Chapter 35: Drugs for the Treatment of Diabetes

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Welcome back to another Deep Dive.

Today, we are shifting gears a little bit.

We are going into full Last Minute Lecture mode.

Cram session.

Exactly.

We have a step of notes here, and we are laser focused on chapter 35 of Brenner and Stevens Pharmacology, the sixth edition.

That's right.

We are zeroing in on drugs for the treatment of diabetes.

And just to set the stage here, because I know we have a massive mix of listeners, this one is, well, it's specifically tailored for the students who are sweating bullets over their pharmacology exam tomorrow morning.

It's for the med students trying to keep the alphabet soup of drugs straight.

But honestly, it's also for anyone who just wants to understand the mechanics of a condition that affects, I mean,

millions and millions of people.

It is a massive topic.

Yes.

And to keep this useful and, you know, precise, we are sticking strictly to the text provided.

We aren't going to wander off into the latest clinical guidelines from this year or experimental treatments that just hit the news.

We are looking at the core textbook facts you need to pass the exam and understand the fundamental drug classes as laid out in chapter 35.

Exactly.

Textbook only.

So if you're panicking about your test, take a deep breath.

We are going to walk through this chapter in the exact order it's presented.

We're going to demystify the GLP -1s, the SGLT -2s, the DPP -4s.

The acronyms.

All of them.

They look like license plate numbers, and we're going to make sense of them.

And crucially, we're going to look at the why.

Because if you understand the mechanism, if you understand the biology, you don't have to just memorize a list.

You can actually deduce the answer.

I love that.

Work smarter, not harder.

So let's unpack this.

Where do we even begin?

We have to start with the body itself, right?

Before we start throwing drugs at the problem, what is actually happening in the pancreas?

We have to.

We have to look at the anatomy first.

The pancreas isn't just a, you know, uniform blob of tissue.

The endocrine portion, the part that deals with hormones, is organized into these little clusters of cells called the islets of Langerhans.

The islets of Langerhans.

It sounds like a lovely vacation destination.

It does, doesn't it?

But it's actually a hormone factory, a very busy command center.

Okay.

So what's happening in this factory?

Well, inside those islets, you have three major players you really need to know for this chapter.

First, you've got the alpha cells.

Alpha cells.

They produce glucagon.

And you can think of glucagon as the fuel mobilizer.

It increases glucose output from the water.

Okay.

So if my blood sugar is crushing, the alpha cells are the emergency responders.

They're hitting the gas.

Exactly.

They hit the gas pedal to raise blood sugar.

Then you have the beta cells.

These are really the stars of the show when it comes to diabetes.

Beta cells.

Got it.

They produce insulin and another hormone called amylin.

Insulin does the exact opposite of glucagon.

It promotes the uptake and storage of glucose, which, you know, effectively lowers blood sugar.

Alpha raises it.

Beta lowers it.

It's like a constant tug of war.

Precisely.

It's a balancing act.

And the third type, just to be complete, is the delta cells.

They secrete some adestatin, which kind of acts as a regulator on the other two.

But really, for our purposes, the main dance is between the alpha and beta cells.

And diabetes is when that dance gets out of sync.

That's it.

Diabetes mellitus results when that beta cell function,

specifically insulin secretion or its activity, just isn't enough to keep blood sugar in the normal range.

Okay, so let's zoom in on insulin itself.

The text has this great visual, box 35 .1, showing the structure.

It's not just a single protein strand, is it?

This isn't just a random string of amino acids.

No, no, not at all.

And this structural detail is actually critical because it explains how we design the drugs we use today.

Insulin starts as a precursor called pro insulin.

Pro insulin.

Right.

Imagine a long chain.

To become active insulin, it gets cleaved, it gets snipped, it splits into the active insulin molecule and a leftover piece called C -peptide.

So it's like tearing a perforated coupon off a sheet.

You have the coupon, that's the insulin, and then you have the little stub left over, which is the C -peptide.

That's a perfect way to view it.

And the insulin molecule itself, the coupon, it consists of two parts, an A chain and a B chain.

And they are handcuffed together by these disulfide bridges, these sulfur to sulfur bonds.

That specific 3D structure is what fits into the receptor.

Okay.

Now going back to that stub, the C -peptide, is that just trash?

Does the body just toss it out?

Well, functionally, its physiologic role is, according to the text, still a bit of a mystery.

It's not doing the heavy lifting like insulin is, but diagnostically.

Diagnostically, it's huge because the pancreas releases insulin and C -peptide in equal amounts, even molar amounts.

Coupon one stub every single time.

Exactly.

So imagine you have a patient who has high insulin levels in their blood.

You need to know, is their body making that insulin or do they inject too much?

Oh, I see.

If they injected it, there won't be any C -peptide because pharmaceutical insulin is pure.

It's just the coupon.

But if their own body is making it, the C -peptide level will be high right along with the insulin.

It tells you the source.

That is a brilliant and crucial distinction.

Okay.

So we have the structure.

How does the pancreas know when to release it?

It's not just steady stream all day, is it?

No, it's actually a really sophisticated two -phase system.

Figure something with 5 .1 and the text illustrates this beautifully.

You have what we call basal secretion and then meal stimulated secretion.

Okay, break that down.

What is basal?

Basal secretion is like a slow, steady drip.

It's about 0 .5 to one unit of insulin per hour, roughly.

This happens all the time, even when you're sleeping or fasting.

And what's its job?

Its main job is to talk to the liver, to tell the liver, hey, relax, don't dump too much sugar into the blood.

It retards hepatic glucose output.

So that's the background noise.

It just keeps the liver in check.

And then I eat a bagel.

Then you get the spike.

That's the meal stimulated component, also called the postprandial release.

Postprandial, after eating.

Right.

When you digest carbs,

blood glucose rises.

The pancreas senses that and releases a huge burst of insulin.

The text says about one unit for every 10 grams of carbs you eat.

Wow.

One unit per 10 grams.

That's a really specific ratio.

It is.

And in a healthy person, that spike happens incredibly fast.

It rises within minutes, it peaks, and it returns to baseline within about two hours.

So insulin is now floating around in the blood.

We call it the storage hormone.

I like to think of it as the storage manager at a huge warehouse.

It sees a delivery truck of glucose arrive and starts yelling at the workers, telling them where to put it.

That is a perfect analogy.

And it has three main warehouses or targets.

First, the liver.

Okay.

Insulin tells the liver to stop making sugar,

to stop gluconeogenesis, and to start storing it as glycogen.

Warehouse number two.

Skeletal muscle.

This is a huge sink for glucose.

Insulin tells the muscle cells to open their doors and suck up glucose, either to use for energy right away or to store as glycogen for later.

And the third one.

Adipose tissue.

Fat cells.

Insulin promotes the conversion of glucose into fatty acids for storage, as triglycerides.

And, just as importantly, it inhibits lipolysis.

It stops the breakdown of fat.

Wait, hold on.

You said insulin is a storage hormone.

But if I'm, say, running a marathon and I'm drinking Gatorade, isn't insulin helping me burn that sugar, not just store it?

That's a great distinction to make.

And muscle, yes, it promotes uptake for immediate use if you're active.

That's true.

But the primary evolutionary drive of insulin is to save that energy for a rainy day.

So it's a hoarder by nature.

It's a hoarder.

It wants to build fat, build glycogen, and stop you from burning your reserves.

This is why when insulin levels are high, it's very difficult to lose weight.

So if you have high insulin, your body is in lockdown mode for fat.

It will not burn it.

Precisely.

Now, here is where it gets really interesting for the biochemistry fans and where we need to demystify some of the jargon from the chapter.

How does insulin actually open the door for glucose?

It doesn't just knock.

This is the mechanism of action.

And the text mentions something called a tyrosine kinase receptor.

That sounds intimidating.

It does.

And this is where students' eyes usually glaze over.

So let's simplify.

Insulin binds to a specific receptor on the outside of the cell membrane, the insulin receptor.

This receptor is a tyrosine kinase.

OK.

Think of it like a lock and key and more like a doorbell that's wired to a very complex Rube Goldberg machine inside the house.

OK, I like that.

So insulin rings the bell on the outside.

Right.

And the receptor is a protein that spans the whole wall.

When the bell rings outside, the part of the receptor that's inside the cell changes shape.

It activates itself by adding phosphate groups to itself.

That's the kinase part.

This one action sparks a huge chain reaction.

The dominoes start falling inside the cell.

Exactly.

This is what they call the phosphorylation cascade.

Protein A is a transporter called GLUT4.

GLUT4.

OK, I need to remember that one.

You do.

GLUT4 is the door for glucose.

The cell normally keeps GLUT4 locked away in a storage closet, a vesicle, deep inside the cell.

But when that signal from insulin hits, when the last domino falls, the closet door opens and GLUT4 rushes to the surface of the cell membrane to let all that sugar in.

So without insulin or without that working properly, GLUT4 stays in the closet.

The door stays closed and glucose just stays stuck out in the blood.

And that right there is the fundamental mechanical problem in diabetes.

OK, so that's a perfect pivot.

Let's pivot to the disease itself.

The text breaks it down into the two classic categories we all know.

Type one and tech two.

How does the text distinguish them?

Well, type one is usually described as youth onset, typically appearing before age 30 with around 12.

And it's an autoimmune disease.

The body's own immune system mistakenly identifies those beta cells we talked about, the insulin factories, as foreign invaders and just

destroys them.

So the factories burn down, there's nothing left.

Completely.

And this leads to a severe absolute insulin deficiency.

Because there is no insulin, the body panics.

It thinks it's starving, even though there's sugar everywhere.

And it starts breaking down fat rapidly for fuel.

But wait, didn't you just say breaking down fat is a good thing for energy?

Not at this speed and not without insulin to regulate it.

When you break down fat that fast, the byproduct is ketones.

These are acidic compounds.

And this leads to a condition called diabetic ketoacidosis or DKA.

It's a life -threatening emergency.

The blood becomes acidic.

These patients absolutely require exogenous insulin shots just to survive.

OK, so that's type one now versus type two, which is the much more common form, right?

About 85 % of all cases, this is usually adult onset, typically after age 30.

And it's very strongly associated with obesity.

And the problem here is different.

The factory isn't necessarily destroyed?

Not initially, no.

The problem here is insulin resistance.

The storage manager is yelling, but the workers are all wearing earplugs.

That's a great analogy.

The receptors are there, but the signal transduction, that Rube Goldberg machine we talked about, it just doesn't work right.

The dominoes don't fall properly.

So there's insulin, but it's not effective.

Exactly.

In fact, patients might actually have normal or even high levels of insulin, especially early on.

But the cells just aren't listening.

And because they still have some insulin activity, they rarely go into ketoacidosis.

But they suffer from chronic high blood sugar.

There is a phrase in the text describing the pathophysiology of diabetes that really stuck with me.

It calls the disease starvation in the midst of plenty.

It's a profound description, isn't it?

Think about it.

The blood is full of glucose.

There's plenty of energy available.

But because the insulin isn't working, the cells can't access it.

They're literally starving while swimming in a sea of food.

And that cellular starvation is what leads to the classic symptoms.

We always hear about the polys.

Right.

So because the cells are starving, the liver tries to help by making more glucose, which of course just makes the hyperglycemia even worse.

When the blood sugar gets too high, the kidneys can't reabsorb at all, and sugar starts to spill into the urine.

That's glycosuria.

And sugar acts like a magnet for water, doesn't it?

It does.

It causes what's called osmotic diuresis.

The sugar in the urine pulls water out of the body with it, and that leads to polyuria peeing too much.

Which then leads to?

That dehydrates you, leading to polydipsy -excessive thirst.

And because you are literally peeing out calories and your body is breaking down muscle for energy, you get weight loss and polyphagia

It's just this terrible vicious cycle, and the text mentions that long -term, the sugar that's everywhere.

It coats everything and causes damage.

Yes.

The term is glycosylated proteins.

We measure this with the hemoglobin A1C test.

It basically tells us how sugar -coated your red blood cells have been over the last three months.

And that's bad.

It's very bad.

High levels of this lead to microvascular damage.

That's retinopathy in the eyes, nephropathy in the kidneys, and macrovascular damage, like heart disease.

In fact, the text notes that coronary artery disease is the leading cause of death in these patients.

Okay, we understand the enemy.

Now let's talk about the weapons.

We are entering section three, insulin preparations.

The actual drugs.

The drug classes, yes.

First off, where do we get this insulin from?

Are we still grinding up pig pen creases or something?

Not anymore, thankfully.

Years ago, yes, we used pork and beef insulin.

But today, it's almost exclusively human insulin made via recombinant DNA technology.

So we use bacteria.

We use E.

coli bacteria, or sometimes yeast.

We insert the human insulin gene into them and become little factories that crank it out for us.

It's purer and causes fewer allergic reactions and less resistance.

And we administer it mostly via subcutaneous injection, a shot under the skin.

But here is the part that trips up every single student.

There isn't just insulin.

There is rapid, short, intermediate, long.

Why?

Why can't we just have one kind of insulin?

It's all about trying to mimic that natural physiology we talked about, that slow basal drip and the sharp mealtime spike.

But to do that, there's a fundamental chemistry problem we have to solve first.

Okay, what's the problem?

In nature,

insulin is, well, it's social.

It doesn't like to be alone in a concentrated solution.

Six insulin molecules will huddle together to form a hexamer around a zinc ion.

It's a very stable but also very bulky cluster.

Like a tiny rugby scrum.

Exactly like a rugby scrum.

And a whole scrum can't fit through the narrow door of the capillary wall to get into the blood.

It has to break apart into single players, into monomers before it can be absorbed.

And that takes time.

So if I just inject natural human insulin, it just sits there under my skin in a huddle for a while before it starts working.

Yes.

And that delay is precisely why we needed to engineer the different types, starting with the rapid acting insulins.

So let's look at those.

Lispro, Aspart, Glulicene.

How did scientists make them so fast?

Well, if the huddle was the problem, we needed to make the insulin molecules antisocial.

We had to ruin the handshake that holds the scrum together.

Huh.

How do you do that?

It's actually brilliant.

For example, with insulin Lispro, scientists just swamp two amino acids, proline and lysine, at the very end of the B chain.

That tiny geometric shift is enough to prevent the hexamer from forming.

So they just stay as single players, as monomers.

Correct.

So the second you inject them, they are ready to go.

They slide right into the blood.

The onset is like 10 to 20 minutes.

It peaks in under an hour.

This is perfect for taking right before you eat to mimic that natural post meal spike.

Okay.

That makes sense.

Next up is short acting insulin.

This is also just called regular insulin.

This is the original.

It's the unmodified human insulin structure.

And because it's unmodified, it forms those crystalline hexamers around zinc that we just talked about.

What's up with slow?

It's slower.

Because it has to break down from hexamers to monomers under the skin, it takes longer to work.

The onset is more like 30 to 60 minutes.

So if I'm hungry now, regular insulin is kind of annoying.

It is.

For mealtime coverage, you have to plan ahead and inject it 30 minutes before you eat.

If you eat right away, the food hits your blood way before the insulin does.

That mismatch is a real problem.

But it must be useful for something.

Oh, it's crucial.

Regular insulin is the one we can give intravenously or IV.

Why does being able to give it IV matter so much?

Because in an emergency like DKA, we don't care about absorption time from under the skin.

We are putting it straight into the vein for immediate effect.

Yeah.

Regular insulin is the standard of care for IV use.

Got it.

Okay.

Now let's slow things way down.

Intermediate acting insulin, NPH.

Neutral protamine hagedorn.

This is the cloudy one.

They took regular insulin and added zinc in a protein called protamine.

Protamine.

That sounds familiar from somewhere else in pharmacology.

It is.

It's used to reverse eparin.

But here, it binds to the insulin and makes it clump up even more than usual.

It forms a solid precipitate under the skin.

After you inject it, it has to dissolve very, very slowly.

And because it's a suspension, a cloudy one.

You have to roll the vial to mix it.

You never shake it.

You roll it.

If you don't mix it properly, you get a really erratic dose.

It has an onset of one, two hours and lasts about 18, 24 hours.

It's a cheaper way to get basal or background coverage, but the absorption is a bit unpredictable.

Which brings us to the modern standard for basal coverage, the long acting insulins.

Glargine, datamir, digludec.

These are the heavy hitters.

Chemistry here is just brilliant.

Let's look at Glargine first.

They change the amino acids to shift what's called the isoelectric point.

Basically, Glargine is soluble in the acidic solution that's inside the panorvile.

But as soon as you inject it into the neutral pH of the body, it precipitates.

It turns into a solid under the skin.

Micro precipitates.

Tiny little crystals.

And these crystals slowly dissolve over a full 24 hours.

And this means there is no peak.

It's just a flat, steady release of insulin all day long.

That sounds much, much safer than something with a big peak that could cause low blood sugar.

It is.

It's much better at mimicking the body's natural basal rate.

Then you have datamir and digludec.

They use a totally different trick.

They attached a fatty acid chain to the insulin molecule.

A fat chain.

Yeah, a long one.

And this fatty acid acts like a hook.

It binds to albumin, the main protein in your blood.

Ah, so it hitches a ride on albumin and just hangs out in the bloodstream.

Exactly.

It circulates bound to albumin and then slowly falls off to do its job.

This extends the duration to 24 hours, or in the case of digludec, even longer.

Before we leave insulin, the test mentions one more.

An inhaled version.

Afrenza, yes.

It's a very fine powdered human insulin.

You inhale it.

It hits the surface area of the lungs and it absorbs almost instantly.

It's used for mealtime control, just like the rapid acting ones.

Okay, so the textbook gives us a great case study in box 35 .2 that ties all this together.

It's about a 52 -year -old man.

Right.

Let's look at him.

He has type 2 diabetes, he's already on oral meds, and he takes a basal shot of glargine at night.

So he has his long -acting background insulin.

Correct.

And his fasting sugar, the one he takes when he wakes up, is good.

So that tells us the glargine is working overnight, but his sugar after breakfast and after lunch is sky high.

So the background noise is quiet, but the spikes from his meals are totally out of control.

Exactly.

And the solution wasn't to just increase his glargine dose, that would just make his sugar go too low overnight.

The solution was to add a rapid acting insulin, like aspart, just before his breakfast and lunch.

Ah, targeted strikes.

Targeted strikes.

Yeah.

And this whole case highlights the importance of self -monitoring blood glucose.

Or SMBG.

You have to know when the sugar is high to be able to treat it effectively.

That makes perfect sense.

Okay, let's brace ourselves.

We're moving to section 4.

This is the biggest section by far.

The non -insulin agents.

The orals.

The alphabet soup of type 2 treatment.

The text organizes these by mechanism, which I think is the only way to stay sane.

We have secretagogues, sensitizers and cretins, and excretion inhibitors.

But I like to think of them in different eras or strategies.

Let's start with the old guard.

The squeezers.

Category A.

The insulin secretagogues.

The classic class here is the sulfonylureous.

These are drugs like glipizide, glabaride, glipuride.

These spin around forever.

How do they work?

Okay, so we have to go back to the membrane of the beta cell.

There's a specific channel there called the ATP -sensitive potassium channel.

Normally, when glucose enters the cell, it gets metabolized and creates ATP.

That ATP then closes this potassium channel.

And when that potassium channel closes?

Potassium, which is a positive ion, gets trapped inside the cell.

The inside of the cell becomes more positive.

That's called depolarization.

That change in voltage opens up calcium channels.

Calcium rushes in.

And that influx of calcium is the trigger that causes the insulin to be released.

So that's the normal, natural process.

Glucose ATT channel closes insulin out.

Right.

Sulfonylureous just bypass the glucose and ATP step.

They bind directly to a protein on that potassium channel and slam it shut.

So the cell thinks, oh, there must be lots of sugar.

And it dumps out insulin, even if there isn't any actual sugar around.

Exactly.

They are potent, but they are, for lack of a better word, dumb.

They squeeze the pancreas, regardless of what your blood sugar level is.

Which leads us to their biggest, most significant risk.

Hypoglycemia.

Low blood sugar.

And we aren't just talking about feeling a little hangry here.

Sulfonylureous -induced hypoglycemia can be really dangerous.

It is, because the drug doesn't know you skipped lunch.

Your sugar drops to 40 or 30.

You get the shakes, the cold sweat, confusion.

In an elderly person, this can mimic a stroke or lead to devastating falls.

Huge downside compared to the more modern agents.

And the text mentions a weird interaction with alcohol.

A disulfiram -like reaction, yes.

For some patients, it can make them violently ill -flushing nausea palpitations if they drink alcohol while taking certain sulfonylureous.

Also, because insulin is a storage hormone, and these drugs are just pumping out insulin all the time, they cause weight gain.

Then there are the mclitinides, rapaglinide, and netaglinide.

They're in the same category.

Same mechanism.

They also work by closing that potassium channel.

But they are much faster and much shorter acting.

We tend to use them for people with erratic meal schedules.

The motto for them is, skip a meal, skip a dose.

Okay, moving to category B, insulin sensitizers.

These don't squeeze the pancreas.

They make the body listen better to the insulin that's already there.

And the first one is the absolute champion of diabetes care.

Metformin, the only drug in the big one -eyed class.

Why is metformin the first -line champion?

Why does almost everyone with type 2 start on this?

For a lot of reasons, but mainly safety and efficacy.

Metformin works primarily on the liver.

It tells the liver to stop its excessive manufacturing of glucose, that gluconeogenesis we talked about.

It does this by activating an enzyme called AMP -activated protein kinase.

And the benefits are huge, right?

Crucially, it does not cause hypoglycemia when used by itself.

Because it doesn't stimulate insulin secretion, it just stops the liver from dumping too much sugar.

It's weight neutral, or in many people it helps with some modest weight loss.

And it improves lipid profiles.

It sounds perfect, so what's the catch?

The GI tract.

Metformin is famous, or maybe infamous, for causing diarrhea, nausea, and bloating.

The text says it happens in up to 30 % of patients.

And there is a very rare, but very serious, risk called lactic acidosis.

So it's contraindicated in people with significant kidney or liver failure, because they can't clear the acid from their system.

The other sensitizers are the thiazolid indidones, TZDs, pioglitazone, and rossiglitazone.

These act on a totally different level.

These are what I like to call the genetic rewriters.

They are PPAR gamma agonists.

PPR gamma, say that again.

PPAR gamma, it's a nuclear receptor.

These drugs actually go into the cell nucleus, they bind to the DNA, and they change gene transcription.

They change your genes.

They change the expression of your genes.

They turn on genes that increase insulin sensitivity in your fat and mothel cells.

They literally make your body produce more GLUT4 transporters, more doors for the sugar.

Since they work on DNA and gene expression, I'm guessing they aren't very fast acting.

Correct.

The text specifically notes it can take four to six weeks to see the full effect.

Gene transcription is a slow process.

And the side effects, I know there's a big one here.

The big one is fluid retention, edema.

This can be very dangerous for patients with heart failure because the extra fluid puts a huge strain on an already weak heart.

They also carry a risk of bone fractures, especially in women, due to effects on osteoporosis.

So we've talked about squeezing the pancreas with self -anilaries, which is kind of risky,

and sensitizing the liver with metformin.

Is there a smarter way to get the pancreas to work better, but only when we actually need it to?

That is the billion dollar question.

And to answer it, we have to leave the pancreas for a moment and go down to the gut.

This brings us to the incretins.

Category C, the incretin mimetics.

Let's start with the physiology because it's really cool.

When you eat food, your gut releases hormones called incretins and the main one is called GLP1.

These hormones travel through the blood to the pancreas and basically say, hey, food is coming.

Get ready.

So like an early warning system.

It is.

It's a feed -forward mechanism.

They stimulate insulin secretion, they suppress glucagon secretion, and this is key.

They slow down gastric emptying.

They make you feel full.

This whole process is called the incretin effect.

But there's a problem, right?

Our natural GLP1 disappears in like minutes.

Right.

An enzyme in our body called DPP4 chops it up almost immediately.

So scientists needed to find a workaround.

And this is the part of the chapter where I had to double check I wasn't reading a sci -fi novel.

We found the solution to modern diabetes in a lizard.

The Gila monster specifically.

It's a venomous lizard that lives in the southwest U .S.

and Mexico.

It only eats a few massive meals a year.

So when it eats, it needs a huge sustained hormonal signal to manage all that fuel.

And its version of GLP1 is tougher.

Much tougher.

Its peptide is resistant to our DPP4 enzyme.

So we synthesize it and that became the first drug in this class, exenitide.

So we are injecting synthesized lizard spit.

That's amazing.

Technically, yes.

But it works wonders.

So we have exenitide, liraglutide, semaglutide.

These are the GLP1 receptor agonists.

And they're effective.

They are very effective.

They dramatically increase insulin secretion.

But only when glucose is high, which is smart, they stop glucagon.

And they cause significant weight loss because they make people feel full.

Nausea.

There's always a but.

Nausea.

It's very, very common, especially at first because your stomach is emptying so slowly.

And there is a small but real risk of pancreatitis.

The text also notes that in rodents, they caused a specific type of thyroid c -cell tumor.

So we avoid them in people with a personal or family history of that specific cancer.

Though we have the other side of the coin.

The DPP4 inhibitors.

The gliptons.

Like citagliptin.

Right.

So if the bucket has a leak, you can either pour more water in.

That's the GLP1 agonist.

Or you can just plug the leak.

The DPP4 inhibitors plug the leak.

They block the enzyme that destroys your own natural GLP1.

So they're kind of like GLP1 light.

That's a great way to put it.

They prolong the action of your own natural signals.

Because of that, they are a bit weaker than the agonists.

They don't cause weight loss.

They're just weight neutral.

But they are very well tolerated.

Almost no nausea.

OK.

Last big category.

Category D absorption and excretion inhibitors.

Or as I like to call them, the blockers and the plumbers.

Good way to think about them.

First,

the alpha -glucosidase inhibitors.

A carbose and miclitol.

These work entirely in the gut.

They block the enzyme that breaks down complex starches into simple absorbable sugar.

So the carbs just stay in your gut for longer?

Yes.

They delay carbohydrate, digestion, and absorption.

This blunts the post -meal spike in blood sugar.

But if the carbs stay in your gut undigested, the bacteria in your colon have a feast.

Which means?

Gas, bloating, a lot of flatulence.

It's a major and often impolorable side effect for many people.

The text has a crucial safety tip for this class, too.

Yes.

And this is a classic exam question.

If a patient on one of these drugs gets hypoglycemic for some other reason, say they also take insulin,

you cannot give them table sugar, sucrose, or sugary soda to treat it.

Why not?

Because the drug blocks the breakdown of sucrose into glucose.

You have to give them pure glucose, like from glucose tablets or gel.

The sucrose just won't work.

That is a critical, critical exam fact.

Finally, the last major class.

The SGLT2 inhibitors.

The glyphosins.

Cannot glyphosin, diaglyphosin.

These are the plumbers.

These work in the kidney.

Normally your kidney filters all the glucose from your blood and then reabsorbs 100 % of it back into the circulation via a transporter called SGLT2.

These drugs block that transporter.

So you literally just pee out the sugar.

You dump glucose into the urine.

This is a totally insulin -independent mechanism,

and it lowers blood sugar, it causes weight loss because you're peeing out calories, and it lowers blood pressure because water follows the sugar.

But if you have sugary urine, that sounds like a recipe for infection.

It is.

You are basically feeding the bacteria and yeast down there.

So the big risks are urinary tract infections and genital yeast infections.

And because you are losing so much water, you're at risk for dehydration and dizziness.

Wow.

Okay.

We have covered a massive amount of ground.

Let's bring it all home with Section 5.

Management protocols.

How do we put this entire toolbox to use?

For type 1, it's pretty straightforward, but it's very demanding on the patient.

It's all about insulin replacement.

The basal bolus regimen is the gold standard.

Basal bolus.

That means a long -acting insulin like glargine, once a day for the basal coverage, and then rapid -acting insulin shots like Lisbro at every meal for the bolus coverage.

And if they don't treat it properly, they can get DKA.

Diabetic ketoacidosis, a life -threatening emergency.

The text outlines the treatment protocol very clearly.

Number one is IV fluids to fix the severe dehydration.

Number two is IV insulin,

regular insulin to stop the ketone production.

And critically, number three is potassium.

Why potassium?

That's the one that people forget.

Because when you give insulin, it doesn't just push sugar into cells.

It pushes potassium into the cells as well.

So if you don't replace it, the blood levels of potassium can drop dangerously low hypokalemia, which can cause fatal heart arrhythmias.

Okay.

And for type two, the text describes a step approach.

It's a stepwise approach.

Step one is always lifestyle modification,

diet and exercise.

Step two is typically starting a single oral agent.

And that is almost always metformin, unless there's a contraindication.

Well, if metformin alone isn't enough.

Step three is adding a second agent.

And this is where you look at the whole patient profile.

Do they need to lose weight?

Then a GLP -1 or an SGLT -2 is a great choice.

Skowska's huge issue.

A sulfonylurea might be considered.

Do they have heart failure?

You avoid the TZDs.

And eventually if the orals aren't cutting it.

Step four, if the oral agents fail to control the glucose, we move to insulin.

Usually we start by just adding a single basal shot at night and continue the oral meds.

The goals are pretty specific, right?

The numbers we're aiming for.

Yes.

Fasting glucose under 140, post -meal glucose under 175, and a hemoglobin A1C generally under 7%.

Those are the targets that have been shown to reduce those long -term complications we talked about.

Wow.

Okay, let's wrap this up.

That was a marathon sprint through chapter 35.

It was.

But if you're studying, just remember the big picture.

Diabetes is a disease of balance.

It's insulin versus glucagon.

It's energy storage versus energy mobilization.

The goal of all these different drugs, whether we are squeezing the pancreas, sensitizing the muscle, or dumping sugar out in the urine, is to try and restore that delicate balance.

Starvation in the midst of plenty.

We are just trying to find a way to feed the cells without flooding the entire system.

Exactly.

And for the students listening right now, go back and review table 35 .3 in the text.

It summarizes the key metabolic effects, which drugs lower lipids, which ones cause weight gain or weight loss.

That table is extremely high yield for your exam.

Thank you for listening to this deep dive.

We really hope this helps you crush that exam tomorrow, or just understand your own health a little bit better.

Good luck.

From the Last Minute Lecture Team, signing off.