You eat carbs and your pancreas
makes insulin. What does insulin make
you do with those carbs?
Store them as fat? Maybe if you're
eating enough calories to make that
happen. But in the context of a healthy
energy balance insulin is going to make
you burn those carbs for energy. If you
want to know how it does that, listen on.
A ketogenic diet has neurological benefits.
Why do we have to eat such an
enormous amount of food?
Complex science.
Clear explanations.
Class is starting now.
In the last lesson we saw that
insulin is primarily a gauge of the
energy status of the pancreatic
beta-cell. But the way that carbs and
fats are wired to the pancreas and to
other organs, in the context of the
anatomy and physiology and the relative
expression of glucose transporters and
lipoprotein lipase, directs carbs as the
primary source of energy for the
pancreatic beta-cell; and for that reason
carbohydrates are especially good at
giving us more insulin signaling. Now in
the next few lessons we're going to look
at what insulin does to that
carbohydrate or does to that fat,
and we're eventually going to converge on
the question of, can insulin actually
make you fat as is often promoted in
many corners of the internet? Or is
insulin just helping you make decisions
about which energy to spend and how?
And we're going to start this foray
into the effects of insulin by looking
in this lesson at, what does insulin do to
carbohydrate metabolism?
So without further ado let's get
right into those details.
As shown on the screen insulin
outside the cell binds to the
insulin receptor. The insulin receptor is
present in the cell membrane and insulin
doesn't need to come into the cell to
carry out any of its effects. Instead the
event of insulin binding to its receptor
initiates a cascade of multiple
phosphorylations and ultimately this
leads to the activation of certain
enzymes that dephosphorylate many of the
enzymes that are directly involved in
energy metabolism. Exactly which thing
phosphorylates which thing in this
cascade is extremely complex and is
more the subject of the molecular and
cellular biology of insulin signaling.
We're going to focus more on energy
metabolism, the topic of this course,
so we're glossing over a lot of the
details of these events here. The first
thing that insulin binding to its
receptor does to glucose metabolism is
in tissues that express GLUT4 which is
primarily expressed in muscle and
adipose tissue, insulin causes GLUT4
to be transported from intracellular
vesicles to the cell surface.
And when that happens that makes the
GLUT4 available to transport glucose into
the cell or out of the cell.
Now remember that glucose transporters don't provide
any direction to glucose transport. They
only increase the rate of glucose
transport. So simply bringing GLUT4
to the membrane is not necessarily going
to bring more glucose into the cell all
by itself unless there's something that
keeps glucose at very low concentrations
within that cell.
As we've discussed in previous lessons,
it's hexokinase, the enzyme that
phosphorylates glucose that provides
directionality to the flow of glucose
into the cell. The glucose transporter
allows the reversible transport of
glucose in or out of the cell, but when
hexokinase metabolizes glucose to
glucose-6-phosphate
that makes the concentration of free
glucose extremely low in the cell.
It is only free glucose that's
recognized by the glucose transporter.
So if the free glucose inside the cell is
extremely low because it's all become
glucose 6-phosphate then that makes it
energetically favorable for glucose
outside the cell to follow its
concentration gradient and come in.
So it's GLUT4 that's increasing the rate
of glucose transport in response to
insulin, but it's hexokinase that's
providing directionality to make sure
that the glucose comes into the cell.
And so insulin couldn't do much to bring
glucose into the cell if it didn't have
an effect on hexokinase. And in fact,
there's a specific isoform of hexokinase
or a specific isozyme of hexokinase
known as hexokinase 2.
Hexokinase 2 is the insulin-responsive
form of hexokinase just like GLUT4 is the
insulin-responsive form of glucose
transporters. By stimulating GLUT4 and
hexokinase 2, insulin helps increase the
rate of glucose transport and increase
the directionality to make sure that the
glucose is coming into the cell.
Shown on the screen is a possible model
of how hexokinase is regulated by insulin to
increase its activity.
In the absence of insulin,
hexokinase would largely be located in
the cytosol where it would have access to
glucose and ATP as they diffused through
the cytosol, and when they happen to come
in contact with hexokinase, hexokinase
would catalyze their conversion to
glucose 6-phosphate
and ADP. That ADP would have to go back
to the mitochondrion to become ATP, that
ATP would have to come out of the
mitochondrion and then diffuse through
the cytosol until it came into contact
with glucose and hexokinase. In this
model many other enzymes could have
access to that glucose or that ATP.
It may be the case that what hexokinase
does, or hexokinase 2 does in response
to insulin to increase its activity is
that hexokinase may bind to the voltage-
dependent anion channel or VDAC in
the outer mitochondrial membrane. We are
going to talk a lot more about VDAC in
the next lesson when we talk about fatty
acid transport. But for now we'll say
that VDAC transports many things
including ATP and ADP in the outer
mitochondrial membrane. And if insulin
makes hexokinase 2 bind to VDAC, then
this would give it preferential or even
exclusive access to the ATP coming from
the mitochondrion. Instead of coming
through VDAC and diffusing until it
came into contact with hexokinase, ATP
would go straight to hexokinase, glucose
would be turned into glucose 6-phosphate
because hexokinase has the exclusive
access to any ATP that comes through
VDAC; and the ADP would go straight back
through VDAC, back into the
mitochondrion to be turned into more ATP.
Now this hasn't been shown for certain.
But I'll tell you this, there's a body of
literature showing that insulin
stimulates the activity of hexokinase 2.
There's a small number of studies
from a long time ago
showing that the way it
does that is it increases the binding of
hexokinase to the mitochondrial membrane.
There's now a newer body of literature
showing that several percent of the
VDAC pores in the mitochondrial
membrane are always bound by hexokinase.
And this is of particular interest to
cancer researchers because it seems that
in certain types of cancer where glucose
metabolism is greatly ramped up in the
context of what's called the Warburg
effect, something beyond the scope of
this lesson, in those cases you have a
very large percent of VDAC that are
bound to hexokinase. But in normal
healthy people it's always the case that
several percent of the VDAC in the
outer mitochondrial membrane is bound
by hexokinase. So if we put together the
older literature showing that insulin
increases its activity by making it bind
to the mitochondrial membrane, and the
newer research showing that the
hexokinase bound to the mitochondrial
membrane is bound to VDAC,
then the model that I've put on the screen
strikes me not merely as possible,
but highly probable. In any case,
insulin increases the
activity of hexokinase 2 probably by
the mechanism shown on the screen,
perhaps by some other poorly understood
mechanism that we don't know that much
about right now.
Once glucose becomes glucose 6-phosphate
it is not yet irreversibly committed
to glycolysis. It's only irreversibly
committed after fructose 6-phosphate
becomes fructose 1, 6-bisphosphate, the
conversion of which is catalyzed by
phosphofructokinase.
As discussed previously,
phosphofructokinase is the key
regulator of the flux through the
glycolytic pathway, and it's regulated by
energy status. When the cell has a lot of
energy ATP inhibits it; when the cell has
very little energy AMP activates it.
So if insulin makes glucose become
glucose 6-phosphate,
and energy status is low,
phosphofructokinase activity is very high,
and glucose 6-phosphate becomes
irreversibly committed to the glycolytic pathway
and is burned for energy. This is
important because glucose 6-phosphate
can also be used for glycogen synthesis.
But glucose 6-phosphate itself is an
activator of the enzyme glycogen
synthase and glucose 6-phosphate only
accumulates at a high enough
concentration to activate glycogen
synthase when phosphofructokinase
activity is inhibited by high energy
status. Now there's some debate about the
relative importance of insulin and
glucose 6-phosphate in stimulating
glycogen synthase. The majority opinion
is that glucose 6-phosphate is the
dominant regulator of glycogen synthase,
the key rate limiting enzyme for glycogen
synthesis. If that's true, then insulin is
primarily signaling that carbohydrate is
available and enhancing the effect of
glucose 6-phosphate if high energy status
inhibits phosphofructokinase and makes
glucose 6-phosphate accumulate.
But even if you were to make the argument that in
some contexts insulin can become more
important than glucose 6-phosphate as an
activator of glycogen synthase, it's
still the case that glycogen content is
the strongest regulator of glycogen
synthase out of everything known. So if
insulin does direct glucose into
glycogen synthesis it's only going to do
that until glycogen content is replete.
Even in that circumstance that would
make glucose 6-phosphate become
available for the glycolytic pathway and
it would still be the energy status of
the cell that's the dominant factor in
what you burn for energy. Now if we think
about what should be the case, that cell
is going to starve to death if it's need
for energy doesn't take predominance
over its need to restore glycogen.
So it seems extremely doubtful that
insulin is more dominant than
glucose 6-phosphate in stimulating glycogen
synthase. Most probable is the situation
described in the typical textbook and by
the majority of researchers in this area
where glucose 6-phosphate itself is the
key activator and insulin has a
secondary role. In that context then it's
the energy demand of the cell that is
the overwhelming determinant of whether
you take glucose 6-phosphate and burn it
for energy or store it as glycogen.
And what that means is that insulin enables
you to do either one of those things, but
if you need more energy you burn the
glucose for energy and if you don't you
store it as glycogen until the glycogen
content is full. So the picture that this
paints is that in the context of low
energy status when the cell needs ATP, in
other words when you're in a relative
caloric deficit instead of a relative
caloric excess, then the net effect of
insulin is to irreversibly commit
glucose to glycolysis. Because insulin
stimulates GLUT4, increasing the rate
of glucose transport. Insulin stimulates
hexokinase 2, increasing the
directionality of glucose transport from
outside the cell to inside the cell
because of the rapid depletion of
glucose as it's converted to glucose
6-phosphate. Glucose 6-phosphate is
reversibly converted to fructose
6-phosphate along a concentration
gradient and fructose 6-phosphate is
irreversibly committed to glycolysis by
phosphofructokinase when energy status
is low because of the activation by AMP.
But everything that insulin does to
glycolysis is like everything else that
insulin does to energy metabolism, which
is that the cell integrates
what insulin is telling it about the
needs and abilities of the body, with its
own signals about its own needs and
abilities; and the cell integrates that
information and it makes the final
decision of what it does with the glucose.
So we talked in previous lessons,
especially in lesson 5, about how AMPK
also stimulates GLUT4. So GLUT4
increases in response to low energy
status or a caloric deficit within that
cell and in response to insulin, which
signals a high availability of glucose
systemically throughout the body.
GLUT4 is integrating both of these signals and
whether it increases is
determined by the balance of both of
those signaling processes. Glucose
is then converted to glucose 6-phosphate.
This is definitely stimulated by insulin
and it's definitely stimulated by low
glucose 6-phosphate, because remember
glucose 6-phosphate is a negative
feedback inhibitor of its own production
by inhibiting hexokinase 2. Glucose
6-phosphate is maintained at low
concentrations during the context of low
energy status because AMP activates
phosphofruktokinase and clears glucose
6-phosphate through the glycolytic
pathway. At a minimum, then, hexokinase 2
is integrating signals from insulin
about whole body glucose availability
and from glucose 6-phosphate,
which is determined by
phosphofructokinase activity, which is in
turn determined by energy status.
It's probably also the case, I suspect, that
AMPK stimulates hexokinase 2. The
research seems less clear to me about
that, but this is probably another way of
the cell responding to energy status as
well as insulin in determining what
to do with glucose.
Now on top of everything that insulin does
to glycolysis it also stimulates the
burning of pyruvate, the end-product of
glycolysis, for energy, by stimulating its
conversion to acetyl CoA. But just like
everything else that insulin does to
energy metabolism the cell is going to
integrate information from insulin with
the many other relevant factors that are
going to determine what it decides to do
with the pyruvate. And principal among
those factors are the cells own need for
energy. So the pyruvate dehydrogenase
complex, which remember takes pyruvate
from glycolysis, decarboxylates that to
release carbon dioxide, takes the energy
from that process and puts part of it on
NAD+, so NADH can carry the energy to the
electron transport chain, and puts part
of it into acetyl CoA and acetyl CoA
then takes the rest of that energy down
into the citric acid cycle; that complex
pyruvate dehydrogenase is inhibited by
its own products, acetyl CoA and NADH.
But on top of this it can be
phosphorylated which makes it less
active, as signified by the red arrow at
the top saying phosphorylation
inactivates the complex, or it can be
dephosphorylated which makes it more
active, signified by the green arrow at
the bottom saying dephosphorylation
activates the complex. The enzyme that
phosphorylates it is pyruvate
dehydrogenase kinase.The enzyme that
dephosphorylates it is a phosphatase.
Now the phosphorylation of pyruvate
dehydrogenase is regulated by many
factors that directly stimulate or
inhibit either the kinase or the
phosphatase. Insulin stimulates the
phosphatase, that makes pyruvate dehydrogenase more
active by putting it into its
dephosphorylated state. But insulin is
hardly the only thing that impacts that;
calcium ions also activate the
phosphatase. Remember that calcium in
its ionic form inside a cell often
activates the cell. Not the only example,
but the prototypical example of that is
that when you contract your muscles your
nervous system is causing calcium ions
to be released within your muscle cell
and those calcium ions are what
are activating the muscular contraction.
So when calcium ions are released inside
a cell that allows the cell to
anticipate that very rapidly its energy
needs are going to increase and that
calcium acts as an anticipatory signal
to ramp up energy metabolism. So just
like insulin, which signals the
availability of carbohydrate to be
burned for energy through this reaction,
calcium signals the need for energy
inside the cell no matter where it comes
from, but one of those places is going to
be pyruvate. The pyruvate dehydrogenase
kinase, which is inactivating pyruvate
dehydrogenase, is inhibited by pyruvate.
Pyruvate signals that, hey there's
pyruvate available to go through this
complex and become acetyl CoA.
So pyruvate stops the kinase from
inactivating the complex and makes the
complex more active. NAD+ and
coenzyme A in its free form are present
in low energy states. In high energy
states NAD+ becomes NADH; CoA
becomes acetyl CoA, or another acyl CoA.
So signals of the need for energy are
inhibiting the kinase, preventing it from
inactivating the complex, and like
pyruvate making the complex more active.
By contrast acetyl CoA and NADH, which
are the products of the pyruvate
dehydrogenase complex and are also
signals of high energy, as well as ATP,
another signal of high energy, all
activate the kinase, making it more
likely to inactivate pyruvate
dehydrogenase. Now this can sound pretty
complicated to talk about something
inactivating this thing that stops it
from inactivating that thing and makes
that thing more active. So let's go to a
different diagram that simplifies this
information. Once glucose goes through
glycolysis to generate pyruvate, the
pyruvate is decarboxylated by the
pyruvate dehydrogenase complex;
releasing CO2 and becoming an acetyl group that
joins two free CoA to make acetyl CoA.
This is an oxidative process so NAD+
oxidizes the intermediates to become
NADH carrying electrons and hydrogen
ions to the electron transport chain. The
acetyl CoA can then enter the citric
acid cycle to be burned for energy.
Insulin is stimulating the pyruvate
dehydrogenase complex as a signal that
there's plenty of glucose and pyruvate
available for this reaction. Acetyl CoA
and NADH are both products of the
reaction and are inhibiting it in a
negative feedback loop. If they're being
produced at rates beyond what the
electron transport chain can oxidize in
the case of NADH, and beyond what the
citric acid cycle can metabolize in the
case of acetyl CoA, these come back and
tell pyruvate dehydrogenase to stop
making the products that are
accumulating. But ATP also comes as a
general signal of having enough energy
to inhibit the pyruvate dehydrogenase
complex. In the context of today's lesson
we're going to look at this as a way of
augmenting the earlier regulation of
glycolysis, where insulin comes in to
tell pyruvate to be burned for energy,
but having enough energy contradicts
that signal. Once again, we see insulin
as not the key determinant of what happens
in the cell, but simply as a messenger
that provides some information about
what's going on in the rest of the body
that then allows the cell to integrate
that piece of information with
information about its own needs and
abilities to make a concerted decision
about what to do that integrates all
these different pieces of information.
Eventually we'll come back to this
because we'll see that the predominant
reason that we're still regulating
pyruvat , even though we already told
glucose to come down through to pyruvate
to get burned for energy, because of the
earlier regulation in glycolysis,
the primary reason we still need to regulate
pyruvate is because pyruvate itself
could have multiple fates such as
conversion to alanine, such as conversion
to oxaloacetate for anaplerosis, and such
as rewiring up through the process of
gluconeogenesis. When we get to the point
where we're ready to talk about
gluconeogenesis we'll come back and talk
about the functions of these regulators
in that context. But for now we can
simply see this as another example of
insulin helping us burn carbohydrate for
energy, which is a signal that's
contradicted when we have all the energy
we need. So in the context of healthy
energy balance where when we eat a meal
because we need the energy in that meal,
the combination of insulin from
carbohydrate and the need for energy
because of our caloric balance, is going
to lead to the net effect of burning
carbs for energy. Insulin is going to
lead to glucose uptake and glucose
phosphorylation. Energy status is going
to take over and through regulation of
phosphofructokinase is going to drive
glucose 6-phosphate through glycolysis to make
pyruvate. Insulin then stimulates the
conversion of pyruvate to acetyl CoA.
Once we have acetyl CoA, we have the
same acetyl CoA that we could have
gotten from protein or from fat. We have
it entering the citric acid cycle, which
is not governed by hormones, but is
instead governed by the need for ATP and
the abilities of the electron transport
chain to meet the demands placed on it.
The audio of this lesson was generously
enhanced and post-processed by
Bob Davodian of Taurean Mixing.
Giving you strong sound and dependable quality.
You can find more of his work at
taureanonlinemixing.com.
To continue watching these lessons, you
you can find them on my YouTube channel
youtube.com/chrismasterjohn.
Or on my Facebook page at
facebook.com/chrismasterjohn.
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All right, I hope you found this useful.
Signing off, this is Chris Masterjohn of
chrismasterjohnphd.com. You've been
watching Masterclass with Masterjohn.
And I will see you in the next lesson.
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