Systems biology course 2018 Uri Alon - Lecture 8 C - Dynamic Compensation
Summary
TLDRThe script delves into the dynamics of glucose and insulin in the body, explaining how insulin resistance can lead to an increase in glucose levels. It discusses the concept of dynamic compensation, where the body adjusts to maintain a steady state despite changes in parameters like insulin sensitivity. The talk also touches on the phenomenon of glucose toxicity and its role in diabetes, highlighting the balance between robust control systems and the risk of mutant cell takeover. The speaker explores the evolutionary purpose of glucose toxicity as a defense against rogue cells and the implications for understanding diabetes and aging.
Takeaways
- 📈 Glucose levels increase immediately due to insulin, leading to cell proliferation until a steady state at 5 millimolar is reached.
- 🔄 Insulin resistance, common in obesity, results in higher glucose and insulin levels, altering the body's compensatory mechanisms.
- 🔄 Dynamic compensation allows the body to maintain normal glucose dynamics despite changes in insulin sensitivity.
- 🔍 The concept of 'steady state' is crucial, where the number of cells dividing and dying is balanced to maintain glucose levels.
- 🧬 The body's feedback loops, like the one involving insulin and glucose, are essential for maintaining homeostasis and can be modeled mathematically.
- 📉 In the presence of insulin resistance, the body compensates by increasing insulin production to maintain glucose tolerance, despite the need for higher insulin levels.
- 🚫 Glucose toxicity occurs when glucose levels are too high, leading to cell death and a vicious cycle that can result in type-2 diabetes.
- ⏳ Aging affects cell proliferation rates, which in turn influences the position of stable and unstable fixed points in glucose dynamics, increasing the risk of diabetes.
- 🧬 Glucose toxicity serves an evolutionary purpose by acting as a selective pressure against cells with mutations that misread glucose levels, thus protecting against uncontrolled cell proliferation.
- 🔄 The body's systems are designed to balance the risk of mutant cell takeover and the onset of diseases like diabetes, influenced by genetic background and lifestyle.
Q & A
What happens to glucose levels in the body when insulin resistance occurs?
-When insulin resistance occurs, glucose levels initially increase because the body's cells do not respond effectively to insulin. This leads to a higher glucose concentration in the blood.
How does the body compensate for insulin resistance?
-The body compensates for insulin resistance by increasing the number of beta cells, which produce more insulin to try to bring glucose levels back to normal.
What is the role of the 5 millimolar glucose level in cell division?
-The 5 millimolar glucose level is a critical threshold for beta cells to stop dividing. When glucose levels reach this point, cell proliferation halts.
What is dynamic compensation in the context of the body's response to insulin resistance?
-Dynamic compensation refers to the body's ability to maintain the same physiological response to meals despite changes in parameters like insulin sensitivity, through adjustments in the number of beta cells and insulin production.
How does the body's response to glucose change after insulin resistance has developed?
-After insulin resistance has developed, the body initially shows an abnormal glucose tolerance test due to the beta cells not having expanded enough to compensate. However, once a new steady state is reached, the glucose tolerance test becomes indistinguishable from before, but with higher insulin levels.
What is the significance of the hyperbolic relationship between insulin and glucose levels?
-The hyperbolic relationship signifies that for every unit increase in insulin, there is a corresponding increase in glucose uptake and utilization, which helps maintain glucose homeostasis.
What is glucose toxicity and how does it relate to diabetes?
-Glucose toxicity refers to the phenomenon where high glucose levels lead to the death of beta cells. This can result in a vicious cycle where less insulin is produced, leading to even higher glucose levels, which is characteristic of type-2 diabetes.
How does aging affect the body's ability to handle glucose?
-Aging typically reduces cell proliferation rates, which can cause the fixed points in glucose regulation to shift, making it easier for glucose levels to cross the threshold into glucose toxicity.
What is the evolutionary purpose of glucose toxicity?
-Glucose toxicity serves as a mechanism to eliminate cells that have mutations causing them to misread glucose levels, which could otherwise proliferate uncontrollably and disrupt glucose homeostasis.
How does the body balance the risk of mutant cell takeover and diabetes?
-The body balances the risk of mutant cell takeover and diabetes by optimizing the levels of glucose toxicity and the rate of cell proliferation, which can be influenced by genetic factors and lifestyle choices.
Outlines
💉 Insulin Resistance and Cell Compensation
The paragraph discusses the dynamic relationship between glucose, insulin, and beta cells in the context of insulin resistance. It explains how an increase in glucose levels leads to an increase in insulin production, which in turn affects cell proliferation and death rates. The concept of steady-state equilibrium is introduced, where insulin resistance causes a shift in this equilibrium, leading to higher insulin levels and a compensatory increase in beta cells. The speaker emphasizes the importance of dynamic compensation, where the system adjusts to maintain balance despite changes in parameters like insulin sensitivity. The paragraph also introduces the mathematical concept of rescaling variables to prove the invariance of the system's dynamics.
🔄 Dynamic Compensation and Biological Systems
This section delves into the broader implications of dynamic compensation in biological systems, beyond just insulin and glucose. It highlights how the body maintains invariant dynamics in response to changes in parameters such as insulin sensitivity and cell division. The speaker uses the example of blood calcium levels and the role of PTH to illustrate similar regulatory mechanisms. The paragraph also touches on how total blood volume can affect insulin dilution and how the body compensates for this. The discussion concludes with the question of how diseases like diabetes arise despite these compensatory mechanisms.
🚨 Glucose Toxicity and Cell Death
The focus of this paragraph is on the phenomenon of glucose toxicity, where excessively high glucose levels lead to cell death, particularly in beta cells. It explains how high glucose levels can cause an increase in reactive oxygen species, which damage cells and lead to their death. The speaker discusses how this process can create a vicious cycle in diabetes, where cell death leads to less insulin production and subsequently higher glucose levels. The paragraph also introduces the concept of a new fixed point in the system dynamics that is unstable, which can lead to the progression of type-2 diabetes.
🌡 Aging and the Risk of Diabetes
This section explores how aging affects cell proliferation and the risk of developing diabetes. As people age, cell division slows down, which can shift the stable and unstable fixed points in the system's dynamics. This shift can make individuals more susceptible to glucose toxicity and diabetes. The speaker also discusses the role of genetics and lifestyle in determining an individual's risk for diabetes and how these factors can influence the position of the fixed points.
🧬 Evolutionary Purpose of Glucose Toxicity
The paragraph delves into the evolutionary rationale behind glucose toxicity, suggesting that it may serve as a protective mechanism against mutations in beta cells. It explains how mutations can lead to cells that misread glucose levels and proliferate uncontrollably, which could be dangerous if not for glucose toxicity. The speaker argues that glucose toxicity acts as a selective pressure against such mutants, preventing them from taking over and causing systemic issues. The discussion also touches on how different genetic backgrounds and historical patterns of feast and famine may influence the positioning of glucose toxicity thresholds.
🌟 Conclusion and Future Research
In the concluding paragraph, the speaker expresses excitement about the potential to understand complex biological systems through the lens of dynamical systems theory. They highlight the importance of balancing robustness against mutations and other perturbations with the need for flexibility in these systems. The speaker also mentions that their research group is deeply engaged in exploring these phenomena, which have direct implications for understanding aging and disease.
Mindmap
Keywords
💡Glucose
💡Insulin
💡Insulin Resistance
💡Cell Proliferation
💡Steady State
💡Dynamic Compensation
💡Glucose Toxicity
💡Fixed Point
💡Reactive Oxygen Species
💡Mutations
Highlights
Glucose levels increase immediately due to insulin, leading to cell proliferation.
Insulin resistance in obesity leads to higher glucose and insulin levels, affecting the body's parameters.
Dynamic compensation occurs when the body adjusts to maintain steady-state glucose levels despite insulin resistance.
The body's response to insulin resistance involves a rescaling of variables to maintain the dynamics of glucose and insulin.
The model demonstrates that the dynamics are invariant to changes in certain parameters, a phenomenon known as dynamic compensation.
Insulin resistance can initially cause abnormal glucose tolerance, but the body can compensate over time.
The body's feedback loop involving glucose and insulin is crucial for maintaining glucose homeostasis.
Glucose toxicity occurs when glucose levels are too high, leading to cell death and a vicious cycle in type-2 diabetes.
The body's response to glucose toxicity is a key factor in the development of type-2 diabetes.
Aging affects cell proliferation rates, which in turn influences the body's ability to maintain glucose homeostasis.
Gluco toxicity serves an evolutionary purpose by providing a selective disadvantage to cells with mutations that misread glucose levels.
The body must balance the risk of mutant cell takeover with the need for dynamic stability, influenced by factors like genetics and lifestyle.
The concept of dynamic compensation is not only applicable to glucose and insulin but also to other body systems like blood calcium regulation.
The mathematical model of glucose and insulin dynamics can help predict and understand the body's response to various health conditions.
The interplay between glucose sensitivity, cell proliferation, and insulin resistance is complex and influenced by multiple factors.
The lecture concludes by emphasizing the importance of understanding the body's dynamic systems in the context of health and disease.
Transcripts
glucose over weeks increases right away
because of the insulin X now says oh
look glucose is increasing I proliferate
more than I die and you get more better
cells more better cells get more insulin
for insulin you get less glucose when
does it stop it stops when glucose
reaches five millimolar again because
that's the only time the cells stop
dividing and so what you have is when
you have insulin resistance like in
people with obesity they have five of
the more glucose I have more better
cells and also more insulin so their
parameter goes down s went down and I
steady-state went up and exactly s times
I steady-state equals constant turns out
because you want and I will prove that
in a second so this gives you this
compensation and if I'm not going to
zoom into the first time skill so I'm
gonna zoom in here so before insulin
resistance so you look at this day here
so this here is weeks right now I want
to look at this day and then this day I
ate three meals fine right now every one
day I get five more glucose I get some
response to these meals and some insulin
response to these meals
now insulin resistant changed and if I
look at a day here not too long after
insulin resistant change this is I'm
still not compensate it's still not at
steady state I give the same meals and I
get so I see something wrong I get long
and slow insulin so here this is
okay this is not okay
so after insulin resistance I see
something changed but then it X goes
back up in this point here I eat the
same meals and I get back exactly intact
the dynamics everything to normal but my
insulin is higher because that's how
compensation works have more insulin and
to get back to the normal state and to
prove that the dynamics are invariant
you need to use just like last time
rescale variables so if you call if you
make a new insulin that's s times
insulin and the new cells that's s time
cells so rescale the variables then you
can notice that this equations are built
so here I write I this is just this this
includes I if I multiply by s here here
in here I get these rescaled parameters
and if I multiply by s here in here I
get rescale parameters and that's
because cells are always make cells
that's the reason you can have X and
then these equations are invariant
equations are invariant to s and also
invariant to Q by the way you can also
rescale make you and so you can prove
just like the ability for change
detection that there's something about
the symmetry of this equation that makes
it that are the fast time scale after
they reach steady state they do cause
glucose of T forgets about s but insulin
remembers so you get higher insulin a it
for lower insulin sensitivity that
exactly met it balances out the
basically you get I twiddle steady state
is some constant and
exactly s times I which gives you this
hyperbolic relationship because these
equations are invariant so that's that's
talked about the nice knife's edge just
better cell insulin glucose model the
right plot and we could see this this
feature which this feature of being
completely invariant to a parameter is
really a very unusual in fact quite
amazing and this feature of being
invariant to parameter it's called
dynamic compensation and the reference
Carine 2016 almost alleyne here
advisement
so in fact we actually solved two
problems at once here one is that we can
now forget about how well other tissues
are listening to me insulin sensitivity
and still get exactly the same meal
response after we compensated so that's
one problem the second problem is the
number of better cells which divide and
die is maintained at a certain size the
certain amount that amount make sure
that look of the five millimolar so the
amount better selves adjusts itself
according to the biological parameters
but doesn't explode to infinity or go to
zero it's exactly the right size so this
circuit does two things right it makes
the dynamics invariant to us and solves
the problem of the knife's edge because
of this feedback loop where the growth
rate is determined by the parameter that
those cells but by the variable that
those cells control we added here X mix
insulin you have this motif here
and and I went to the same motif in
principal seems to happen in other body
systems for example when you look at
control of a blood calcium which is
another very important parameter it's a
fix it around 10 millimolar between
different people that's controlled by
special gland power thyroid gland which
makes a hormone called PTH it's the same
idea
calcium PTH except that the signs are
different PTH makes calcium go down and
calcium increases the production so
these arrows are flipped and calcium
inhibits the production of cells that
make PTH so some of these arrows of -
science but it's exact it's the same
property and indeed parathyroid glands
can grow it's very famous actually you
can have this hyperparathyroidism
diseases of calcium etc similar to
diabetes but so we think is the same
kind of mathematics is compensating
different organ systems I also want to
say that and things like total blood
volume so as you growing up as a kid or
when you become pregnant blood volume
can change that enters this parameter Q
because now it's as if you when you
crease blood volume insulin gets diluted
out you can see and it turns out that
this same way better cells can expand
and shrink to compensate for blood
volume exactly also so as you're growing
your organs can grow just measuring
through their blood glucose that make
exactly enough insulin to be diluted in
your total blood volume so when you
think about it after you think about you
have to say how can the body work with
all these changes and these are very
essential kind of feedbacks that you
have to have on organs feeding back on
their activity they explain myself and
then you say if this is so perfect how
do we get diabetes where these disease
come from
what's going on with diabetes right so I
have more glucose
cells can expand go back everything's
fine so how can you get disease so
that's the last thing I want to tell you
in a in a few minutes how we get there
biddies hear about this just to explain
and say what what what is it here what I
try to say thanks so what I try to say
is so here we have an event of insulin
resistance so before and you have you
had a good glucose towards you necessary
drink 75 grams of glucose and you have a
good glucose tolerance glucose in the
blood
now there's an insulin resistance so in
a scale of a few let's say about a week
after this insulin resistance happens
you'll have an abnormal glucose
tolerance test but that's because better
cells have not yet expanded it takes him
a long time right to grow to exactly
balance out to make it so during and
after you reach steady state after
better cells have reached their new size
the glucose tolerance test is
indistinguishable from before even
though the parameters change what is
different is insulin so you reach the
same glucose stores with higher insulin
why because this is the sensitivity is
lower so you need more insulin to bounce
out it's lower effect now explain
yourself now
that's that's
yes yeah anyway and these arrows are
dependent on sense sensory systems
inside inside the better cells then look
how much glucose there is basically how
much glycolysis they're making and in
the cells you can see they kill
themselves if they're making too much
glycolysis and the reason they're
killing themselves is because the
Colossus makes these reaction reactive
oxygen species the damage to them and
peda cells are extremely sensitive to
this much more than almost any other
cell and then they so oh maybe I should
so they I want to talk about a so if you
change the glucose sensitivity or
anything in the circuit basically this
makes you have too much glucose the
cells were now proliferate more than die
and the end will return back to and
expand and pushing glucose back though
they have to get the glucose back to
five millimolar and otherwise they keep
proliferating
ah okay so let me tell you about why
could there be the questions about where
you get diabetes in general well end
Tony didn't have compensation model
and that's because I basically totally
you only have the truth here there is
unfortunately another or fortunately
another part of this graph again very
well known where if you reach the
regions of ten ten milli molar glucose
debt they start dying
that's called glucose toxicity and
that's very well known phenomenon the
glucose like I said before the better
cells seem to be very raised very very
sensitive to oxidative stress and caused
by glycolysis and they die and that's a
problem because why
and that's related very much to diabetes
because the situation this creates a new
fixed point you see here you have a new
crossing of these two lines and this
fixed point is a big problem because as
long as you're here proliferation is
bigger than death and who and more
better cells and less glucose but if
you're here if because it's very high
over weeks very high over weeks check
out what happens in this rate here death
this region here is bigger than
proliferation death is bigger than
proliferate that means better cells die
here better cells die there's less
insulin less insulin more glucose and
this is an unstable fixed point so this
glucose explicitly leads to an unstable
fixed point I just want to give credit
to the people who just discussed this
glucose oxy city in terms of diabetes
and that's a vicious cycle cycle cycle
more glucose less better cells more
glucose because it less insulin more so
that's a problem and that's that's you
can say a definition of what's called
type-2 diabetes and it happens when
you're better cells get
exhausted insufficient is it so we have
to you have to be here for weeks if
you're if you go back here you can be
fine right before you lost all your
better cells if you go back change your
diet you go back here you can be fine
you flow back but if you're here for too
long you can in principle lose your
better cells and you are unable to
compensate for Google you have big
problems you can have the this vicious
cycle here is caused by glucose toxicity
so this rising iron here creates another
fixed point and that is a big topic of
research as to how to deal with Google
toxicity we said do what is it - what is
Google exists how it happens is this
reactive oxidant species into damage but
I want to ask ya know I didn't say that
I said that in fact that is in this
region they go there number goes down
down down down down
and so you basically don't have enough
insulin to balance your insulin
resistance and you have high glucose
yeah yeah so for example yeah if you
change that's why even if you have tied
to the business you wanna change your
diet to be here
let's blue coats oh you can you can
there you can have in certain stages if
you change your Google you go here you
you you get really big improvement in
your but maybe you think oh maybe you
think of type one diabetes
yeah let's analyze it see why yeah we
say so the quick problem is age is a big
risk factor for type 2 Davies and what
happens with the age is also very
interesting for the age the universal
thing happens in our body is cell
proliferation goes down cells divide by
less quickly so what happens if
proliferation goes down here it is graph
let's just analyze it this is what
happens with age
so one thing you can observe is if for
healthy people the fixed point creeps up
so that's well known with age instead of
five you have five point five five point
six but this one the unstable fixed
point moves to lower glucose levels see
so that's like now this Google toxicity
is really depending on genetics you can
get it at higher or lower glucose level
so here is genetics plays in right where
the position of these fixed points and
your lifestyle accent determines the
fluctuations and glucose so all this
together
tie into like we can start to understand
why these risk factors affect something
so complex like a diabetes like a
disease like that yeah how they can be
understood in terms of dynamical system
at least a very simplified way but you
can can give you some ideas right do you
explain myself with this points aging
proliferation goes down the fixed points
come closer together and it's more risky
that glucose will cross this threshold
and you get all white okay so let's
finish up with this question just fish
it why does our body have gluco toxicity
is it just an annoying byproduct of
cells the cells are weak and lazy right
- my high glucose they eat a lot early
that's maybe like why is it does it have
to be that way they'd have to be that
way and so what is the evolutionary
purpose of side of Google toxicity yes
right because in biology at least we
want to not reject the hypothesis we
want I think we should start with a
positive if you see something important
it has a reason it has a reason and
maybe you find out that there's no
reason okay but the initial philosophy
should say there is a reason let's find
out and it turns out that it has a
really crucial reason and that is to
address the third problem mutations look
if we didn't have bucco toxicity if this
was our perfect control circuit with
just one stable fixed points suppose I
can engineer would build it right great
an engineer would build it but engineer
doesn't have to worry that the little
thermostat gets mutations okay well she
have to worry so the bad cells are
dividing dividing dividing they make
themselves better cells or stem cells
apparently they do now once in a while
so they transport glucose and they have
like proteins like Luca kinase it
phosphorylates glucose and you know once
in a while in this division you get a
mutant now you get a lots of measles but
if you get a mutant in the sensory
system of glucose for example a gluco
kinase that phosphorylates glucose too
much seven in the cell this mutant self
thinks there's more glucose than there
actually is okay so once in a while
you'll get a mutant that thinks or
senses miss reads I'll call it miss
reads glucose as it's more than the
actual level so it could be in other
contexts would be a receptor that's
firing too much or acceptor that's lost
you always have to worry about those
cells and this occurs very often so once
every and estimated anagram of tissue
okay over a 80-year lifespan you'll get
every possible mutation in the genome a
thousand times you have an example of a
cell with agitation a thousand
times just because Tichenor is ten to
the minus nine if ten to the nine cells
per gram you have this a division once
per month you multiply everything how
many of months in the lifetime if not
thousands 100 or 10,000 bits a lot right
now what's the problem those mutants the
body as in the blood everything is fine
is 5 milli molar
but those mutants think there's 20 milli
molar so what will they do what will
they do now proliferate so certain
mutants because of this feedback loop
will proliferate will grow they have an
advantage over their brothers and
sisters and eventually they'll take over
that little island now ok so yeah but
that's not so good because now you have
all these better cells it's you really
have five in the mode but all their
cells think there's twenty millimolar
what will they do they'll create so much
insulin to push insulin back to what
they think is five millimolar but
exactly I'd say 1 millimolar and then
you die so meters will proliferate take
over push glucose down to what they
sense as 5 millimolar and then you die
so that's not good so what is glucose of
Sicily do
look at accessory basically kills the
strong strong mutants because for them
they die more than the right so it gives
mutants that mystery the signal a
selective disadvantage and that's the
way we think that if because of organ
sized problems and robust is to
parameters you need to have a feedback
loop over cell proliferation it's based
on the control signal glucose but then
inherently mutants in that read the
signal certain mutants will have a
growth advantage and will spoil the
system is very dangerous so you need to
have a biphasic situation where you have
to have like a to art like a drop and
then arise and death rate or a
proliferation or something in order to
get rid of those strongest mutants it's
just that there's still sensitivity to
mutants that miss read here which is
still these mutants here that miss read
the signal from five it's still a
problem so you can do certain things to
deal with that like make these islands
so that Amita takes over only an island
or not the entire thing and make the
proliferation rate small there and slow
down proliferation we think that's what
sets the slope will appear in race to
the age for example you can yeah is
there less and less of a problem but
they're still then you can basically
I've need to optimize how close you put
this glucose accessory how wide you to
optimize it because in one hand it
protects you against mutants on the
other hand makes you prone to diabetes
so it's like and that depends on your
lifestyle so there's a certain rodents
called a some onyx someone some both o
besos right now
they roll in to live here in the desert
and if you give them you into a lab and
you give them a regular food for mice
they get a Google Doc City and they die
basically so because they're used to
very they're really fasting diet and
what happens well as evolution pushed
this vice this
toxicity very close here this is in this
Simonis or basis because they rarely go
above they don't a problem with their
lifestyle you can see because they eat
they show shits my Lewis all these like
very great and so in different genetic
backgrounds probably also push this in
differently and we see that in different
ethnic backgrounds depends on a recent
pass of a starvation in history and
feast famine so so you can balance they
see the risk between a mutant take over
and dynamic instability this this is a
big lecture we talked about robustness
to three different things organized
controlled vibration and parameters
dynamic compensation how we can have
equations that whose dynamics is
invariant to a parameter of a distant
issue resistant to mutation and more
generally how to take our way of
thinking to the level of not proteins
and cells same way of thinking two level
of balance between different organs in
the body
hormonal systems that this field is very
fresh and of course much more to explore
as you can see it's linked directly to
aging diseases and that's say right now
taking major research interest in my
group is just to understand these
phenomena and basically I'm kind of in
love with this possibility right now I
hope you enjoyed it
I wish you a lot of health and see you
next week
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