How One Drug Changed Diabetes Forever – Let’s Talk About Hormones | Corporis

How One Drug Changed Diabetes Forever – Let’s Talk About Hormones | Corporis

November 11, 2019 16 By William Morgan


Doctors have made huge advancements in the
treatment and diagnosis of diabetes, especially
when it comes to reducing premature deaths.
But we still haven’t /cured/ it, which means
we still have to put some funding and research
into the /management/ of the disease.
And while there’s a ton of cool biotech
to get into with diabetes monitoring devices,
today we’re focusing on two chemicals: the
hormone insulin, and metformin, a drug that
is /not/ a hormone.
We’ll start with insulin.
Diabetes has been on medical radar FOREVER.
Like even ancient Indian doctors gave it a
term that literally means “honey urine”
because it attracted ants. The official term
diabetes came around in the first century
while 17th century scientist Thomas Willis
threw the term mellitus on the end to confirm
that diabetic urine was indeed sweet tasting.
I… okay….use the tools you have I guess.
Luckily the 1800s would feature a lot more
microscopes than tasting parties.
In 1869, Paul Langerhans identified a bunch
of clear cells in the pancreas that became
known as the islets of Langerhans. He thought
these were immune cells, but they weren’t.
These types of cells secrete lots of different
hormones.
Then in 1889, two scientists, Oskar Minkowski
and Joseph von Mering removed the pancreas
from a dog and it started urinating a /lot/.
And not only was it peeing more, but it’s
urine was /12 %/ sugar.
They repeated the pancreas removal with a
couple more dogs and same thing. These dogs
had diabetes.
And that’s where hormones really start coming
in here.
Minkowski and Mering would take pancreatic
tissue, throw it back in the dog, and it would
delay on the onset of diabetes. It’s the
/same strategy/ Berthold used with the rooster
testicles or that Emil Theodor Kocher used
with thyroid tissue.
Put a bit of endocrine organ in the body and
it still pumps out hormones.
Fast forward to the 1920s and the medical
community is full steam ahead on endocrinology.
Remember, hormones had just been discovered
a few years prior, so even though doctors
didn’t know the answer to everything, they
could at least entertain the idea that “mmm,
maybe it has to do with hormones”
Knowing what we knew about the function of
the whole organ AND a little bit more about
its physiology now, researchers identified
a hormone from the Islets of Langerhan in
1921 and named it insulin after the “islets”
or “island” cells it came from.
The very next year, they starting injecting
diabetics with insulin and saw some /dramatic/
results.
But this kind of insulin was almost an emergency
medicine of sorts. It was fast acting only,
so patients had to deal with frequent injections.
So over the next couple years, we’d get
different versions of promethazine zinc insulin
which has a much longer release time and is
pretty similar to the insulin strategy we
have today.
Now, I’d argue this is about as magic bullet
as it gets for any particular disease. Diabetes
is a deficiency or lack of the body’s ability
to create insulin, so by artificially giving
the hormone your body can’t produce, you
fix the problem.
But you probably know that diabetics are also
concerned with their diet and exercise, and
that doctors will usually advise that diabetics
adopt a healthier lifestyle.
And it’s true, regular exercise is a big
part of the treatment of diabetes, but we’re
more likely to rely on a couple prescriptions
and blood glucose monitoring than just a gym
membership, so why is that?
While the discovery of insulin was an enormous
moment in diabetes treatment, it didn’t
fix everything. So the next place we looked
was a couple prescription drugs, and exercise.
We knew diabetes was a metabolic problem.
A fuel source, glucose, isn’t being used
by the cells, and insulin lets that happen.
Exercise would hopefully do the same thing,
which makes sense. We need energy to exercise,
glucose is a source of energy, so maybe exercise
would remove glucose from our blood and we
could avoid some of those diabetic complications.
And some studies in the early 1900s showed
exactly that.
Exercise reduced blood glucose concentration
and had a synergistic effect when the subject
took insulin before exercise.
But we also saw the opposite — patients
that exercised so much they became hypoglycemic,
their blood sugar went too low.
Unfortunately it took us 50 years from the
first clinical use of insulin for us to formally
study the physiology behind the mechanism
and ask like, ya know, “how does this actually
work”?
A big moment was in 1984 when research published
in the American Journal of Physiology showed
that muscles in diabetics could use glucose
regardless of whether they or not they were
on insulin.
And that was huge!
Previous research hinted that muscles still
needed some minimum threshold of insulin to
let glucose in, but this research showed the
opposite.
The research team took a bunch of rats in
severe ketoacidosis, then just to be sure,
used a chemical mixture that wiped out any
extra insulin. The scientists hooked the rats’
hind legs to electrodes and made them contract
— simulating exercise, and muscular glucose
uptake increased across the board.
Now, this was a far cry from exercise “curing”
diabetes, but it was still a big discovery!
Muscles didn’t need insulin to contract
after all. Doctors could prescribe exercise
as a way to lower blood sugar in both the
short and long term now.
BUT, of course, as behavioral scientists will
tell you, It is really really hard to get
people to change their exercise habits.
As the author Marshall Goldsmith said “Meaningful
behavior change might be most difficult thing
for sentient beings to accomplish”, so good
luck cardiac rehab therapists!
So if were a doctor back then, you’re in
a bit of a pickle.
Insulin is already doing the heavy lifting
in your treatment, but you want to do more.
So do you prescribe exercise knowing your
patient probably isn’t going to do it, or
do you look for an another way to supplement
your treatment?
Luckily in the mid 90s, a drug called metformin
was introduced in the US after a kind of sketchy
past.
We’d known that this class of drugs, or
biguanides, lower blood glucose by preventing
the liver from converting fats and amino acids
into glucose since roughly the 1920s.
But in the 70s, two of metformin’s cousins,
buformin and phenformin, were linked to lactic
acidosis, so science became less interested
in the biguanide drugs, but research picked
up again in the 80s and 90s, and by 1995,
metformin was available in the United States
as a first line of defense against type 2
diabetes.
And this was great timing, because by the
early 2000s, the percentage of people with
diabetes in the US had multiplied many times
over in the past 50 years.
So if you were a doctor back then, you all
of a sudden had a powerful treatment strategy.
You had the old insulin injections to lower
blood sugar, metformin to keep a bunch of
sugar from coming out of the liver, and exercise
as a way to improve insulin sensitivity.
But the question remained: the incidence of
diabetes is climbing super fast, so how can
we prevent it?
So in 2002, the medical community was very
much listening when a paper published in The
New England Journal of Medicine answering
that exact question.
The study took over 3200 /non-diabetic/ subjects
and randomly assigned them a placebo, metformin
twice a day, or lifestyle modification including
a 7% reduction in body weight and 150 minutes
of physical activity per week. That’s 30
minutes of exercise 5 days a week, which is
a pretty challenging exercise prescription
for people who might not exercise.
Remember, these people weren’t diabetic,
but they were recruited because they were
at increased risk for diabetes, and we wanted
to find a prevention strategy.
They had to be adults, because we’re only
looking at adult onset, or type 2 diabetes,
have a BMI over 24 since obese folks are more
likely to develop the condition, and have
elevated fasting and post-prandial glucose
levels, giving us a hint that insulin might
not be working as expected.
Going into the study, we already had some
data to show that exercise and diet worked,
but metformin was the wildcard. It had only
been introduced in America a year before the
study started, and had only been studied in
diabetes treatment, not prevention.
But if you know that exercise is gonna be
effective, you can’t tell the drug groups
not to exercise because ETHICS. So they got
/some/ information about healthy exercise
and diet, but it wasn’t enforced.
On the other hand, the exercise group worked!
This group completed /16/ 1-on-1 coaching
sessions about healthy eating, exercise, and
behavior change that was all designed to be
culturally sensitive, flexible, and individualized
to the patient.
Like it’s exhausting listening to this,
these researchers were not messing around
with their exercise prescription. And what’s
surprising is the subjects /actually/ followed
through.
After 24 weeks, half of that group had lost
the 7% in body weight, and three quarters
of them actually did their assigned exercise.
If this were a New Year’s resolution, it
would runaway, undoubtedly be the most successful
resolution in history.
I’m going into so much detail here because,
1, if you want to design a successful behavioral
change tudy, take notes to what they did in
this study, and 2, it’s results time!
Remember, all these participants were at risk
of developing diabetes.
The placebo group had the highest rate, 11%
of their participants were diagnosed with
diabetes, 7.8% in the metformin group, and
4.8% in the lifestyle modification group.
But that’s amazing, right! Look at how effective
exercise and diet are at preventing diabetes.
Like, here’s what they say in the results
section.
“our study showed that treatment with metformin
and modification of lifestyle were two highly
effective means of delaying or preventing
type 2 diabetes”
Waaait a second, that phrasing makes it seem
like these two strategies are the same.
Now there’s a chance you’re kind of mad
at the outcome of this. Like if exercise is
so much more effective at preventing diabetes
than drugs, why aren’t we spending more
effort promoting exercise, right?
Like every way you manipulate these statistics,
lifestyle modification is clearly the best
choice, this has gotta be a big pharma media
manipulation story, right?
No dude, it’s way more complicated than
that.
Take you clinical hat off and put the public
health hat on.
Diabetes is a /global/ problem. It takes a
baseline of privilege to implement the intense
lifestyle change they did in the study, and
if we want to do the most good to the most
amount of people, we have to use the tools
available.
Generic metformin is cheap.
Waaaay cheaper than eventually being put on
insulin. So if health care providers can help
with frequent screenings and cheap, effective
drugs, we have to.
And I wanted to tell the metformin story because
of that.
You’re not going to get everyone to exercise
30 minutes a day — it’s /amazing/ that
the 2002 study did — but if metformin helps,
it helps.
Whether we’re teachers, clinicians, or even
dating someone, the key to communication change
is meeting people where they’re at.
This video was a collaboration with my friend
Willie’s channel, Khanubis which you can
find right here. He put a video together about
the last 100 years of medicine which is totally
worth checking out right here. Also, I just
wanted to say thank you. It’s been 10 months
since I rebranded the channel to Corporis
and I’m really happy with how things are
going lately. Have fun, be good. Thanks for
watching.