Insulin. Is the control of insulin
secretion finally something we've
arrived at that is all about
carbohydrate or is even insulin
secretion mostly just about
cellular energy status?
Find out in today's lesson.
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.
Hi. I'm Dr. Chris Masterjohn of
chrismasterjohnphd.com. And you're
watching Masterclass with Masterjohn.
We are now in our 23rd in a series of
lessons on the system of energy metabolism.
And today we are layering in for the first
first time the effects of hormones.
And to begin our discussion of insulin
we're going to talk about what controls
insulin secretion. We still at this point have
been talking about fat versus
carbohydrate, we're not ready yet to
layer in protein because of its
complexity. So although protein effects
insulin secretion, we're going to talk
about it only to a limited extent today and
we're primarily going to focus
on fat versus carbohydrate.
Nevertheless we're going to tackle
what seems like an incredible conflict
between what we know about the
effects of nutrition and what
happens at the cellular level. Because
we know nutritionally that you get more
insulin when you have more carbohydrate
and less when you have less. And yet when
we look at the mechanisms governing energy
secretion in the pancreatic beta-cell,
it seems to be all about energy status.
So let's carve out this problem and show it
exists and then let's try to explain it.
Shown on the screen is the design of a
study looking at the effects of
different meal patterns on insulin and
glucagon. Glucagon is a hormone that
opposes the action of insulin.
Although it's associated with the fasted state,
you also get a lot of glucagon when you
eat things that aren't carbohydrates,
especially protein.
One of the reasons for this is that insulin,
in the case of protein, is taking amino acids
into cells, and if you just had protein
stimulating insulin for that purpose it would
lower your blood sugar. So you need to have the
opposing effect of glucagon to allow
certain functions of insulin and prevent
other functions of insulin that are
undesirable in that context. We'll
talk about that in much more detail when
we get to protein, but for now let's just
take a look at these meals. We have an
oral glucose tolerance test which is a
100% glucose. We have a high-fat
meal that's deriving from fat 72% of
its calories and only 23% from
carbohydrate. We have a high protein
meal that's deriving 64% of its energy
from protein and 26% from
carbohydrate. And we have a mixed meal which
is really the high carbohydrate meal, it's the
meal that is 60% carbs. So all of these
are mixed, but there's more emphasis on fat
versus protein versus carbohydrate.
In this diagram plasma insulin following
the meal is shown on the left and plasma
glucagon is shown on the right. You can
see that the glucose is shown with the
filled in circles and the glucose
produces the most insulin and it
produces the least glucagon. In fact what
you see here is that glucose on its own
not only raises insulin, but it
suppresses glucagon; high insulin and low
glucagon gives you the most activity of
most of the processes downstream from
insulin. In other words a high insulin-to-
glucagon ratio gets you the most insulin
signaling. The mixed meal, which is really
a high carbohydrate meal, is next in line
for high insulin and next in line for
lowest glucagon. You see that protein and
fat both stimulated similar amounts of
insulin, again this is in the context of
a mixed meal where there is carbohydrate
in the meal, but having the predominant
source of calories be protein or fat led
to considerable insulin and considerable
glucagon. For insulin the rise was fairly
similar between the high-fat meal and
the high-protein meal, but the insulin
peaked earlier for the protein meal and
peaked later for the fat meal. And for
glucagon the glucagon was highest in a
high-protein meal and was next highest
in the high-fat meal. So carbohydrate
gives you the highest insulin to
glucagon ratio and the highest absolute
insulin amount, that translates into the
greatest insulin signaling. Contrast this
with what we know about what governs the
secretion of insulin by the pancreatic
beta-cell. Inside the pancreatic beta-cell,
the single most important governor
of insulin secretion is a high ratio of
ATP to ADP. That means that it's the
cellular energy status that is the
central governor of insulin secretion in
the pancreatic beta-cell. This diagram
shows what happens in more detail.
And this is, in the context of a field over
insulin secretion in which there are
many controversies and disagreements,
this right here on the screen is the one
least controversial thing that you will
find as the consensus in any scientific
paper about what triggers insulin
secretion. When you have a low energy
state you have more ADP and less ATP.
This doesn't literally mean that you
have more ADP than ATP,
it just means relative to higher energy
conditions ADP is predominating. And when
you have a low-energy state mediated
through the ADP-to-ATP ratio, this
activates potassium channels in the cell
membrane. Those channels allow potassium
to leave the cell. Potassium is
positively charged, so having those
channels open means a net loss of
positive charge from the inside of the
cell and a net gain of positive charge
outside the cell. This leads to a
polarization of charge across the
membrane. Outside the cell is more
positive in general because of the
potassium, inside the cell is more
negative. When you have a polarization of
charge across the membrane you have a
voltage. You have voltage-sensitive
calcium channels that are blocked when
the membrane is polarized; they're
blocked in response to the voltage
across the membrane. When the calcium
cannot enter the cell, the calcium
concentration inside the cell is low.
Calcium is very frequently used as an
intracellular messenger. A low
concentration of intracellular calcium
ions keeps insulin from being secreted.
Some of that insulin is stored in the
middle of the cell where it's ready to
be moved at a later time; some of that
insulin is right associated with the
inside of the membrane ready to go when
first called. If the energy state of the
beta-cell increases, you get an abundance
of ATP relative to ADP. This change in
the ratio inhibits the potassium
channels.The potassium now cannot get
outside and that depolarizes the
membrane, meaning the polarity across the
membrane of charge, the voltage across
the membrane, now dissipates.
Positive charges can't get out.
So now you have an equilibration
where you have closer to electric
neutrality on each side of the membrane.
Since the calcium channels are sensitive
to the voltage this loss of voltage or
depolarization opens up those calcium
channels. Calcium comes into the cell, the
rise in intracellular calcium stimulates
a cascade of events that lead to insulin
being delivered to the cell membrane
with the vesicles opening up and
allowing insulin to travel outside of
the cell. This idea of changes
in membrane polarization triggering
some other event or cascade
of events, is extremely common in
cellular biology. This is just one
example of a common phenomenon.
So this being the part of insulin secretion that
is not controversial means that what we
know best about insulin secretion is
that it's governed by the amount of ATP
in the pancreatic beta-cell. How can it
be that nutritionally there's a specific
effect of glucose and yet at the level
of molecular biology and biochemistry
it's all about cellular energy status,
it's all about ATP? I believe the answer
is that we cannot explain the specific role
of glucose in insulin signaling by invoking
biochemistry or molecular biology.
I believe instead we need to
invoke anatomy and physiology.
Anatomy is the relationship between the organs
and the other structural features of our
body; physiology is how metabolism is
coordinated between those different
organs to orchestrate some overall net
result in the body that's more than the
sum of its parts. So let's take a look at
the anatomy and physiology of how
carbohydrates and fats would reach
a pancreatic beta-cell.
The pancreas is closely associated with the
organs of the digestive system.
Inside your torso underneath the cavity where
your lungs are, you have the liver,
you have the gallbladder located tucked
into the liver, you have ducts that lead
together into the small intestine,
you have the stomach, and you have that
lead into the small intestine, the first
section of which is the duodenum.
The pancreas is tucked underneath the
stomach relatively close to the liver
and gallbladder, but tucked into the
curve of the duodenum, giving it very close
access to the small intestine.
It's important to realize that glucose or fat
when we first eat it is going to go from
the stomach into the small intestine.
That does not mean at all that they have
direct access to the pancreas. The reason
The pancreas is tucked in with the
duodenum is because it plays a role in
digestion. Its role in responding to
nutrients to secrete insulin is not
related to the direct proximity to the
duodenum. The key role of the pancreas
in the digestive system is to make
digestive enzymes. So we have bile acids that are
made in the liver and come through the
hepatic duct, can be stored in the
gallbladder and come to the cystic duct
into the common bile duct and then the
pancreatic duct takes digestive
secretions from the pancreas, mixes them
with the bile acids and they
get carried into the duodenum so that
they can begin the digestive processes.
If we look inside a pancreas what we
will find is one to two million islets.
An islet is a collection of many cells
involved in hormone secretion, which
constitute the endocrine function of the
pancreas. The islets are surrounded by
circular arrangements of acinar cells in
acini that are responsible for
digestive secretions. These arrange
circularly around the islet and each of
the acini is itself a circle of cells
that can input the digestive secretions
into the middle of those cells to be
carried through the pancreatic duct into
the duodenum.
Inside the islet we have many, many cells.
We have alpha-cells, beta-cells, delta-cells
and F-cells. The alpha-cells make
glucagon, the beta-cells make insulin, the
delta-cells make somatostatin and the F-
cells make pancreatic polypeptide.
Somatostatin and pancreatic polypeptide
play special regulatory roles that are
not of concern to us in this discussion.
We're briefly touching on glucagon here
but we're primarily going to focus on it
once we get to protein. For our purposes
what we care most about is that 70% of
the cells in the islet are beta-cells.
How would carbohydrate and fat reach the
pancreatic beta-cell? Well in fact their
transport is completely different. If you
have carbohydrate coming into the small
intestine, it's going to travel through
the portal vein directly to the liver.
It's going to go to the liver with all the
other water-soluble nutrients in the
diet. That means the liver gets first
access to the carbohydrate. Well that's
important because the first thing you
want to do with carbohydrate is replete
your hepatic glycogen supply because
hepatic glycogen is what keeps your
blood sugar stable between meals. So you
can imagine already that if you're
running low on carbohydrate that in
itself is going to make less
carbohydrate ever reach the pancreas
because it's going to go to the liver
first to replete the glycogen stored
there. The hepatic veins then take
remaining carbohydrate into the inferior
vena cava, which is the vein that's going
to take those nutrients into the heart.
From the heart those nutrients reach the
aorta and they can go through multiple
arteries to either circulate to many
other organs or to go specifically to
the pancreas. By contrast if fats are in
the small intestine they're going to get
packaged into lipoproteins, which are
spherical particles that help them
transport through our system and are
called chylomicrons.
The chylomicrons are going to leave the small
intestine through the thoracic duct,
which is part of the lymphatic system.
These chylomicrons are going to
have long-chain fats and any other
fat-soluble nutrients. These fats are going
to go through the thoracic duct as part
of the chylomicrons and then empty into
the inferior vena cava, which is where
they first reach the circulatory system
and which is the part where they share
in common with the travel of
carbohydrate that had come from the
liver. Like the carbohydrates that came
from the liver, the fat that came from
the lymphatic system that never yet went
into the liver, is going to reach the
heart first; it's going to go through the
aorta; from the aorta it goes through
multiple arteries that can take it to
the pancreas or to the many other
organs. So the two key differences
between carbohydrate and fat so far is
that carbohydrate goes through the
portal vein and the liver has first
access before it ever gets to the heart
or pancreas. Fat goes from the small
intestine through the lymphatic system and
never goes to the liver until after it
goes through the heart, which has first
access, and then to the general
circulation where it can reach the liver
or the pancreas. If we look at how the
fat or carbohydrate would get inside
cells, it gets even more different.
We digest carbohydrate to free sugars.
In the case of starch, for example, we digest
it into glucose, or if we eat glucose we
get free glucose. If we have free glucose,
it transports
right into the cell through the glucose
transporters in the cell membrane.This
is a very simple transport system. The
transport of chylomicrons, of fats
contained in chylomicrons, is quite
different. In certain cells that make the
enzyme lipoprotein lipase, they can send
the enzyme out into the capillary beds
that nourish them. So let's say this is
the heart, the heart cell makes LPL, puts
it out into the capillaries nourishing the
heart. Same thing with the muscle, the
muscle cell makes the LPL sends it out
into the capillary bed. The capillary bed
is made of capillaries and the lumen of
the capillary is the area in which blood
flows. That lumen is enclosed by the
capillary endothelial cells, which make
the lining of the capillary.
The lipoprotein lipase, or LPL, will come out
of a cell that made it and become
embedded in the capillary endothelial
cell. That LPL will then take
chylomicrons and digest their fats into
glycerol and fatty acids. The chylomicron
gets digested into a chylomicron remnant
and that chylomicron remnant
gets taken up by the liver.
Meanwhile the glycerol and fatty acids
are available to the tissue that
made the LPL because the job of this
capillary is to feed that tissue.
So those nutrients get digested in the
capillary and infused into the cell.
The expression of glucose transporters and
LPL is very different. If you look at
glucose transporters, all tissues in the
entire body express GLUT1 and GLUT3.
These glucose transporters are high
affinity for glucose and not dependent
on insulin. That gives all tissues access
to the glucose that they need under any
condition. The liver and pancreatic
beta-cells also make GLUT2. GLUT2 has
low affinity, meaning it's only activated
at high concentrations of glucose and
it's not dependent on insulin. That
allows the liver and the pancreas to
ramp up glucose uptake when blood
glucose concentrations rise beyond their
normal level. In addition, muscle, heart
and adipose tissue make GLUT4.
GLUT4 has moderate affinity and it's
increased by insulin and AMPK.
AMPK increases GLUT4 because the cell
needs more energy.
Insulin increases GLUT4 because
the body needs the cell to take up
energy or to take up specifically glucose.
So we have all tissues expressing
GLUTs, some more than others,
some extra GLUTs that play specific
functions such as a response to insulin,
response to energy status or response to
circulating glucose. If you look at the
expression of LPL, it's expressed much
more limitedly. Almost all of the LPL is
expressed in muscle, heart and adipose
tissue. We know most about the LPL that's
expressed in those tissues. What we know
is that high energy status shifts
expression away from muscle and heart
and toward adipose. By contrast
low energy status does the opposite.
So think of the fat traveling through the meal,
remember it goes to the heart first.
If it goes to the heart first then if energy
status is low and the heart really needs
fat, the heart gets first access to that
fat and takes it up. But if energy status
is high the heart just looks at the fat and
it's like, "No I don't want this," that leaves
more available to muscle and adipose
tissue, but muscle also looks at that fat
and says "No, I don't want this." By contrast adipose LPL
is high under conditions of high energy
status. That makes fat go to adipose
tissue under conditions of high energy
status. Meanwhile there is also LPL
expression in macrophages, lung, kidney,
brain and lactating mammary glands.
The expression is much smaller than in
muscle, heart and adipose tissue; the
the regulatory mechanisms are
diverse and poorly understood. A typical
review of LPL expression across tissues
won't even mention its expression in the
pancreas, but if the pancreas doesn't
make LPL, how is it supposed to take up
postprandial fat from chylomicrons?
If you know studies that look at human
beta-cell LPL, please send them to me.
I couldn't find any, but I found studies in
mice. And what these studies show is that
in mice pancreatic beta-cells do make LPL.
However, under almost any condition the LPL is
inside the beta-cell. If the LPL is
inside the beta-cell that means there's
no LPL in the capillary lumen. That means
there's no LPL to digest chylomicrons.
That means that LPL does nothing to get
fat into that beta-cell. They've taken
the mice and they've subjected them to
fasting, to refeeding, to a normal chow diet,
to a high-fat diet, and the LPL just
sits in the pancreatic beta-cell.
The only conditions that make it leave the
beta-cell and go into the capillary
lumen, in these mouse and mouse cell
experiments, is high glucose
concentrations. We're talking 20 millimolar,
conditions of untreated diabetic
concentrations of high glucose.
That means that only under conditions of
very high glucose would you ever get fat
going into the pancreatic beta-cell
through locally expressed LPL.
But there's another way that fat in the
postprandial state could reach the
pancreatic beta-cell and that's from
fatty acid spillover. Let's say you have
an LPL-producing tissue that puts LPL
into the local capillary bed; it digests
chylomicron triglycerides into free
fatty acids and glycerol. In general
these are completely or mostly taken up
by the LPL-expressing tissue. But what if
you have so much fat that you overwhelm
that tissue and there's no room to take
up all the fat that's been digested?
Or what if you're fat, what if that tissue
is fat, and all the room within that cell
is taken up by fat; or what if the energy
status of that cell is so high that it's
blocking the uptake of everything?
In those cases you may get digestion of the
chylomicrons into free fatty acids and
glycerol that get left in the blood.
And since they don't get taken up by the
tissue, they leave the capillaries through
the veins and then they eventually make
their way into the circulation to get to
other tissues such as the pancreas.
That's called fatty acid spillover, and it's
thought to be increased by
high-fat diets, obesity and insulin resistance.
So, so far we have glucose
going to the liver first and we're
repleting the hepatic glycogen. Whatever
glucose is left over, it goes to the heart
and eventually can make its way
to the pancreas.
By contrast fat goes through the
lymphatic system, it goes first to the heart
and if the energy status in the heart is
low the heart gets first dibs on the fat,
if it's high that fat preferentially
goes to adipose tissue, not necessarily
ever making it to the pancreas. Glucose
transporters are expressed in the
pancreas. In fact the pancreas also
expresses GLUT2, a special glucose
transporter that makes glucose uptake
kick in even higher than normal whenever
circulating concentrations of glucose are high.
The liver does the same thing.
That means that high blood glucose goes
preferentially first to the liver to
replete hepatic glycogen, and second to
the pancreas for insulin stimulation.
In addition, the pancreas also has a special
form of hexokinase that doesn't get
inhibited by glucose-6-phosphate.
We talked before about how if you don't go
through glycolysis, glucose 6-phosphate
builds up and that rejects the glucose.
In the pancreatic beta-cell we have
glucokinase, a special form of hexokinase
that is not inhibited by
glucose-6-phosphate. That means that the
pancreatic expression of glucose
transporters and hexokinase isoforms is
designed to facilitate glucose uptake
into the pancreas, not because the
pancreas needs more glucose, but
specifically because the circulating
glucose concentrations are high. This is
not true for fat because
the pancreatic beta-cell appears not to
move LPL into its local capillary bed
unless possibly exposed to very high
concentrations of glucose mimicking
untreated diabetes. But the pancreatic
beta-cell still gets some fatty acids in
the postprandial state from fatty acid
spillover if the meal is very high in
fat or if the person is obese or insulin
resistant. So it seems then that it is
the anatomy and the physiology that
coordinate the inter-organ distribution
of these nutrients that drives the
effect on insulin secretion instead of
the biochemistry and the molecular and
cellular biology that occurs within the
pancreatic beta-cell. Nevertheless the
mechanism that I showed you at the very
beginning is what's called "triggering."
There's also an amplification step to
insulin secretion, and the amplification step
is much more complex and much more
controversial. So let's say that it's
glucose that is primarily the nutrient
that can raise ATP levels in the
pancreas, inhibiting the potassium
channels, depolarizing the membrane,
activating the calcium channels, getting
a rise of intracellular calcium,
initiating a cascade of events that
leads insulin to be secreted.
Well there's that and that's the
uncontroversial consensus part of this.
But the amplification step can make the
cell more sensitive to the influx of
calcium or can increase the capacity to
respond to that calcium by making more
insulin ready to be mobilized. And these
amplification signals are, number 1,
very complex, and, number 2, not at all
agreed upon. We may be moving toward a
consensus eventually, but if you look at
even recent reviews of this topic you'll
see lots of controversy about which
mechanisms are more important,
and even some controversy over which
mechanisms actually play out in the live
human at all. If we look at these
amplification signals what we will see
is that anaplerosis, which is the
filling up of citric acid cycle
intermediates, can occur in a way that
overfills the citric acid cycle and leads
to cataplerosis, which is the leaving of
citric acid cycle metabolites including
their transport into the cytosol. Since
anaplerosis is primarily the domain of
carbohydrate and as a secondary source
protein rather than fat, then that means
that cataplerosis is primarily enabled
by carbohydrate and secondarily protein.
That cataplerosis then leads to
amplification signals. Lipogenesis leads
to various downstream processes from the
accumulation of fat in the cell. Lipogenesis
is driven by malonyl CoA.
Malonyl CoA can be derived from
anything that makes acetyl CoA and
citrate because citrate activates the
conversion of acetyl CoA to malonyl CoA,
as we talked about in the
lesson on fat burning. Since carbs,
protein, and fat can all generate acetyl CoA,
and can all generate citrate, and carbs, protein,
and fat can all lead to malonyl Coa and
lipogenesis and can all, to some extent,
lead to that amplification symbol.
That amplification signal.
Some of this is driven by the
pentose phosphate pathway's production
of NADPH, a topic that we haven't covered yet.
It's carbs specifically that support
the pentose phosphate pathway and
provide that NADPH that go into that
amplification signal. So what we see
then is that all of the macronutrients
can make some contribution to
amplification. But carbohydrates are the
most versatile out of all of them and
fats are the least versatile.
Perhaps that versatility in providing
the amplification signal is simply a way
to gauge the versatility of
carbohydrate. Because carbohydrate is
also the most versatile in supporting
the biochemical pathways that you
actually need. So if the body is trying
to judge whether it has enough energy, it
makes sense that part of that signal
would be specifically driven by
carbohydrate because carbohydrate is the
thing that supports the pentose
phosphate pathway, whereas fat doesn't.
Carbohydrate is the thing that supports
anaplerosis of the citric acid cycle,
which fat doesn't to anywhere
near the same extent. And so it
may actually be that the pancreatic
beta-cell is, as the mechanism of
triggering would suggest, simply gauging
energy status. And it may be that the
pancreas correctly looks at carbohydrate
as especially valuable source of energy
because the energetic uses of
carbohydrate are more versatile than
those of other macronutrients,
especially fat. And if carbs provide
energy plus the specific uses of energy
that fat can't, then carbs are a uniquely
valuable source of energy. So when I look
at this what I see is the pancreatic
beta-cell wants to make sure that we
have enough energy; but it wants to
specifically make sure that we have
enough glucose because of the specific
things we can do with that energy that
are much harder to do with the energy we
derive from fat. So is insulin responding
to carbohydrate specifically or is it
responding to energy status in general?
The answer is both.
The anatomy and physiology bias
carbohydrate to the pancreas when
it reaches high concentration providing
the liver has the first opportunity
to replete the hepatic glycogen pool.
That same anatomy and physiology biases
fat toward the heart and muscle under
low-energy conditions and toward adipose
tissue under high-energy conditions, and
biases it away from the pancreas under
any conditions except possibly severe
hyperglycemia.
Then the biochemical pathways
within the pancreatic beta-cell
are mostly responding to cellular energy
status. But because the pancreatic
beta-cell's energy status is best
nourished by carbohydrate, then
carbohydrate plays a specific role in
triggering insulin. Carbohydrate also
plays the dominant role, with protein second
and fat a distant third in amplifying
that insulin signal. Because, perhaps, the
pancreas cares that we don't just have
enough total energy, but that we have the
versatility that we get from having
carbohydrate as a part of that energy.
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
can find them on my YouTube channel at
youtube.com/chrismasterjohn.
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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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