Diabetes, turns out, can be found in many species.
So it's not only humans who develop diabetes,
but if you treat nonhuman primates, monkeys,
with the diet that we eat, they will also get diabetic.
We use rodents and other animal models like fish,
flies, and worms in the laboratories to study diabetes.
You can make them diabetic just by exposing them to a certain
type of diet.
And so this is not a condition or a health condition that
only affects humans, it's essentially a part of nature.
And you can find it everywhere [COUGH] where you look.
And the question then becomes, is diabetic metabolism a product
of evolution, if it goes so far back?
And does it help with survival of the species, or
is it just simply a mistake?
So is there a connection between our body's
response to become diabetic, or other species' response?
Is there a connection between that and
maybe just simple survival of the species?
And [COUGH] one of the most illustrative examples of
the preservation of species is that it doesn't matter that
the individual survives.
It's mainly the propagation of the genetic information,
and that was encapsulated in this term the selfish gene.
And so this is essentially the basis of reproduction and
fertility, that the gene,
the genetic material gets propagated.
And this reproduction function and
fertility requires most of the other
functions of the organism,
including that the organism can eat enough so
sufficient nutrition.
And this all has to do with survival of the individual, but
it serves, ultimately, the higher purpose of
propagating the genetic material of a species and
preserving that species.
So we think about this and
go to a certain scenario where you have here a gazelle
somewhere in Africa grazing and essentially to eating, right?
And what's happening is that when it eats,
serum glucose, blood sugar,
rises because carbohydrates are being digested in the grass.
And when blood sugar goes up, in response to that,
insulin is secreted, and the blood sugar's brought back down.
Now high glucose is not a good thing if it stays high.
And you'll hear later today why, lots of complications and
low glucose is not good.
Because then, the brain stops functioning,
the brain needs enough glucose.
So in response to this high glucose, serum insulin is
secreted, and the glucose is brought back down.
And this is where insulin works.
Insulin comes from the pancreas.
It stimulates incorporation of sugar in skeletal muscle,
it increases the uptake of sugar in the liver, and
it inhibits the breakdown of fat.
That all together in concert brings the blood sugar back down
after a meal.
And so in this gazelle, we have insulin levels that are high,
glucose levels that are controlled.
Two minutes later, this is happening.
So the gazelle is running, and it's been chased, and
it has to survive.
So this is the situation where
survival of the species becomes important, right?
And what we find in this gazelle is that hormones such as
cortisol, norepinephrine, and glucagon,
these are all stress hormones, they're elevated.
And in this situation, glucose levels must remain high.
And insulin levels that would bring blood sugar back down
have to be suppressed, so that sugar stays high, and
the gazelle can use that sugar to run.
So this is a situation, essentially that is
the same pattern that we defined [COUGH] as type 2 diabetes.
So this state of fight and
flight in the gazelle is essentially akin to
what we ultimately in clinics call type 2 diabetes.
And the same thing, by the way, applies to
the cheetah that are following, [COUGH] chasing this gazelle.
They're actually also in this transient state of a metabolic
condition that we would call type 2 diabetes.
Now this is transient.
This is not a disease, but this is,
The same pattern that we find in type 2 diabetes.
And so how does this all connect together?
So diabetes, is there a connection between reproduction
and fertility in diabetes?
And is there actually a connection between diabetes
and survival?
So this transient state of diabetes,
essentially would help this gazelle to survive.
And so if we look at these stress hormones,
cortisol has been known to elevate blood sugar, and
high cortisol levels cause diabetes in certain individuals.
High norepinephrine levels do as well, but glucagon caught our
attention back when we were thinking about this.
And just to tell you a little bit about glucagon,
it also comes from the pancreas,
from the islets of Langerhans just like insulin.
It does the opposite to what insulin does.
It stimulates blood sugar release from the liver, and
it stimulates the breakdown of fat to mobilize energy, so
that the liver can make enough sugar for
the rest of the body, especially for the brain.
Now, high glucagon levels are found in
individuals who have type 2 diabetes.
And so this is a schematic that you might encounter because
it's in many textbooks.
There's a person who is exercising on the right,
is insulin sensitive.
Their organism doesn't need a lot of insulin to control sugar.
And the person on the top right of the graph is insulin
resistant, it's a couch potato, and the curve that you see from
A to B is how much insulin a beta cell releases.
And so insulin sensitive people
require less insulin to control their blood sugar.
Insulin resistant people require more.
And this is where the benefit of exercise, for
example, is illustrated.
Now, in diabetes, what happens is that
the response of insulin release departs from this curve and
moves from B to C which is then impaired glucose tolerance,
there's just not enough insulin being produced.
And from C to D, well then, blood sugars get out of control,
blood sugar levels get out of control, and
that ultimately is called diabetes.
And in these conditions, in C and
D, glucagon levels are elevated.
And so we have this hypothesis that glucagon,
this essentially a stress hormone that
is supposed to keep blood sugar levels high, that it actually,
might be causing this insulin production to be suppressed.
Just like in the gazelle, where the fight and
flight situation actually demands that blood sugar levels
stay elevated, and insulin levels get suppressed.
So this transient state of diabetes.
Would this be possible this glucagon is actually causing
this in the organism?
And so the hypothesis says that glucagon stimulates
a signaling pathway in the liver, but
then causes beta cells to fail, and we tested that.
We made a mouse where this signaling pathway's
activated in the liver, and we take its serum or
plasma and put it on to islets of Langerhans.
And just look at how much insulin do this islets of
Langerhans release.
And as you see on the graph over there on the right,
the plasma of these mice with the activated glucagon
signalling only in the liver suppresses insulin secretion.
That's that dark black bar, the second one from the left.
And this suppressive activity can be diluted away, so
if you dilute the plasma, this activity goes away.
So there's something in the circulation of these mice,
that is stimulated, that is probably coming from the liver,
stimulated by glucagon signaling,
that inhibits insulin secretion.
So essentially what we would expect in that gazelle.
So to find that, we use [COUGH] a method called,
we use a gene expression array,
just like a little chip with all the genes that are known.
And we see what are the changes between these two
different mouse models, the one that we have the activated
signaling versus its control counterpart.
And we identified this gene that is highly expressed in
the liver, surprisingly it's called,
it's a gene that is called KISS1.
And it encodes for a protein called kisspeptin,
I'll tell you what that is in a little bit.
And if we take a mouse and inject kisspeptin into that
mouse, its insulin secretion, that's on the bottom right
panel, is suppressed in response to blood sugar.
So we can elevate blood sugar in this mouse, but when this mouse
gets kisspeptin, its insulin secretion suppressed.
Essentially mimicking [COUGH] what we have postulated to occur
in the gazelle running away from the cheetah.
So what I've shown you now is that, in the liver, glucagon
signaling, glucagon comes from alpha cells in the islets,
stimulates in the liver the production of glucose, but
it also stimulates kisspeptin.
So a third hormone in this loop and
this kisspeptin inhibits beta cells from secreting insulin.
And remember, glucagon levels are elevated in diabetes.
So what we think is that glucagon starts the process in
type 2 diabetes.
And this is documented in epidemiologic studies that
people who are at risk of becoming diabetic,
they actually have elevated glucagon levels.
So we have this situation where the liver is being told to
increase blood sugar, and at the same time, the signal
comes out from the liver to suppress insulin secretion, so
that blood sugar levels can rise.
Kisspeptin was discovered in the hypothalamus, and
it regulates gonadotropin release.
And it regulates puberty and fertility.
So that's where this connection suddenly becomes apparent.
It was discovered in Hershey, Pennsylvania, and
the scientists back then decided to name his favorite peptide,
kisspeptin, after Hershey kisses.
>> [LAUGH] >> It has nothing to do with
sexuality, it has purely to do with chocolate.
>> [LAUGH] >> So
humans lacking kisspeptin are infertile, and
humans with kisspeptin receptor mutations are infertile and so.
And there's very little known, at this point,
whether they're protected from diabetes.
We don't know that yet.
That will be interesting to find out, but
there are very few of these patients.
But what I've shown you now is that there
is a connection between diabetes and survival, and
this is three-way connection because it also includes
the ability to reproduce, and it includes fertility.
And it's essentially a mysterious revelation for us.
It was quite surprising.
And just to close off, what we are thinking going forward,
is that this one peptide that we found that is circulating and
regulates the beta cell,
which is here in the middle of this schematic.
There are probably many more circulating peptides that
are regulated and that in turn, regulate beta cell function and
the response of the beta cell to secrete insulin.
And so this is a schematic showing you what is known
so far.
So there are signals from the brain obviously, but then there
are signals from adipose tissue up in the top left.
There are signals from the intestine, some of the signals
from the intestine are actually used as treatment for diabetes,
they stimulate beta cell function, for example,
GLP1 and GIP.
And then there are signals from skeletal muscle.
And since this schematic was published earlier this year,
there are three more peptides that have been described that
regulate beta cell function.
So I think in the future what the scenario looks like
from the perspective today, is that there are many
more peptides that regulate beta cell function, and
their balance might be determining whether somebody
slips into diabetes or not.
I think this is my last slide, I'll close here.