systems to cells Flashcards
what is the main energy source of the body
glucose
what is the first law of thermodynamics
energy cannot be created or destroyed, only transformed from one form to another
what does “energy needs to be balanced” mean
there needs to be a balance between energy usage and energy storage
give 3 examples of what energy is needed for
cell growth and division
building new molecules and replacing old ones
movement (e.g. muscle contraction is ATP dependent)
what is the currency of energy
ATP
in which two ways can ATP be formed
substrate level and oxidative phosphorylation
where is the energy of ATP stored
in the bond of the gamma phosphate - in the bond between the second and last phosphate
how much ATP does the average human body have
100-250g
what is the human daily requirement of ATP
50-75kg
approximately how many times a day is ATP reformed from ADP
1000
what is glucose broken down to during glycolysis under aerobic conditions
pyruvate
what is pyruvate converted to in order to enter the krebs cycle under aerobic conditions
acetyl coA
under anaerobic conditions what is pyruvate from glycolysis converted into
lactate
give two examples of how glucose is stored in the body
starch
glycogen
which tissues have an absolute requirement for glucose
brain nerves erythrocytes testes kidney medulla
blood sugar levels are kept constant by a range of ……….. mechanisms
homeostatic
what happens very basically to glucose after a meal
glucose gets stored as glycogen in the liver and muscle cells or triglycerides in adipose tissue
in what form is glucose stored in liver and muscle cells
glycogen
in what form is glucose stored in fat cells/adipose tissue
triglycerides
what happens to liver, muscle and fat cells when blood glucose levels are low
these tissues become net exporters of glucose
what is hyperglycaemia
high blood glucose
what is hypoglycaemia
low blood glucose
what are the different levels of organisation involved in glucose metabolism
system
tissue/organ
cellular
subcellular
are mitochondria static
no they can move around the cell
………. can rapidly increase and decrease in size
lipid droplets
……..…. can increase in number
mitochondria
…… .…… needs to be regulated for a steady supply of glucose
food intake
what is signal transduction
when an extracellular signal is transformed into and intracellular response
what is insulin
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
what is glucagon
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
insulin increases glucose up take into ……. and ……… cells
fat and muscle
insulin increases ………… ………… in the liver
glycogen synthesis
insulin inhibits ………….. in the liver
gluconeogenesis
insulin signals the fed/fasted state and the removal/addition of glucose from/to the blood
fed
removal
glucagon/insulin stimulates gluconeogenesis
glucagon
glucagon inhibits …… ……. in the liver
glycogen synthesis
glucagon/insulin triggers lipid breakdown
glucagon
glucagon/insulin stimulates the release of glucose into the blood
glucagon
when someone is the starved/fed state they undergo gluconeogenesis
starved
what is gluconeogenesis
a metabolic pathway that results in the generation of glucose from non carbohydrate substances such as lactate or amino acids
what is the normal blood glucose concentration
90mg/100ml
what are the steps in the homeostatic control of blood glucose, starting with eating a meal
- stimulus - rising blood glucose - e.g. after eating a meal
- insulin is released from the B cells of the pancreas
- the liver and body cells (fat and muscle) take up glucose and store it as glycogen
- blood glucose level declines to a set point and the stimulus for insulin diminishes
- homeostasis is reached
- stimulus - dropping blood glucose level (e.g. after skipping a meal
- alpha cells of the pancreas are stimulated to release glucagon into the blood
- the liver breaks down glycogen and stimulates the release of glucose into the blood
- blood glucose level rises to a set point and the stimulus for glucagon is diminished
- homeostasis is reached
where is glycogen mainly stored within the body
liver and muscle cells
around which cellular organelle are lots of glucose granules found
mitochondria - they are right next to the muscle fibres to provide ATP for muscle contraction
what is the fed state
high circulating glucose - after a meal
what is the fasted state
low circulating glucose - the middle of the night
what does glucokinase convert glucose into
glucose-6-phosphate
what converts glucose-6-phophate back into glucose
glucose-6-phosphatase
what converts glycogen into glucose-1-phosphate
glycogen phosphorylase
what does glycogen synthase do
converts glucose-1-phosphate to glycogen
what enzyme converts between glucose-6-phosphate and glucose-1-phosphate
phosphoglucomutase
which two pathways are reciprocally regulated and what does this mean
glycogen –> glucose-1-phosphate
glucose-1-phosphate –> glycogen
reciprocal regulation means that when one pathway is active, the other is not and vice versa
what is hexokinase
a class of enzymes that phosphorylate 6 C sugars - glucokinase in particular phosphorylates glucose, a 6 C sugar
what is flux through a metabolic pathway controlled by
regulatory enzymes
what mechanisms can mammalian enzymes be regulated by
changing the rate of biosynthesis/degradation levels
changes in activity
changes in location
reversible covalent modification
what effect does insulin have on the glucose-1-phosphate and glycogen conversion
insulin promotes glycogen synthase to convert glucose-1-phosphate to glycogen and inhibits glycogen phosphorylase which inhibits the reverse step
what effect does glucagon have on the glucose-1-phosphate and glycogen conversion
insulin promotes glycogen phosphorylase to convert glycogen to glucose-1-phosphate and inhibits glycogen synthase which inhibits the reverse step
give examples of types of reversible covalent modification
prenylation - addition of hydrophobic molecules e.g. lipids
ubiquination - addition of ubiquitin molecules
glycosylation - adding carbohydrate groups
phosphorylation - adding phosphate groups
what is a phosphatase
an enzyme that removes a phosphate from a molecule
what is a kinase
an enzyme that adds a phosphate to a molecule
what is phosphorylation
the covalent addition of a phosphate transferred from ATP by the action of a class of enzymes called kinases
is phosphorylation reversible or irreversible
reversible
what is the charge on a phosphate at physiological pH
-2
how can phosphorylation affect a enzyme
it can turn it on or off by changing its conformation because of the high charge density of the protein bound phosphoryl group
what do negatively charged protein bound phosphoryl groups often bind to
they make salt bridges with nearby positively charged arginine or lysine residues
what are the 2 main classes of kinase
- those that phosphorylate tyrosine residues
2. those that phosphorylate serine/threonine residues
what form of reversible covalent modification is a key metabolic control process in glucose metabolism
phosphorylation
what does a kinase do
adds phosphates
what does a phosphatase do
removes phosphates
glycogen synthase is turned on/off by phosphorylation by PKA
off - glucagon stimuli results in PKA phosphorylation and inactivation of the glycogen synesis pathway
what stimulates phosphorylation of glycogen synthase and glycogen phosphorylase by PKA
signals from glucagon
glycogen phosphorylase is turned on/off by phosphorylation by PKA
on - glucagon stimuli results in PKA phosphorylation and breakdown of glycogen to release glucose
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
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
are glycogen synthesis and glycogen degradation ever occurring at the same time
no - the would provide no net benefit as glycogen would be getting broken down at the same rate as it was getting made
glycogen synthase is turned on/off by dephosphorylation by protein phosphatase 1
on - insulin stimuli results in dephosphorylation by protein phosphatase 1 and activation of the glycogen synthesis pathway
glycogen phosphorylase is turned on/off by dephosphorylation by protein phosphatase 1
off - insulin stimuli results in dephosphorylation by protein phosphatase 1 and inactivation of the glycogen degradation pathway
what are the 5 effects of insulin
- increased activity of glycogen synthase, reduced activity of glycogen phosphorylase = net storage of glycogen
- gluconeogenesis is suppressed
- glycolysis is turned on
- glycolytic enzyme expression is turned on, gluconeogenic enzyme expression turned off
- blood glucose level falls
what are the 5 effects of glucagon
- decreased activity of glycogen synthase, increased activity of glycogen phosphorylase = net breakdown of glycogen
- gluconeogenesis is activated
- glycolysis is turned off
- glycolytic enzyme expression is turned off and gluconeogenic enzyme expression is turned on
- blood glucose levels rise
if biosynthetic and degradative pathways like glycogen synthesis and breakdown are distinct, how does this affect thermodynamics
if the pathways are distinct then they can both be thermodynamically favourable
what are the rates of chemical reactions governed by and give an example of this
activities of key enzymes glycogen synthesis and breakdown is regulated by phosphorylation - not mas action (the amount of substrate)
what is allosteric modulation
altering an enzymes activity by binding to a site other than the active site
in the case where a metabolic pathway can be reversed, hoe is this controlled
it will be controlled by an irreversible step
how do enzymes effect rate of reaction
they increase it by decreasing the activation energy
what is the rate determining step
the slowest step of the reaction which determines the rate at which the overall reaction proceeds
the rate determining step is often a key ……. ………
control point
what are the two rate limiting steps in glycolysis
- phosphorylation of glucose by glucokinase to form glucose-6-phosphate
- phosphorylation of fructose-6-phosphate by phosphofructokinase to form fructose-1,6-bisphosphate
are the 2 rate limiting steps of glycolysis reversible or irreversible
irreversible
which of the rate limiting steps of glycolysis is also a key regulatory step
fructose-6-phosphate phosphorylation to produce fructose-1,6-bisphosphate
why are the rate limiting steps of glycolysis irreversible
because they coupled with hydrolysis of ATP
enzymes can be controlled by allosteric interactions with other molecules - what can these other molecules be
other molecules and intermediates downstream in the pathway
molecules which potentiate ……. …….. will often be negative regulators of the other ………..
one direction - e.g. glycolysis
direction e.g. gluconeogenesis
what type of hormones are insulin and glucagon
they are polypeptide hormones and they are both released from the pancreas
where are the receptors for insulin and glucagon located
they have different receptors enriched in the muscle, fat and liver cells
what disease is now classified as a silent epidemic
diabetes
what percentage of deaths globally can be attributed to diabetes each year
9%
what are some complications that can occur with diabetes
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
what are some reasons for the increase in the prevalence of diabetes
lack of exercise
poor diet - westernised diet
type of work - less manual work now than previously
out of diabetes as a total what is the prevalence of T1D
10%
out of diabetes as a total what is the prevalence of T2D
90%
outline the cause of T1D
- pancreatic B cells destruction
- autoimmune/idiopathic
it is caused by pancreatic B cell destruction due to an autoimmune process of unknow aetiology
outline the cause of T2D
- insulin resistance
- B cell dysfunction
results from a defect in insulin action almost always with insulin resistance as the root cause
is diabetes a disease of the overweight
no you can be skinny and diabetic
which ethnicities are more likely to get diabetes
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
what causes the differences in diabetes prevalence in different ethnicities
genetic predisposition
which part of the pancreas connects to the small intestine
the pancreatic duct
what is most of the pancreas made up of
acinar cells
what do acinar cells do in the pancreas
they produce and secrete digestive enzymes into the pancreatic duct which aid digestion
which cells of the pancreas secrete hormones
islet cells - the beta and alpha cells are found in the islet cells - these cells secrete hormones
why are the islet cells of the pancreas highly vascularised (surrounded by blood vessels)
so they can sense changes in the blood glucose levels and so the can release insulin ad glucagon into the blood
mature insulin mRNA encodes what
pre-proinsulin polypeptide
how many exons and introns does insulin pre-mRNA have
3 exons
2 introns
what was the first sequenced protein
insulin
what is pre-proinsulin made up of
signal sequence
polypeptide A
polypeptide B
connecting peptide
which parts of pre-proinsulin are part of the final insulin product
polypeptides a and b
what happens during the conversion of pre-proinsulin to proinsulin
- the signal sequence is cleaved off
2. disulphide bond form between polypeptide a and b
is proinsulin the active product
no further modifications are required
what happens during the conversion of proinsulin to mature insulin
the connecting polypeptide is removed leaving the a and b polypeptides connected by disulphide bonds
highlight the steps in the production of insulin from start to finish and transport to the ER
- ribosome on rough ER sees mRNA and begins to read along
- signal sequence emergence triggers a translational pause signal to the ribosome and it arrests
- the signal sequence is recognised by an SRP receptor on the ER which holds the signal sequence really tightly
- 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
- translocation resumes and the signal sequence is cleaved off by the signal sequence peptidase complex
- translocation continues into the ER lumen
- the insulin peptide is co-translationally passed into the ER.
what does SRP stand for
signal recognition particle
why don’t we just make insulin in the cytoplasm
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
do disulphide bonds form in reducing or oxidising environments
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.
what is the translocon sec61 complex
a tunnel through which the growing polypeptide chain can pass into the ER
when is the signal sequence cleaved
as soon as translation is restarted
where is pre-proinsulin made
the ribosomes of the rough ER
membrane bound compartments ………… different reactions and functions
compartmentalise
during exocytosis what happens to the vesicle membrane
the inside of the vesicle becomes the outside of the call
what was the palade study
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
what is a lysosome
cell organelle containing degradative enzymes
what is an endosome
cell organelle that serves as a temporary vesicle for transportation
how do macromolecules move through the secretory pathway
via vesicular transport
vesicles bud off from the ER and keep the protein inside the membrane bound compartment - what is this process called
exocytosis
does insulin ever see the cytoplasm
no - it is transported in vesicles which allow it to avoid the reducing environment
where can vesicles be targeted
the cell surface cytoplasm endosome lysosome etc
where are vesicles targeted in the case of insulin
they are targeted to the secretory granules
where is pre-proinsulin translated and what happens to it as it is translated
it is translated on ribosomes in the rough ER and as it is translated it is inserted into the ER lumen
describe the processing that occurs once the pre-proinsulin has been inserted into the ER lumen
- the signal sequence is cleaved by signal peptidase
- disulphide bonds form between the A and B chains, stabilising the 3D structure
WE NOW HAVE PROINSULIN - proinsulin traffics to the Golgi via vesicular transport
- once trafficked through the Golgi proinsulin is packaged into secretory granules
- 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 - 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
what is the net result of have the crystalline complex in secretory granules
we get very high insulin concentrations in specialised packages
in response to a suitable signal, secretory granules fuse with the …………… ………………….. and release their content
plasma membrane
for each of the locations what stage of insulin do we have nucleus rough ER Golgi immature secretory granules mature secretory granules
nucleus - pre-proinsulin gene and mRNA
rough ER - pre-proinsulin –> proinsulin
Golgi - proinsulin
immature secretory granules - insulin
mature secretory granules - insulin (hexamer/ZN crystal)
what is the difference between immature and mature secretory granules
the secretory granules mature when the crystalline structure forms
why is it important that insulin isn’t active until it reaches its final form
because if miss trafficking occurred the released substance would not be biologically active and so would not cause any harm
compartmentalisation leads to specialisation and hence ……..…………..
greater efficiency
what is insulin released in response to
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
the ability of a cell too sense extracellular glucose concentration and adjust …………………… are in direct proportion
intracellular metabolism
what is GLUT2 and where is it expressed
it is a low affinity glucose transporter expressed in beta cell plasma membrane and in liver cells
why does glucose interact with water
because it is polar - they form H bonds with each other
why is it important the glucose and water interact
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
what kind of transporters and glucose transporters
facilitative diffusion transporters - molecules move down their concentration gradient with the help of the transporters
what is the alternating conformation model
the glucose transporter oscillates between 2 conformational forms
what are the differences between transporters and channels
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
how many different GLUTs are there
12 in the human genome
what is a voltage gate
they gate channels and are sensitive to changes in membrane potential of the cell. changes in membrane potential can open or close a channel
what is a Michalis menten curve
a curve that shows the reaction velocity with respect to concentration
what is Km
the substrate concentration that produces 1/2 Vmax
low Km = …………… affinity
high Km = ……………. affinity
high
low
GLUT2 is low/high affinity
low
GLUT3 is low/high affinity
high
in most cells [ATP} is invariant but this is not the case in what type of cells
beta cells of the pancreas
glucose metabolism in beta cells is inefficient and as a result beta cells respond to changes in extracellular glucose concentrations by rapidly changing what
[ATP/ADP] ratio
what enzyme is used for glucose phosphorylation in beta cells
glucokinase - a low affinity/high Km enzyme
glucokinase is not saturated at physiological [glucose], what does this result in
phosphorylation rate by glucokinase is directly proportional to intracellular glucose concentration
what does glycolytic rate depend on
glucose entry/[blood glucose]
where is GLUT2 found
liver, pancreas, kidney, enterocytes
where is GLUT3 found
brain and other tissues
list the 3 main GLUT transporters in order of increasing Km and decreasing affinity
GLUT3 (low) , GLUT4 (intermediate), GLUT2 (high)
where is GLUT4 found
in insulin sensitive tissues - fat and muscle
what does the low affinity of GLUT2 allow for
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
the amount of glucose brought into the cell reflects the amount of glucose in the …………..
blood - glucose conc inside and outside of the cell are proportional
where does GLUT2 transport glucose
from the outside of the cell (the blood) to the inside of the beta cells of the pancreas
the amount of glucose coming into the bets cells proportionally increases in response to ……………………..
increased blood sugar concentration
why is glucokinase used for glucose phosphorylation as opposed to other hexokinases
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)
what happens to ATP concentration when glycolysis (using glucose) increases
we get increased ATP (which is proportional to the amount of glucose in the blood)
is glycolysis reversible
no it is irreversible because it is coupled with ATP production
do the ATP sensitive potassium channels of beta cells ten d to be opened or closed and why
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
what happens in beta cells when ATP conc starts to rise due to glycolysis of the glucose taken in from the blood
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
what happens in response the inside of the beta cell becoming more positive - depolarising
- closing of K channels due to higher ATP conc causes depolarisation
- voltage gated potassium channels sense the change in potential difference and open
- the rise in intracellular calcium leads to fusion of insulin containing secretory vesicles with the PM leading to insulin release from the cell
describe the state of the potassium and calcium channels when glucose is present and absent
present - K closed, Ca open
absent - K open, Ca closed
what is the potassium channel sensitive to
ATP conc
what is the calcium channel sensitive to
voltage
in what two ways is the release of insulin from the cell controlled
by hormonal and neuronal regulatory systems
where is the only place that insulin is correctly processed
the secretory granules
where are the secretory granules waiting before release of insulin out of the cells
they are lined up at the PM and some are already docked
where are the calcium channels located
right next to the docked secretory granules, generating a rapid influx of calcium in exactly the right place
how many secretory granules are already docked before the calcium signal and how many are waiting to be docked
600 already
2000 waiting
what are the 3 types of pancreatic cells that interact with each other in clusters
beta, alpha and delta
where are beta cells found
in the islets of the Langerhans of the pancreas
what does a single islet contain
beta, alpha and delta cells
what islet cells coupled with
they are couple by gap junctions and paracrine signals to promote coordinated oscillatory insulin output
how do islets signal to each other
they have neuronal and hormonal connections
what is meant by release of insulin in waves
one islet cluster releases then another cluster releases afterwards
what kind of receptor is the insulin receptor
a ligand activated tyrosine kinase
when insulin is released, where is it targeted and why
fat, liver and muscle cells because these tissues have the insulin receptor
describe the structure of the insulin receptor
it is an alpha2beta2 polypeptide held together by disulphide bonds (alpha on the outside and beta on the inside of the membrane)
what happens when insulin binds to its receptor
- insulin binds to the alpha subunits inducing a conformational change which is transmitted to a the beta subunits
- this activates an intrinsic tyrosine kinase within the cytosolic domain (phosphorylates tyrosine aa)
- this kinase then phosphorylates many target molecules (one insulin molecule activates a large response)
- the tyrosine kinase of the receptor phosphorylates specific residues within the receptor (auto-phosphorylation)
- 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
- 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
- SH2 domain containing proteins are then activated and signals are propagated
what are the two main classes of kinase
those that phosphorylate tyrosine residues and those that phosphorylate serine/threonine residues
what happens to phosphorylated residues of the insulin receptor
they become docking sites for other signalling molecules and docking sites recognise p-tyrosine not regular tyrosine
are all SH2 domain containing proteins the same
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
what is the 2 pronged plug concept
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
summarise the assembly of the insulin receptor signalling complex
- insulin binds to receptor
- autophosphorylation of specific tyrosine residues
- results in recruitment of SH2 domain containing proteins to the receptor, different receptors recruit different proteins
- different SH2 domain containing proteins recognise p-tyr in different sequence contexts - specificity
what is a signalling complex
multiple proteins assembled with the correct spatial and temporal coordinates
what is Akt
a serine/threonine kinase activated by insulin
compare glucose uptake with insulin concentration between diabetics and non diabetics
in T2D glucose uptake still increases with increasing insulin concentration but less glucose is taken up compared to that in non diabetics
what is GLUT4
a specialised glucose transporter expressed only in fat and muscle cells
when does GLUT4 move to the surface of the cell
in response to insulin binding too its receptor and the movement is induced by cAkt
where is GLUT4 contained before implantation into cell membranes when insulin is not present
in secretory vesicles
what is trafficking of GLUT4 secretory vesicles to the fat and muscle cells membranes triggered by
cAkt
once glucose has made its way into the cell via GLUT4, it can undergo ………..
glycolysis
describe the process of GLUT4 delivery to cells
- delivery of GLUT4 to the cell surface requires Akt which is produced in response to insulin binding to its receptor
- in response to these signals, regulated exocytosis of GLUT4 containing vesicles delivers cargo to the plasma membrane in response to a specific signal.
what is Akt
a serine/threonine kinase - there are 2 Akts (1 and 2)
what do inhibitors of Akt do
they decrease GLUT4 recruitment
insulin inhibits lipolysis, what is this
hydrolysis of lipid triglycerides
what promotes lipid drop formation in fat cells
insulin
what is the effect of cAkt in fat, liver and muscle cells
fat cells - activates GLUT4 trafficking to the cell surface
liver/muscle cells - phosphorylates and activates phosphatase, promoting glycogen storage
how does insulin control gene expression
through IRS1 it signals to transcription factors
which transcription factor does insulin activate in liver and fat cells
LxR
what does activation of LxR tf by insulin trigger
expression of SREBP1 in fat cells which is involved in lipogenesis, controls fatty acid synthase, acetyl coA carboxylase, lipid metabolism genes are turned on
……..….. ………… enters the lipogenesis pathway and is converted to triglycerides
acetyl coA
LxR drives the genes involved in lipogenesis to be turned on, what are these genes
acetyl coA carboxylase
fatty acid synthase
SCD1
other than insulin, what else regulates SREBP1 and LxR
oxidative stress and nutrients
what is a promotor region involved in
driving transcription - the sequences are recognised by tfs
what affect does a transcription factor binding to binding sites have
it either upregulates or downregulates transcription
what do activators do
they help tf and RNA pol. assemble –> transcription
what do repressors do
block tf and RNA pol. assembling –> no transcription
define endocrine
relating to or denoting glands which secrete hormones or other products directly into the blood
define paracrine
relating to or denoting a hormone which has effect in the vicinity of the gland secreting it
define autocrine
denoting or relating to a cell produced substance that has an affect on the cell by which it is secreted
what are the problems with being fat
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
describe the mouse genetic model study
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
where is grehlin secreted from
the stomach
where is leptin secreted from
adipose tissue
what did prof steve bloom make
an injection that contained a cocktail of adipocytokines (cytokines secreted by adipose tissue) that could be given monthly that mimicked gastric band surgery
what are the effects of gastric band surgery
reduces the volume of the stomach
increased levels of satiety hormones
preference to eat less fatty foods
if leptin is secreted by fat, obese people have more fat deposits so should secrete more leptin so why are they obese
this suggests that obesity might be associated with leptin resistance
what are endocrine cells
cells responsible for producing and releasing hormone molecules into the bloodstream and are typically grouped in organs referred to as endocrine glands
what are neuroendocrine cells
cells that receive neuronal input and release hormones into the blood
what are enteroendocrine cells
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
what is grehlin
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.
what is leptin
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.
what does GLP1 stand for
Glucagon-like peptide 1
where is GLP1 secreted from
ileal L (enteroendocrine cells)
what is GLP1 secretion dependent on
the presence of nutrients in the lumen of the small intestine and is released in response to major nutrients such as carbohydrates and lipids
what is the half life of GLP1 and what enzyme degrades it
2 mins
dipeptidyl peptidase - 4 (DPP4)
what does GLP1 do
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
why is release of insulin when plasma glucose is in the normal range dangerous
it can cause hypoglycaemia but GLP1 stops this from happening
when plasma glucose is in the normal range is GLP1 present or absent
absent
what are the physiological actions of GLP1
potentiation of glucose stimulated insulin secretion
enhancement of B cell growth and survival
inhibition of glucagon release
gastric emptying
summarise the effect of incretins on insulin secretion
- glucose in the lumen of the intestine stimulates secretion of incretins
- incretins enhance glucose dependent insulin secretion and absorbed glucose in the circulation stimulates insulin secretion by pancreatic beta cells
what are incretins
a group of metabolic hormones which promote a reduction in blood glucose by several mechanisms
how do incretins promote a reduction in blood glucose
they augment glucose stimulated insulin release from beta cells
they suppress glucagon release
they regulate absorption of nutrients from the gut
what are the main incretins
GLP1 and GIP (gastric inhibitory peptide)
why is incretin therapeutic use limited
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
describe the platypus adaptation
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
describe the dolphin adaptation
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
there are cycles of natural obesity and ……. …….. in hibernating animals
insulin resistance
how do hibernating animals sense change
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
what happens to the liver during metabolism
it changes profile from carbohydrate to fat based metabolism
what about migratory birds makes their long journeys possible
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
describe the migration of the northern bald ibis
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
describe the relationship between migration and the gut
digestive organs increase in size and capacity to convert more food into energy
list some adaptive changes for migratory birds
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
how do we use our energy in a 200m sprint
1 sec - stored in ATP in muscles
4 sec - creatine phosphate
rest of sprint - anaerobic fermentation of glucose
