 1

A

off - insulin stimuli results in dephosphorylation by protein phosphatase 1 and inactivation of the glycogen degradation pathway

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77
Q

what are the 5 effects of insulin

A
  1. increased activity of glycogen synthase, reduced activity of glycogen phosphorylase = net storage of glycogen
  2. gluconeogenesis is suppressed
  3. glycolysis is turned on
  4. glycolytic enzyme expression is turned on, gluconeogenic enzyme expression turned off
  5. blood glucose level falls
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78
Q

what are the 5 effects of glucagon

A
  1. decreased activity of glycogen synthase, increased activity of glycogen phosphorylase = net breakdown of glycogen
  2. gluconeogenesis is activated
  3. glycolysis is turned off
  4. glycolytic enzyme expression is turned off and gluconeogenic enzyme expression is turned on
  5. blood glucose levels rise
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79
Q

if biosynthetic and degradative pathways like glycogen synthesis and breakdown are distinct, how does this affect thermodynamics

A

if the pathways are distinct then they can both be thermodynamically favourable

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80
Q

what are the rates of chemical reactions governed by and give an example of this

A

activities of key enzymes glycogen synthesis and breakdown is regulated by phosphorylation - not mas action (the amount of substrate)

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81
Q

what is allosteric modulation

A

altering an enzymes activity by binding to a site other than the active site

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82
Q

in the case where a metabolic pathway can be reversed, hoe is this controlled

A

it will be controlled by an irreversible step

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83
Q

how do enzymes effect rate of reaction

A

they increase it by decreasing the activation energy

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84
Q

what is the rate determining step

A

the slowest step of the reaction which determines the rate at which the overall reaction proceeds

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85
Q

the rate determining step is often a key ……. ………

A

control point

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86
Q

what are the two rate limiting steps in glycolysis

A
  1. phosphorylation of glucose by glucokinase to form glucose-6-phosphate
  2. phosphorylation of fructose-6-phosphate by phosphofructokinase to form fructose-1,6-bisphosphate
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87
Q

are the 2 rate limiting steps of glycolysis reversible or irreversible

A

irreversible

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88
Q

which of the rate limiting steps of glycolysis is also a key regulatory step

A

fructose-6-phosphate phosphorylation to produce fructose-1,6-bisphosphate

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89
Q

why are the rate limiting steps of glycolysis irreversible

A

because they coupled with hydrolysis of ATP

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90
Q

enzymes can be controlled by allosteric interactions with other molecules - what can these other molecules be

A

other molecules and intermediates downstream in the pathway

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91
Q

molecules which potentiate ……. …….. will often be negative regulators of the other ………..

A

one direction - e.g. glycolysis

direction e.g. gluconeogenesis

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92
Q

what type of hormones are insulin and glucagon

A

they are polypeptide hormones and they are both released from the pancreas

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93
Q

where are the receptors for insulin and glucagon located

A

they have different receptors enriched in the muscle, fat and liver cells

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94
Q

what disease is now classified as a silent epidemic

A

diabetes

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95
Q

what percentage of deaths globally can be attributed to diabetes each year

A

9%

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96
Q

what are some complications that can occur with diabetes

A

macular degeneration - can make you blind due to high blood glucose concentration
major cause of heart disease and atherosclerosis
leading cause of stroke
affects peripheral circulation
can have a severe mental impact

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97
Q

what are some reasons for the increase in the prevalence of diabetes

A

lack of exercise
poor diet - westernised diet
type of work - less manual work now than previously

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98
Q

out of diabetes as a total what is the prevalence of T1D

A

10%

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99
Q

out of diabetes as a total what is the prevalence of T2D

A

90%

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100
Q

outline the cause of T1D

A
  • pancreatic B cells destruction
  • autoimmune/idiopathic
    it is caused by pancreatic B cell destruction due to an autoimmune process of unknow aetiology
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101
Q

outline the cause of T2D

A
  • insulin resistance
  • B cell dysfunction
    results from a defect in insulin action almost always with insulin resistance as the root cause
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102
Q

is diabetes a disease of the overweight

A

no you can be skinny and diabetic

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103
Q

which ethnicities are more likely to get diabetes

A

1/2 of all south Asian, black African, African carribeans will develop T2D by the age of 80
20% of all Europeans will develop T2D by the age of 80
south Asian men are typically 5 years younger on diagnosis compared to all other ethnic groups

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104
Q

what causes the differences in diabetes prevalence in different ethnicities

A

genetic predisposition

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105
Q

which part of the pancreas connects to the small intestine

A

the pancreatic duct

106
Q

what is most of the pancreas made up of

A

acinar cells

107
Q

what do acinar cells do in the pancreas

A

they produce and secrete digestive enzymes into the pancreatic duct which aid digestion

108
Q

which cells of the pancreas secrete hormones

A

islet cells - the beta and alpha cells are found in the islet cells - these cells secrete hormones

109
Q

why are the islet cells of the pancreas highly vascularised (surrounded by blood vessels)

A

so they can sense changes in the blood glucose levels and so the can release insulin ad glucagon into the blood

110
Q

mature insulin mRNA encodes what

A

pre-proinsulin polypeptide

111
Q

how many exons and introns does insulin pre-mRNA have

A

3 exons

2 introns

112
Q

what was the first sequenced protein

A

insulin

113
Q

what is pre-proinsulin made up of

A

signal sequence
polypeptide A
polypeptide B
connecting peptide

114
Q

which parts of pre-proinsulin are part of the final insulin product

A

polypeptides a and b

115
Q

what happens during the conversion of pre-proinsulin to proinsulin

A
  1. the signal sequence is cleaved off

2. disulphide bond form between polypeptide a and b

116
Q

is proinsulin the active product

A

no further modifications are required

117
Q

what happens during the conversion of proinsulin to mature insulin

A

the connecting polypeptide is removed leaving the a and b polypeptides connected by disulphide bonds

118
Q

highlight the steps in the production of insulin from start to finish and transport to the ER

A
  1. ribosome on rough ER sees mRNA and begins to read along
  2. signal sequence emergence triggers a translational pause signal to the ribosome and it arrests
  3. the signal sequence is recognised by an SRP receptor on the ER which holds the signal sequence really tightly
  4. the SRP passes the ribosome to a complex of proteins called the sec61 translocon complex which acts as a gateway into the lumen of the ER
  5. translocation resumes and the signal sequence is cleaved off by the signal sequence peptidase complex
  6. translocation continues into the ER lumen
  7. the insulin peptide is co-translationally passed into the ER.
119
Q

what does SRP stand for

A

signal recognition particle

120
Q

why don’t we just make insulin in the cytoplasm

A

the disulphide bonds that hold insulin together make it very stable. The ER lumen environment is required to maintain this stability in order for the hormone to be released into the blood stream
the blood is a really inhospitable environment for proteins because it contains a lot of proteolytic enzymes. So any kind of hormone need to be stable to be entered into the blood and the ER lumen is the only place that provides the right environment
proinsulin insulin will only fold and be oxidised in the lumen of the ER

121
Q

do disulphide bonds form in reducing or oxidising environments

A

they form in oxidising environments and lose their stability and ability to form in reducing environments such as the cytosol. The ER lumen however is an oxidising environment.

122
Q

what is the translocon sec61 complex

A

a tunnel through which the growing polypeptide chain can pass into the ER

123
Q

when is the signal sequence cleaved

A

as soon as translation is restarted

124
Q

where is pre-proinsulin made

A

the ribosomes of the rough ER

125
Q

membrane bound compartments ………… different reactions and functions

A

compartmentalise

126
Q

during exocytosis what happens to the vesicle membrane

A

the inside of the vesicle becomes the outside of the call

127
Q

what was the palade study

A

use of radioactive amino acids to look at transport through cells
during the experiment - radioactive amino acids were tracked and found to move from the rough ER and the Golgi apparatus

128
Q

what is a lysosome

A

cell organelle containing degradative enzymes

129
Q

what is an endosome

A

cell organelle that serves as a temporary vesicle for transportation

130
Q

how do macromolecules move through the secretory pathway

A

via vesicular transport

131
Q

vesicles bud off from the ER and keep the protein inside the membrane bound compartment - what is this process called

A

exocytosis

132
Q

does insulin ever see the cytoplasm

A

no - it is transported in vesicles which allow it to avoid the reducing environment

133
Q

where can vesicles be targeted

A 
the cell surface 
cytoplasm 
endosome 
lysosome 
etc
134
Q

where are vesicles targeted in the case of insulin

A

they are targeted to the secretory granules

135
Q

where is pre-proinsulin translated and what happens to it as it is translated

A

it is translated on ribosomes in the rough ER and as it is translated it is inserted into the ER lumen

136
Q

describe the processing that occurs once the pre-proinsulin has been inserted into the ER lumen

A
  1. the signal sequence is cleaved by signal peptidase
  2. disulphide bonds form between the A and B chains, stabilising the 3D structure
    WE NOW HAVE PROINSULIN
  3. proinsulin traffics to the Golgi via vesicular transport
  4. once trafficked through the Golgi proinsulin is packaged into secretory granules
  5. proinsulin is cleaved into insulin and c-peptide by enzymes called prohormone convertase PC1/3 and PC2 and carboxypeptidase E removes basic residues at the c terminus
    WE NOW HAVE INSULIN
  6. high levels of insulin are packaged into secretory vesicles by making a crystalline complex with Zn ions which are selectively pumped into the secretory vesicles
137
Q

what is the net result of have the crystalline complex in secretory granules

A

we get very high insulin concentrations in specialised packages

138
Q

in response to a suitable signal, secretory granules fuse with the …………… ………………….. and release their content

A

plasma membrane

139
Q 
for each of the locations what stage of insulin do we have 
nucleus 
rough ER 
Golgi 
immature secretory granules 
mature secretory granules
A

nucleus - pre-proinsulin gene and mRNA
rough ER - pre-proinsulin –> proinsulin
Golgi - proinsulin
immature secretory granules - insulin
mature secretory granules - insulin (hexamer/ZN crystal)

140
Q

what is the difference between immature and mature secretory granules

A

the secretory granules mature when the crystalline structure forms

141
Q

why is it important that insulin isn’t active until it reaches its final form

A

because if miss trafficking occurred the released substance would not be biologically active and so would not cause any harm

142
Q

compartmentalisation leads to specialisation and hence ……..…………..

A

greater efficiency

143
Q

what is insulin released in response to

A

secretagogues - substances that promote secretion
elevation of blood sugar is the main physiological trigger
insulin is released as a response to increased ATP concentration from respiration in beta cells

144
Q

the ability of a cell too sense extracellular glucose concentration and adjust …………………… are in direct proportion

A

intracellular metabolism

145
Q

what is GLUT2 and where is it expressed

A

it is a low affinity glucose transporter expressed in beta cell plasma membrane and in liver cells

146
Q

why does glucose interact with water

A

because it is polar - they form H bonds with each other

147
Q

why is it important the glucose and water interact

A

glucose needs to be dehydrated to pass through a highly hydrophobic core in order to pass through the membrane
once passed through, glucose is rehydrated on the other side of the membrane

148
Q

what kind of transporters and glucose transporters

A

facilitative diffusion transporters - molecules move down their concentration gradient with the help of the transporters

149
Q

what is the alternating conformation model

A

the glucose transporter oscillates between 2 conformational forms

150
Q

what are the differences between transporters and channels

A

transporters mediate movement of one solute molecule at a time
channels open and allow for flow of many ions quickly
transporters are faster than channels
they have different structures but both have cores with favourable environments for the solute

151
Q

how many different GLUTs are there

A

12 in the human genome

152
Q

what is a voltage gate

A

they gate channels and are sensitive to changes in membrane potential of the cell. changes in membrane potential can open or close a channel

153
Q

what is a Michalis menten curve

A

a curve that shows the reaction velocity with respect to concentration

154
Q

what is Km

A

the substrate concentration that produces 1/2 Vmax

155
Q

low Km = …………… affinity

high Km = ……………. affinity

A

high

low

156
Q

GLUT2 is low/high affinity

A

low

157
Q

GLUT3 is low/high affinity

A

high

158
Q

in most cells [ATP} is invariant but this is not the case in what type of cells

A

beta cells of the pancreas

159
Q

glucose metabolism in beta cells is inefficient and as a result beta cells respond to changes in extracellular glucose concentrations by rapidly changing what

A

[ATP/ADP] ratio

160
Q

what enzyme is used for glucose phosphorylation in beta cells

A

glucokinase - a low affinity/high Km enzyme

161
Q

glucokinase is not saturated at physiological [glucose], what does this result in

A

phosphorylation rate by glucokinase is directly proportional to intracellular glucose concentration

162
Q

what does glycolytic rate depend on

A

glucose entry/[blood glucose]

163
Q

where is GLUT2 found

A

liver, pancreas, kidney, enterocytes

164
Q

where is GLUT3 found

A

brain and other tissues

165
Q

list the 3 main GLUT transporters in order of increasing Km and decreasing affinity

A

GLUT3 (low) , GLUT4 (intermediate), GLUT2 (high)

166
Q

where is GLUT4 found

A

in insulin sensitive tissues - fat and muscle

167
Q

what does the low affinity of GLUT2 allow for

A

a LINEAR proportional response to changes in blood glucose levels - we want the linear portion of the curve to be sitting in our normal blood glucose range, this way deviations result in an effective linear response

168
Q

the amount of glucose brought into the cell reflects the amount of glucose in the …………..

A

blood - glucose conc inside and outside of the cell are proportional

169
Q

where does GLUT2 transport glucose

A

from the outside of the cell (the blood) to the inside of the beta cells of the pancreas

170
Q

the amount of glucose coming into the bets cells proportionally increases in response to ……………………..

A

increased blood sugar concentration

171
Q

why is glucokinase used for glucose phosphorylation as opposed to other hexokinases

A

glucokinase has low affinity and the linear portion of its Michalis menten curve is within normal fasting glucose concentrations - as glucose concentrations in the cell increase, we see a proportional increase in the rate of reaction catalysed by glucokinase
other hexokinases have very high affinities (in this case glucose conc in the cell would increase but enzyme activity wouldn’t change much)

172
Q

what happens to ATP concentration when glycolysis (using glucose) increases

A

we get increased ATP (which is proportional to the amount of glucose in the blood)

173
Q

is glycolysis reversible

A

no it is irreversible because it is coupled with ATP production

174
Q

do the ATP sensitive potassium channels of beta cells ten d to be opened or closed and why

A

open as a consequence of low ATP conc - in other cells the channel is generally closed due to high ATP but because glycolysis in beta cells is less efficient these cells have lower ATP conc allowing potassium to move through the channel across the membrane

175
Q

what happens in beta cells when ATP conc starts to rise due to glycolysis of the glucose taken in from the blood

A

as the ATP conc rises, the channels close and the plasma membrane depolarises
the beta cell PM is electrically active and is polarised when the channel is open but when the K channel is closed the membrane depolarises and this electrical signal is rapidly transduced across the cell
the inside of the cells becomes more positive on depolarisation

176
Q

what happens in response the inside of the beta cell becoming more positive - depolarising

A
  1. closing of K channels due to higher ATP conc causes depolarisation
  2. voltage gated potassium channels sense the change in potential difference and open
  3. the rise in intracellular calcium leads to fusion of insulin containing secretory vesicles with the PM leading to insulin release from the cell
177
Q

describe the state of the potassium and calcium channels when glucose is present and absent

A

present - K closed, Ca open

absent - K open, Ca closed

178
Q

what is the potassium channel sensitive to

A

ATP conc

179
Q

what is the calcium channel sensitive to

A

voltage

180
Q

in what two ways is the release of insulin from the cell controlled

A

by hormonal and neuronal regulatory systems

181
Q

where is the only place that insulin is correctly processed

A

the secretory granules

182
Q

where are the secretory granules waiting before release of insulin out of the cells

A

they are lined up at the PM and some are already docked

183
Q

where are the calcium channels located

A

right next to the docked secretory granules, generating a rapid influx of calcium in exactly the right place

184
Q

how many secretory granules are already docked before the calcium signal and how many are waiting to be docked

A

600 already

2000 waiting

185
Q

what are the 3 types of pancreatic cells that interact with each other in clusters

A

beta, alpha and delta

186
Q

where are beta cells found

A

in the islets of the Langerhans of the pancreas

187
Q

what does a single islet contain

A

beta, alpha and delta cells

188
Q

what islet cells coupled with

A

they are couple by gap junctions and paracrine signals to promote coordinated oscillatory insulin output

189
Q

how do islets signal to each other

A

they have neuronal and hormonal connections

190
Q

what is meant by release of insulin in waves

A

one islet cluster releases then another cluster releases afterwards

191
Q

what kind of receptor is the insulin receptor

A

a ligand activated tyrosine kinase

192
Q

when insulin is released, where is it targeted and why

A

fat, liver and muscle cells because these tissues have the insulin receptor

193
Q

describe the structure of the insulin receptor

A

it is an alpha2beta2 polypeptide held together by disulphide bonds (alpha on the outside and beta on the inside of the membrane)

194
Q

what happens when insulin binds to its receptor

A
  1. insulin binds to the alpha subunits inducing a conformational change which is transmitted to a the beta subunits
  2. this activates an intrinsic tyrosine kinase within the cytosolic domain (phosphorylates tyrosine aa)
  3. this kinase then phosphorylates many target molecules (one insulin molecule activates a large response)
  4. the tyrosine kinase of the receptor phosphorylates specific residues within the receptor (auto-phosphorylation)
  5. these phosphorylated residues recruit signalling molecules (IRS-1 - insulin receptor substrate 1) to the receptor which are then themselves phosphorylated and the p-tyrosines become docking sites for other proteins which are recruited to the receptor, forming a signal complex
  6. phospho-tyrosine residues from autophosphorylation are recognised by specific proteins: SH2 and PTB (IRS1) domains. this recruits a specific set of target proteins (often phosphorylated by the activated receptors) to the activated receptor to form an active signalling complex
  7. SH2 domain containing proteins are then activated and signals are propagated
195
Q

what are the two main classes of kinase

A

those that phosphorylate tyrosine residues and those that phosphorylate serine/threonine residues

196
Q

what happens to phosphorylated residues of the insulin receptor

A

they become docking sites for other signalling molecules and docking sites recognise p-tyrosine not regular tyrosine

197
Q

are all SH2 domain containing proteins the same

A

no they all bind p-tyr but they are distinct
all SH2 domains have a pocket into which the p-tyr residue fits but not all SH2 domains bind all p-tyr residues, there is specificity dictated by the surrounding sequence in the receptor

198
Q

what is the 2 pronged plug concept

A

pocket 1 - SH2 pockets contain positive residues which interact with negative phosphates. if the tyrosine isn’t phosphorylated the affinity for the pocket is gone
pocket 2 - e.g. a hydrophobic pocket which recognises isoleucine and is specific

199
Q

summarise the assembly of the insulin receptor signalling complex

A
  1. insulin binds to receptor
  2. autophosphorylation of specific tyrosine residues
  3. results in recruitment of SH2 domain containing proteins to the receptor, different receptors recruit different proteins
  4. different SH2 domain containing proteins recognise p-tyr in different sequence contexts - specificity
200
Q

what is a signalling complex

A

multiple proteins assembled with the correct spatial and temporal coordinates

201
Q

what is Akt

A

a serine/threonine kinase activated by insulin

202
Q

compare glucose uptake with insulin concentration between diabetics and non diabetics

A

in T2D glucose uptake still increases with increasing insulin concentration but less glucose is taken up compared to that in non diabetics

203
Q

what is GLUT4

A

a specialised glucose transporter expressed only in fat and muscle cells

204
Q

when does GLUT4 move to the surface of the cell

A

in response to insulin binding too its receptor and the movement is induced by cAkt

205
Q

where is GLUT4 contained before implantation into cell membranes when insulin is not present

A

in secretory vesicles

206
Q

what is trafficking of GLUT4 secretory vesicles to the fat and muscle cells membranes triggered by

A

cAkt

207
Q

once glucose has made its way into the cell via GLUT4, it can undergo ………..

A

glycolysis

208
Q

describe the process of GLUT4 delivery to cells

A
  1. delivery of GLUT4 to the cell surface requires Akt which is produced in response to insulin binding to its receptor
  2. in response to these signals, regulated exocytosis of GLUT4 containing vesicles delivers cargo to the plasma membrane in response to a specific signal.
209
Q

what is Akt

A

a serine/threonine kinase - there are 2 Akts (1 and 2)

210
Q

what do inhibitors of Akt do

A

they decrease GLUT4 recruitment

211
Q

insulin inhibits lipolysis, what is this

A

hydrolysis of lipid triglycerides

212
Q

what promotes lipid drop formation in fat cells

A

insulin

213
Q

what is the effect of cAkt in fat, liver and muscle cells

A

fat cells - activates GLUT4 trafficking to the cell surface
liver/muscle cells - phosphorylates and activates phosphatase, promoting glycogen storage

214
Q

how does insulin control gene expression

A

through IRS1 it signals to transcription factors

215
Q

which transcription factor does insulin activate in liver and fat cells

A

LxR

216
Q

what does activation of LxR tf by insulin trigger

A

expression of SREBP1 in fat cells which is involved in lipogenesis, controls fatty acid synthase, acetyl coA carboxylase, lipid metabolism genes are turned on

217
Q

……..….. ………… enters the lipogenesis pathway and is converted to triglycerides

A

acetyl coA

218
Q

LxR drives the genes involved in lipogenesis to be turned on, what are these genes

A

acetyl coA carboxylase
fatty acid synthase
SCD1

219
Q

other than insulin, what else regulates SREBP1 and LxR

A

oxidative stress and nutrients

220
Q

what is a promotor region involved in

A

driving transcription - the sequences are recognised by tfs

221
Q

what affect does a transcription factor binding to binding sites have

A

it either upregulates or downregulates transcription

222
Q

what do activators do

A

they help tf and RNA pol. assemble –> transcription

223
Q

what do repressors do

A

block tf and RNA pol. assembling –> no transcription

224
Q

define endocrine

A

relating to or denoting glands which secrete hormones or other products directly into the blood

225
Q

define paracrine

A

relating to or denoting a hormone which has effect in the vicinity of the gland secreting it

226
Q

define autocrine

A

denoting or relating to a cell produced substance that has an affect on the cell by which it is secreted

227
Q

what are the problems with being fat

A

lots of subcutaneous fat - difficulties with mobility
visceral fat - dangerous for internal organs
risk of stroke, liver disease and T2D increased
increased risk of osteoarthritis due to additional strain on joints causing loss of cartilage and grinding bones

228
Q

describe the mouse genetic model study

A

mutant strain of mice arose randomly and rapidly put on weight and become profoundly obese
they eat excessively and in an uncontrolled manner
the mutated gene encodes a hormone called leptin
leptin is made mainly in fat cells and regulates feeding by signalling to the hypothalamus to control food intake
the mutant mouse doesn’t make leptin so doesn’t control food intake

229
Q

where is grehlin secreted from

A

the stomach

230
Q

where is leptin secreted from

A

adipose tissue

231
Q

what did prof steve bloom make

A

an injection that contained a cocktail of adipocytokines (cytokines secreted by adipose tissue) that could be given monthly that mimicked gastric band surgery

232
Q

what are the effects of gastric band surgery

A

reduces the volume of the stomach
increased levels of satiety hormones
preference to eat less fatty foods

233
Q

if leptin is secreted by fat, obese people have more fat deposits so should secrete more leptin so why are they obese

A

this suggests that obesity might be associated with leptin resistance

234
Q

what are endocrine cells

A

cells responsible for producing and releasing hormone molecules into the bloodstream and are typically grouped in organs referred to as endocrine glands

235
Q

what are neuroendocrine cells

A

cells that receive neuronal input and release hormones into the blood

236
Q

what are enteroendocrine cells

A

they secrete multiple regulatory molecules which control physiological and homeostatic functions, particularly postprandial secretion and motility
these cells can detect contents of the gut and are located on the villi of intestines along with enterocytes

237
Q

what is grehlin

A

a circulating hormone produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a “hunger hormone” because it increases food intake.

238
Q

what is leptin

A

a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate energy balance by inhibiting hunger, which in turn diminishes fat storage in adipocytes.

239
Q

what does GLP1 stand for

A

Glucagon-like peptide 1

240
Q

where is GLP1 secreted from

A

ileal L (enteroendocrine cells)

241
Q

what is GLP1 secretion dependent on

A

the presence of nutrients in the lumen of the small intestine and is released in response to major nutrients such as carbohydrates and lipids

242
Q

what is the half life of GLP1 and what enzyme degrades it

A

2 mins

dipeptidyl peptidase - 4 (DPP4)

243
Q

what does GLP1 do

A

it is a major regulator of whole body glucose homeostasis by acting both centrally (brain) and peripherally (pancreas, adipocytes, liver etc) to regulate metabolic function of the tissues
it is an anti-hyperglycaemic incretin hormone which acts on the beta cells via receptors to enhance insulin release in response to high blood sugar

244
Q

why is release of insulin when plasma glucose is in the normal range dangerous

A

it can cause hypoglycaemia but GLP1 stops this from happening

245
Q

when plasma glucose is in the normal range is GLP1 present or absent

A

absent

246
Q

what are the physiological actions of GLP1

A

potentiation of glucose stimulated insulin secretion
enhancement of B cell growth and survival
inhibition of glucagon release
gastric emptying

247
Q

summarise the effect of incretins on insulin secretion

A
  1. glucose in the lumen of the intestine stimulates secretion of incretins
  2. incretins enhance glucose dependent insulin secretion and absorbed glucose in the circulation stimulates insulin secretion by pancreatic beta cells
248
Q

what are incretins

A

a group of metabolic hormones which promote a reduction in blood glucose by several mechanisms

249
Q

how do incretins promote a reduction in blood glucose

A

they augment glucose stimulated insulin release from beta cells
they suppress glucagon release
they regulate absorption of nutrients from the gut

250
Q

what are the main incretins

A

GLP1 and GIP (gastric inhibitory peptide)

251
Q

why is incretin therapeutic use limited

A

because they have very short half lives in circulation

clinical options use other analogues that are longer lasing and research is looking into ways of inhibiting DPP4

252
Q

describe the platypus adaptation

A

they have high circulating levels of GLP1 because they lack a functional stomach. in the gut this regulates blood glucose and in the venom it fends of other platypuses
the platypus version of GLP1 has evolved o be long lasting making it desirable for T2D treatment

253
Q

describe the dolphin adaptation

A

dolphins fasted overnight exhibit blood chemistry akin to T2D
when dolphins have a fish meal they exhibit an insulin resistant response - sustained high blood glucose and insulin levels - akin to T2D
when dolphins are given a dextrose meal they have an insulin deficient response - sustained post prandial high blood glucose with no insulin - akin to T1D
they can switch easily between T1D and T2D and this could be a model for human treatment

254
Q

there are cycles of natural obesity and ……. …….. in hibernating animals

A

insulin resistance

255
Q

how do hibernating animals sense change

A

the annual cycle of bodyweight fluctuation is an intrinsic rhythm entrained by light
this depends on melatonin secretion from the pineal gland
it is independent of temp or food availability

256
Q

what happens to the liver during metabolism

A

it changes profile from carbohydrate to fat based metabolism

257
Q

what about migratory birds makes their long journeys possible

A

accumulation of large fat deposits that are selectively mobilised during the flight and used when other food supplies are absent
increase in flight muscle size
gluconeogenesis form butyrate provides glucose if levels fall

258
Q

describe the migration of the northern bald ibis

A

migrate 3000km
during take off and early flight they primarily use their carbohydrate (glycogen) stores to fuel their flying. this is a consequence of the need for more power output and higher energy expenditure during early flight
the glycogen reserves don’t last long and they become anaerobic shortly after take off
birds quickly go into fat metabolism and this continues until the end of flight

259
Q

describe the relationship between migration and the gut

A

digestive organs increase in size and capacity to convert more food into energy

260
Q

list some adaptive changes for migratory birds

A

increased muscle size and capacity for oxidative metabolism
liver metabolic profile changes
coordinate regulation of metabolic processes e.g. change in diet to aid rapid fat deposition

261
Q

how do we use our energy in a 200m sprint

A

1 sec - stored in ATP in muscles
4 sec - creatine phosphate
rest of sprint - anaerobic fermentation of glucose

FTIB (6 decks)

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