15 Insulin (S24E15)

You know, it's pretty wild when you think about
it. Insulin, we hear the word all the time, but
it's story. Even finding versions in things like
cone snails, using it as a weapon. Yeah, it's
amazing. It's like chemical warfare for snails.
And it really challenged those early assumptions
that... Hormones would all be these tiny molecules.
Insulin's quite large, relatively speaking. A
big protein doing this fundamental job. It highlights
just how, well, how deep its biological roots
go. Yeah, exactly. That cone snail example. It
just drives home how essential this molecule
is way beyond just humans. It's ancient. Absolutely.
And that's actually a great place for us to start
today. Welcome back to The Deep Dive. We are
really going deep on insulin this time. We are.
And for this, we've pulled together quite a range
of sources where we're looking at the core science
from research papers, medical guidelines, but
also regulatory info, historical accounts, trying
to get that full picture. Right. So for you,
the learner, our mission here is to unpack this
really critical hormone. We want you to walk
away with a solid understanding of where it came
from, how it works, how it's made, which is fascinating
in itself, the rules around it, the controversies
even, and just its massive impact. OK, so let's
jump right in. What is insulin fundamentally?
Well, at its core, it's what we call a peptide
hormone. So basically a protein built from amino
acids acting as a messenger. And it's produced
by very specific cells, the beta cells, in the
pancreas. In those islets of Langerhans. That's
them, little clusters within the pancreas. And
their main job, the big one, is managing your
blood glucose, your blood sugar. OK, so how does
it do that? What's the mechanism? It works in
primarily two key ways. First, it basically tells
cells in your body thick muscles, fat tissue.
Hey, soak up glucose from the blood. Opens the
door, sorta. Exactly. And second, it signals
to your liver to put the brakes on making more
glucose. So it reduces glucose coming into the
blood and increases glucose leaving it. It's
a balancing act. Hmm. Sounds pretty sophisticated.
More than just flipping a switch. Oh, definitely.
And the molecule itself, it goes through a whole
production line before it's ready. It starts
as this inactive precursor, pre -pro insulin.
Okay. Then inside the cell, in an endoplasmic
reticulum and Golgi apparatus. Think of them
as the cell's factory and processing plant. It's
modified. Bits are snipped off. It folds correctly.
And you end up with the final active insulin.
Right. The active form has two chains, A and
B, linked together by the sulfide bonds. And
interestingly, when a piece called the C -keptide
is cut off to make active insulin, it gets released
too. we can actually measure C -peptide in the
blood to see how much insulin the body is making
itself. Ah, that's clever. A useful byproduct.
And you mentioned earlier this basic structure.
It's found across lots of different animals.
Yes. The sequence of amino acids, the blueprint,
is remarkably similar across species. It's highly
conserved, evolutionarily speaking. It hammers
home how vital it is. So even though, say, cow
or pig insulin isn't identical to human insulin.
Right. There are small differences, three amino
acids different in cows, one in pigs. But they
still work well enough in humans. It shows the
core function is preserved even with minor tweaks.
OK. So this hormone is crucial for keeping blood
sugar stable. What happens when that system goes
wrong? when you don't have enough or it's not
working properly. Yeah, that's when we run into
problems, primarily high blood sugar hyperglycemia,
which is the hallmark of diabetes. And there
are the two main types we hear about, type 1
and type 2. How does insulin play out differently
there? They are quite distinct. In type 1 diabetes,
it's an autoimmune issue. The body's own immune
system mistakenly attacks and wipes out those
beta cells in the pancreas. So the factory gets
destroyed, basically. Exactly. The result is
an almost complete inability to produce insulin.
It's an absolute deficiency. OK. And type 2 is
different. Less about destruction, more about
malfunction. It's generally more complex, yes.
There can be some beta cell loss in type 2, maybe
linked to things like amyloid protein buildup
in the islets, but it's usually not the main
driver. And it's not typically autoimmune. So
what is the main issue, then? Often it's a combination.
The remaining beta cells might not secrete enough
insulin when needed, and crucially, the body's
tissues, muscles, fat, liver become resistant
to the insulin that is there. It's like the locks
are getting rusty, the key doesn't work as well.
So the signal isn't getting through properly.
Precisely. Plus, in type 2, there's often another
issue. The hormone leukogon, which raises blood
sugar, isn't properly regulated. It keeps getting
released even when blood sugar is high. So you've
got multiple things pushing blood sugar up. Wow,
okay. So it's not just about less insulin. It's
also about sensitivity and other hormones getting
involved. That's a good way to put it. And beyond
type 1 and 2, you have other conditions too.
Like insulinomas, rare tumors that make too much
insulin, causing low blood sugar. And things
like metabolic syndrome or PCOS are often linked
with insulin resistance. It really is central
to so much of our metabolism. Now, obviously,
we haven't always had insulin available as a
medicine. It has this incredible history of discovery,
right? Oh, absolutely. A long and fascinating
journey. People knew something was wrong with
the pancreas and diabetes way back in the 19th
century. But isolating the active substance,
that took time. The early 20th century was key,
wasn't it? Banting and Best and McLeod. Yes.
Their work in the early 1920s, leading to the
first successful treatments, was monumental.
But the scientific understanding kept evolving
rapidly after that. John Jacob Abel crystallized
insulin in 1926, a huge step for studying its
chemistry. Getting a pure form. Exactly. And
researchers like Somogy, Doisy, and Schaffer
proved it was definitely a protein around 1924.
Then Jensen and Evans Jr. identified key amino
acid components like phenylalanine and proline
in 1935. Little by little, the picture got clearer.
But figuring out the entire sequence, every single
amino acid in order, that sounds incredibly difficult
for the time. It was a Herculean task. Frederick
Sanger finally cracked it in 1951, determined
the full amino acid sequence. Groundbreaking
work earned him a Nobel Prize. Oh, once they
knew the sequence, could they make it? Well,
that was the next big challenge. Synthesis, making
it from scratch in the lab. Two groups, Quetzianices
and Zans, managed it pretty much simultaneously
in the mid -1960s, and Chinese scientists also
synthesized bovine insulin around them. And then
seeing its actual 3D shape. That came in 1969.
Dorothy Hodgkin used X -ray crystallography to
map out its complex three -dimensional structure.
Another Nobel Prize -winning effort. It took
decades of brilliant work from many people. An
amazing scientific story. And for a long time,
the insulin people used actually came from animals.
That's right. For many, many years, the source
was purified insulin from the pancreases of cows
and pigs. It saved countless lives, absolutely.
But it wasn't identical to human insulin. And
sometimes it could cause immune reactions or
allergies. Which leads us nicely into how insulin
is used clinically today. What are the main reasons
someone would need insulin therapy? Well, the
most obvious is type 1 diabetes, where the body
makes virtually none. Insulin replacement therapy
is simply essential for survival there. No question.
But it's also used quite a lot in type 2 diabetes,
isn't it? Even though the body might still be
making some. Yes, absolutely. In type 2, treatment
usually starts with lifestyle changes. maybe
metformin or other oral drugs. But if blood sugar
targets aren't met, or if someone presents with
really high symptomatic blood sugar, then insulin
is often the next step. How is it typically started
in type 2? Often the first step is adding a basal
insulin that's a longer acting type designed
to cover the body's background insulin needs
overnight and between meals. People usually continue
their other medications alongside it. And then
sometimes more insulin is needed. Yes. If blood
sugar still spikes after meals, a bolus insulin
might be added. This is a rapid -acting type
taken just before eating to cover the glucose
coming in from food. We hear about different
kinds, like analogs. What are those? Insulin
analogs are basically versions of human insulin
that have been tweaked, genetically engineered,
to change how quickly they work or how long they
last. To make them work better for certain situations.
Exactly. Rapid -acting analogs, for instance,
kick in faster and wear off sooner than regular
human insulin. That can be really helpful for
matching insulin delivery to meals, potentially
reducing lows later on. And the long -acting
ones? Long -acting analogs are designed to provide
a steadier, peakless background insulin level
over ideally 24 hours. This predictability is
a big reason why analogs both rapid and long
-acting, have become so common, especially in
type 1 management. Makes sense. And how people
take insulin has evolved, too, right? It's not
just vials and syringes anymore. Definitely not.
Insulin pens, pre -filled devices that make dosing
easier and more discreet, are hugely popular.
And then you have insulin pumps. Right, the ones
that deliver it continuously. Yes, small devices
worn on the body that deliver insulin through
a tiny tube under the skin. They offer a lot
more flexibility and fine tuning. And now, we're
seeing really exciting advances in automated
systems. The artificial pancreas type systems.
Exactly. Hybrid closed -loop systems, sometimes
called the bionic pancreas, they link a continuous
glucose monitor with an insulin pump via a smart
algorithm. The system automatically adjusts insulin
delivery based on real -time glucose readings.
That sounds like a game -changer, especially
for type 1. It really is proving to be. The real
-world data and patient experiences are incredibly
positive. It takes away a lot of the constant
calculation and burden. Amazing progress. OK,
let's shift gears a bit. How is this stuff actually
made today? I assume it's a far cry from grinding
up animal pain creases now. Oh, completely. The
vast majority of insulin produced today uses
recombinant DNA technology. It's a biological
manufacturing process. Which means it's different
from making a typical chemical drug. Yes, very
different. Because you're working with living
cells in complex biological processes, there's
inherent variability. quality control, risk management.
They have to be incredibly stringent every step
of the way. It's not like just mixing chemicals
A and B. So what are the general steps if you're
making a biologic like insulin? Well the WHO
lays out general guidelines. You start with your
source material, the engineered cells. You process
them, create carefully controlled cell banks,
master banks, working banks to ensure consistency.
Like a library of the producer cells. Sort of,
yeah. Then you grow these cells in huge batches
in bioreactors under very specific conditions
that cell culture or fermentation They produce
the protein you want, like pro -insulin. And
then you have to get the insulin out. Right.
That's the purification stage. Very complex,
multiple steps to isolate the target protein
and get rid of everything else, cell debris,
other proteins, et cetera. Then it might be formulated,
maybe combined with other things to stabilize
it or adjust its action profile, and finally
field into vials or pens. You mentioned recombinant
DNA. We often hear about E. coli bacteria being
involved. How do they fit in? E. coli is a real
workhorse for this. Scientists engineer these
bacteria by inserting a piece of circular DNA,
a plasmid, into them. Okay. And this plasmid
contains the human gene, the instructions for
making either the A and B chains of insulin separately,
or the single -chain pro -insulin precursor.
So the bacteria become tiny insulin factories?
Essentially, yes. They're grown in large tanks
with nutrient broth. Often, an antibiotic like
kanamycin is added. The plasmid also contains
a gene for resistance to that antibiotic. Ah,
so only the bacteria that successfully took up
the insulin -making plasmid survive. Exactly.
It's a selection mechanism. Then later, techniques
using special enzymes, restriction enzymes like
Bamahi, are used. They cut the DNA at specific
points. Like molecular scissors. Right. And by
looking at the pattern of DNA fragments produced,
scientists can confirm that the insulin gene
is present and correct in the E. coli colonies
they've selected. It's like checking the genetic
blueprint is right before mass production. Fascinating.
A real blend of biology and engineering. Now,
what about the rules, the regulations around
insulin? Has that been straightforward? Not always,
especially in the US. There's some unique history
there. A very early step was the 1941 Insulin
Amendment. It actually required the FDA to batch
test insulin for purity and potency. That was
quite forward thinking for the time. But it wasn't
treated like other biologics for a long time.
That's the key point. Historically, insulin in
the U .S. was regulated under the Food, Drug,
and Cosmetic Act, not the Public Health Service
Act, like most protein therapies, most biologics.
And that difference mattered? It did. Particularly
for the approval pathway for biosimilars, those
highly similar, potentially more affordable versions,
they had to use a different... arguably more
complex pathway, the 505b2 pathway, instead of
the dedicated biosimilar pathway, 351k. But that's
changed recently, or is changing. Yes, the transition
happened around 2020. The idea was to bring all
biologics, including insulin, under that same
section 351 umbrella in the PHS Act. The hope
was to streamline biosimilar approvals. Okay,
so what are biosimilar insulins and what are
the hurdles? You mentioned affordability. Right.
A biosimilar is a biologic drug shown to be highly
similar to an existing approved biologic, the
reference product. No clinically meaningful differences
in safety, purity, and potency. Because they
come from living systems, they aren't exact identical
copies like small molecule generics. So getting
them approved requires showing they're really,
really close. Exactly. And a key concept, particularly
in the U .S., is interchangeability. This is
an extra designation. It means a pharmacist can
substitute the interchangeable biosimilar for
the original brand name biologic without needing
to check with the prescriber first. Like how
generics are substituted now. Pretty much. But
achieving that interchangeability designation
requires additional studies and data, and it's
a high bar set by the FDA. It's seen as crucial
for driving real market competition and price
reductions. The approach differs elsewhere though
the EMA in Europe, for example, doesn't make
that specific interchangeability call at the
EU level. Which brings us to the elephant in
the room. The cost. Insulin prices, especially
in the U .S., are notoriously high. They are.
It's a huge issue. Despite insulin being a central
discovery, the U .S. market is dominated by just
three main companies. There hasn't been the kind
of robust biosimilar competition that many hope
for or that exists for other drugs. And that
lack of competition is seen as a major driver
of the high prices. It's certainly a huge factor.
Prices in the U .S. are dramatically higher than
in Canada, Europe, other developed nations. It's
led to significant access and affordability crises
for many people. Have there been efforts to figure
out why this is happening beyond just lack of
competition? Oh, yes. There's been a lot of scrutiny
on the whole supply chain, particularly the role
of pharmacy benefit managers. These are the intermediaries
between manufacturers and health plans. Investigations
by Congress, the FTC, they're looking into the
rebate systems and business practices to see
if they contribute to inflating list prices while
maybe benefiting the middlemen. Complex stuff.
Are there solutions being talked about? Well,
several things are on the table or have been
tried. Allowing importation from countries like
Canada is one idea, though it has its own complexities.
There have been state and federal legislative
pushes to cap co -pays or somehow control prices.
And, of course, encouraging more biosimilar entry
and uptake is still seen as key. How does this
compare globally? Are other countries handling
biosimilar insulin regulation differently? It
really varies. The EU, Japan, Australia, Canada,
they all have established pathways, maybe with
slightly different data requirements or approaches
to interchangeability. Some places, like Brazil,
even have multiple tiers of biosimilar pathways.
And you see a growing trend in countries like
Brazil, Cuba, Iran, China, to develop local manufacturing
capacity, sometimes through partnerships. It's
often driven by a desire for better access and
lower costs. And patents must play a role in
this competition landscape, too. Absolutely.
Like with many drugs, companies use various patent
strategies sometimes called patent thickets on
the drug itself, the delivery devices, manufacturing
processes. This can significantly delay the entry
of biosimilar competitors long after the main
patent on the molecule has expired. So this whole
regulatory picture, the competition issues, it
all has a massive economic impact, doesn't it?
Huge. Insulin represents a really significant
chunk of healthcare spending, especially with
the high U .S. prices. The potential savings
from wider biosimilar use are substantial, theoretically.
And the price difference drives things like people
traveling to buy insulin. Yes, unfortunately.
The stark price differences between the U .S.
and, say, Canada or Mexico lead some individuals
to travel across borders just to afford their
medication. It highlights the desperation. There's
also ongoing debate about the cost effectiveness
of the newer, more expensive analog insulins
versus the older, cheaper human insulins, especially
for some people with type 2 diabetes where the
clinical benefit difference might be less pronounced
than in type 1. Beyond the dollars and cents,
though, insulins impact on, well, on culture
and just daily life for people with diabetes.
It's profound. Completely transformative. You
have to remember, before insulin, type 1 diabetes
was fatal, usually very quickly. Insulin turned
it into a manageable, albeit challenging, chronic
condition. It gave people their lives back. And
even today, the type of insulin regimen someone
uses can really affect their day -to -day experience,
can't it? Definitely. We look at patient -reported
outcomes, or PROs. How satisfied are people with
their treatment? How does it impact their quality
of life? Studies comparing, say, basal bolus
injections multiple times a day versus using
simpler premixed insulin show varied results.
Things like convenience, fear of needles, complexity.
They all play a role in how people feel about
their therapy. And sometimes responses can even
differ across ethnic groups. And just sticking
with insulin therapy can be hard. Adherence is
a big issue. It really is. Particularly in type
2 diabetes, a surprising number of people don't
take their insulin as prescribed consistently.
Or they stop taking it altogether. That's called
persistence. Why is that? Is it just the injections?
That's part of it, for sure. The frequency, the
timing, the planning involved. It can feel like
a huge burden, but it's also about perceptions.
Some people might see starting insulin as a personal
failure or assign their conditions getting much
worse. Healthcare provider communication is critical
here, understanding those patient perceptions,
explaining the benefits clearly, addressing fears,
building that trusting relationship is key. It
sounds like managing insulin involves so much
more than just the medicine itself. It's psychological,
behavioral. Absolutely. It requires significant
patient education, ongoing support, and a collaborative
approach between the patient and their healthcare
team to overcome those barriers and achieve good
long -term outcomes. It's truly remarkable. We've
gone from, you know, a mysterious substance in
the pancreas to these incredibly sophisticated
delivery systems and manufacturing processes,
yet we're still grappling with issues of access
and cost a century later. It's that contrast,
isn't it? The incredible scientific progress
alongside the persistent societal challenges.
Insulin embodies that, perhaps more than any
other medicine. So thinking about this whole
journey, this deep dive, It's history, the science,
the economics, the human impact. What's the final
thought for our listeners to chew on? Hmm, maybe
this. Considering insulin's century -long history
and how fundamental it is, what does the future
hold? Not just for making better insulin or better
delivery systems, but for ensuring everyone who
needs this life -saving medicine can actually
get it and afford it wherever they are in the
world. That seems like the next big frontier.