Why Too Much Sugar is Toxic | Jerry Hart, Ph.D.

Why Too Much Sugar is Toxic | Jerry Hart, Ph.D.

November 10, 2019 6 By Jose Scott


Okay, so one of the points I
wanted to start out making is, as Americans, we’re all
eating way too much sugar. The average American is
eating about 140 pounds of sugar annually, that equates
to about 57 gallons of soda. 100 years ago or so
we ate about 10 pounds, so it’s gone up enormously. This is mostly in the form of
sucrose, table sugar, glucose, and fructose. And fructose is particularly bad
because sugar is not sugar, as you’ve heard the corn companies
say, it’s simply not the case. Fructose is metabolized quite
a bit differently than glucose. And in fact high fructose corn
syrup is now very cheap compared to sucrose, for example. But it’s ubiquitous, it’s in virtually every
processed food you look. And I encourage you, when you go to the grocery
store, usually the first or second ingredient in things like
ketchup and almost anything. In fact, this weekend I was
trying to find chocolate milk for my granddaughter, and I had
trouble finding chocolate milk where the second ingredient
wasn’t high fructose corn syrup. And I think this is really bad,
because fructose, unlike glucose and table sugar, sucrose has
both glucose and fructose in it. And so glucose is actually
stimulates insulin signaling and is regulated. However, when you eat large
quantities of fructose, almost all of it goes to the
liver and is metabolized as fat, and it doesn’t turn on insulin
signaling to regulate. And it also, eating a lot
of sugar makes you hungry. It actually inhibits the signals
in your brain that tell you to stop eating. And so
if you think about diabetes, and I’m struck by the fact, and
my own family is this way, if people are diagnosed with cancer
or heart disease or something else, they really get upset and
they take it seriously. A lot of people when
they get diabetes don’t think it’s any big deal. It’s a very big deal. The number of people that die
from diabetes every year is on the order of 70,000 directly and 250,000 indirectly a year
In the United States. And why is that? Well, you have hyperglycemia,
or high blood sugar for prolonged times, what happens is you develop particularly the
symptoms shown on this slide. So, for example, your kidney
quits working properly, so you have nephropathy. It’s a major cause of blindness,
you get retinopathies. A lot of people that have
diabetes, something like 74% of them, have neuropathies
of the feet in particular. It’s a major cause
of amputations. Cardiovascular disease, a lot of it is, in fact,
indirectly caused by diabetes. The beta cells, when they’re
exposed to high glucose for a long amount of time lose the
ability to even make insulin, and that contributes to
the later stages of the disease. And of course your liver and
skeletal muscle and adipose become resistant to
insulin the more it’s exposed to high glucose. So why is prolonged
blood sugar so toxic? If you think about
this as a chemist, these sugars are not
toxic molecules at all. They’re not chemically
reactive all that much. So why are they so toxic? Ugh. So it turns, this, I’m not so
a big fan of this thing. So it turns out that several
years ago my laboratory discovered a modification
of proteins that involves the direct attachment of sugar
to practically every regulatory protein in the cell, in
the nucleus and the cytoplasm. What this sugar is is
a molecule of glucose that has a nitrogen and a so-called
N-acetyl group attached to it. It’s an enzymatic
modification and it’s very much analogous to what
you’ve heard about in signaling, about phosphorylation. It acts like a switch that
turns proteins on and off much the same way phosphorylation
does, but it’s a sugar. It’s an extremely
abundant modification. So far, about 4,000 proteins
have been identified. But, you can get a feel for
it in that gel up there, in the corner, is a 2D gel, just
giving you an idea of how many proteins are in the nucleus or
cytoplasm of most cells that have this
sugar attached to them. It’s most abundant,
as it turns out, in the pancreas, the brain,
and lowest in the liver, but it turns out the liver has
the highest dynamic range of this modification. And this sugar cycles on and off
proteins during their lifetime and it turns out it’s
a nutrient sensor. It’s the way your
cells in your body regulate what their proteins
do in response to nutrients. And it’s a perfect nutrient
sensor because the donor of the sugar is a molecule
called UDP-GlcNAc are UDP anti-glucosamine and the
biosynthesis of this molecule is directly tied to glucose,
amino acid, fatty acid and nucleotide metabolism. So the metabolic pathways
in your cell raise and lower the levels of UDP-GlcNAc,
which in turn help determine the amount of this sugar that’s
attached to your proteins. And it turns out that the site
on the molecules where this sugar is attached in many
cases are the same sites that are often phosphorylated in
signaling transduction pathways. And so signaling you can think
of as microcircuitry that controls the protein’s functions
in metabolism much the same way switches do and it turns out that the O-GlcNAc
sugar is like a rheostat that modifies the signaling
in response to nutrients. And because it has this
complex relationship with phosphorylation it’s involved
in virtually everything the cell does including gene
expression by transcription, nutrient sensing, it’s
involved in numerous diseases. So this is an example of how
sensitive, if you take a cell, this one happened
to be a lymphocyte. And you expose it to
increased levels of glucose, you can see from the top panel,
that’s normal glucose. And if you expose it to
diabetic levels of glucose, the number of proteins and
the amount of proteins that have this sugar attached to
them goes up dramatically. And, so, we now, and
others, now think that this is one of the major
molecular mechanism of why so much goes wrong when you have
prolonged hyperglycemia, or too much glucose,
surrounding cells. And, so, how might this work? Well it turns out that,
as I said, signaling molecules, the switches that regulate
metabolism, are regulated by this nutrient sensor, this
sugar attachment to proteins. And so there’s a balance
between phosphorylation and the addition of this sugar that
gets out of whack when sugar stays up too high. It turns out that virtually
every protein that’s involved in regulating the expression of
genes is modified by this sugar, and we’re just beginning to
learn how this sugar plays a role in whether genes get
activated or not activated. And also it turns out that
mitochondria, we’ve known for a long time that in diabetes,
when glucose gets high, the mitochondria
quit working right. We never had understood
the relationship. How does high glucose cause a
mitochondria to not work right? And when the mitochondria
doesn’t work right, it makes these reactive
oxygen species that do further
damage to the cell. So what I wanna do now is just
go through one example or so of each one of these
kinds of processes and how they’re important
to toxicity of glucose. So one of the things that
happens in both adipocyte and muscle is, we know about the
insulin signaling pathway, so insulin binds to
its receptor and then through a complex
cascade of signalling. It causes GLUT-4 vesicals
to go to the surface and bring in glucose and this helps
lower the glucose in the blood stream and it’s very important
in skeletal muscle and. Well it turns out that when the
sugar levels get high, O-GlcNAc, this sugar I’m talking
about goes up and it actually stops insulin
signaling at all the steps that are shown
there with a star. So it’s a molecular mechanism of
what we call insulin resistance. The second thing is we now
know that virtually half and maybe more of the kinases that
regulate these signalling cascades are themselves
modified by this sugar. And I have a list of ones that
have recently shown how they’re regulated by it. And an interesting example of
this, from a collaboration we did with Don Bers at UC Davis
talks about Cam Kinase II. Calcium–calmodulin kinase II. This is the kinase that
regulates your heartbeat. It’s very important in
regulating calcium flux in your heart. And it turns out in diabetes,
this GlcNAc sugar, which normally is not there, attached to it at the position
shown here in the molecule, and it causes this enzyme to
become constitutively active. And so therefore it contributes
greatly to arrhythmias in the heart with individuals
that have diabetes. Another example from work
in our lab by post doc named Sherket Peterson, we were
looking at the expression. So she’s really interested
in diabetic nephropathy, or the kidney function. And there’s two proteins in
the kidney called nephron and potassan. In this cartoon, they’re
the filtration apparatus that make the kidney filter
out large molecules and let the rest of
the urine pass through. What happens when O-GlcNAc is
high, as it is in diabetes, you can see the levels
in this label TMG, which is an inhibitor of the
enzyme that removes the sugar, the addition of this
sugar gets very high. It turns out that when the
addition of this sugar is high on the proteins that
regulate gene expression, called transcription factors. As you can see on this
bar graph, the black and the grey bar going down
on both nephron and potassan these genes
are no longer transcribed. And basically the filtration
apparatus of the kidney begins to fall apart, because the proteins that make
it are not being made properly. And you can reverse this, even in high glucose, if you add
an inhibitor of the enzyme that adds this sugar to proteins,
you can see in the checkered bar that the transcription of
these proteins is restored. Now, coming back to
the mitochondria, so why does the mitochondria quit
working when glucose is high? It didn’t really make a whole
lot of sense biochemically. Well, it turns out there’s about
88 proteins in the mitochondria in the electron transport chain. And this is the portion of the
cell that makes ATP from glucose and other molecules and makes
energy that drives your cells. And 88 proteins involved in
that have this sugar attached to them. And it turns out that in normal
mitochondria, when the levels of this sugar goes up, it actually
makes the mitochondria work better to make more, as it would
If the nutrients are around. But if you look at diabetes, it
turns out that the enzyme that adds this sugar,
by mechanisms we don’t yet understand, becomes
mislocalised. Normally it’s located in
a protein complex called complex IV in the complexes
that make ATP. But in diabetic animals a lot
of it moves to complex III, and as a consequence of that,
a whole different set of proteins become modified with
this sugar that normally would not be modified to this
extent in the mitochondria. And this actually results in
the mitochondria not working properly. So there now is a direct link
to having hyperglycemia, or high glucose, and the
misfunction of the mitochondria. And the last thing I wanna talk
about is appetite control. So we’ve already heard that
there’s a reason in your brain, called the para-ventricular
nucleus in the hypothalamus that,
where lepton signals and other things and it’s
involved an appetite control. And together with Rick Huganir’s
lab in Neurosciences at Johns Hopkins, a graduate
student Olof Lagerlof decided to knock out the enzyme that
adds this sugar in adult mice in that region of
the brain and ask what happens. Well it turns out within two to
three weeks you get a morbidly obese mouse. This mouse cannot stop eating. And it’s a little bit like
the lepton mouse you heard, about except in this case, what
this is telling us is not only is this sugar a nutrient sensor
in every cell in your body, but it is also a nutrient
sensor in your brain. It tells your brain how
much glucose is there and it’s one of the mechanisms
in controlling appetite. And so what I have told you
about is a sugar modification that’s really quite
ubiquitous in biology. All plants and animals. It’s actually required for life, even at the single cell
level in mammals and plants. It has this cross-talk with
other molecules in signaling like phosphorylation. It’s very important
in gene regulation. And we know very little bit how
it works in regulating whether genes get transcribed or
not in response to nutrients. But the bottom line of what
I’m telling you here is that this is a mechanism
that probably underlies why having too much sugar
in your bloodstream and surrounding your cells causes
all of the range of problems that exist and contributes to
the disease we call diabetes. And the future for this, if we
have a drug that could lower the extent of this
GlcNAcylation globally, you’d have to not lower it
too much or it would be bad. But the real of drug
power is in the future. It turns out this enzyme
is regulated by specific targeting proteins, and if you
could make small molecules that stopped it from being targeted
to specific substrates, then you could have
a useful drug for diabetes. And so I just wanted to thank
the people in the lab and collaborators that helped us
do this work and thank you.