Hypoglycemics: Insulin secretagogues

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Introduction0:00–0:43

Hypoglycemics are used to treat high blood sugar, a condition commonly known as diabetes mellitus. As a quick review, Type 1 diabetes mellitus, which most commonly affects children and adolescents, arises when certain cells of the pancreas known as beta cells are unable to produce enough insulin to maintain normal blood glucose levels.
This is in contrast to Type 2 diabetes mellitus where the body is able to produce insulin, but the tissues don’t respond as well to it, or in other words, these individuals are insulin resistant.In this video, we’ll be focusing specifically on the use of insulin secretagogues like sulfonylurea for the treatment of Type 2 diabetes.

Pathophysiology0:43–3:56

In general, diabetes mellitus occurs when your body has trouble moving glucose from your blood into your cells. This leads to high levels of glucose in your blood and not enough in your cells, and remember that your cells need glucose as a source of energy.
So not letting glucose enter, means that the cells starve for energy despite having glucose right on their doorstep. Insulin reduces the amount of glucose in the blood by binding to insulin receptors embedded in the cell membrane of various insulin-responsive tissues like muscle cells and adipose tissue.
When activated, the insulin receptors cause vesicles containing glucose transporter that are inside the cell to fuse with the cell membrane, allowing glucose to be transported into the cell.
Now in Type 2 diabetes, the body usually makes insulin, but the tissues don’t respond as well to it. The exact reason why cells don’t “respond” isn’t fully understood, but the cells don’t move their glucose transporters to their membrane in response, which if you remember, is needed for glucose to get into the cell, these cells are therefore insulin resistant.
Since tissues don’t respond as well to normal levels of insulin, the body ends up producing more insulin in order to get the same effect and move glucose out of the blood.
They do this through beta cell hyperplasia, or an increased number of beta cells, and beta cell hypertrophy, where they actually grow in size, all in an attempt to pump out more insulin.
This works for a while, and by keeping insulin levels higher than normal, blood glucose levels can be kept normal. Although, this beta cell compensation isn’t sustainable, and over time those maxed out beta cells get exhausted, and they become dysfunctional, and undergo hypotrophy and get smaller, as well as hypoplasia and die off.
As beta cells are lost and insulin levels decrease, glucose levels in the blood start to increase, and patients develop hyperglycemia.Let’s take a more detailed look at the pancreatic beta cells, the main site of action of sulfonylureas.
The pancreatic beta cell has calcium and potassium ion channels in its membrane. Typically, the potassium ion channels are open, which allows potassium to flow out of the beta cell, while the calcium channels are normally closed.
When glucose is present in the blood, it gets transported into the cell via a GLUT2 transporter and the glucose is eventually metabolized into ATP.
Normally, the potassium channels are very sensitive to ATP, thus they are also called ATP-sensitive potassium channels; and when the ATP levels begin to increase from breaking down glucose, the potassium channels close.
Therefore, the concentration of potassium inside the pancreatic beta cells increases, since it’s no longer able to exit the cell.
This depolarizes the cell and consequently causes the voltage-gated calcium channel to open. As a result, calcium rushes into the cell.
The increased calcium concentration inside the cell triggers the exocytosis of vesicles filled with insulin into the bloodstream.
This insulin is then able to bind to insulin receptors on different tissues to help increase their uptake of glucose. In Type 2 diabetics, the ATP-sensitive potassium channel is not as sensitive to ATP.

Sulfonylureas3:56–6:21

Thus, there is less beta cell depolarization, which results in decreased insulin release. This is where sulfonylureas come into play.
Sulfonylureas have pancreatic and extrapancreatic effects! In pancreas, these medications work similarly to ATP in that they also cause potassium channels in pancreatic beta cells to close.Again, this increases the intracellular potassium concentration leading to cellular depolarization and the influx of calcium via voltage-gated calcium channels, which results in the release of insulin.
On the flip side, extrapancreatic effects of sulfonylureas include decreased hepatic gluconeogenesis and increased peripheral insulin sensitivity.There are two classes of sulfonylureas, the first generation and second generation, and they are both taken orally.
The first generation medications include chlorproPAMIDE, TOLBUTamide, and TOLAZamide. Second generation sulfonylureas are much more potent and are more commonly used today.
They include glipiZIDE, glyBURIDE, and glimepiride. In general, patients who are most responsive to oral hypoglycemics such as sulfonylureas are patients who only developed type 2 diabetes after the age of 40 and who have had diabetes for less than 5 to 10 years.
Common side effects include hypoglycemia, weight gain, and gastrointestinal disturbance, such as nausea. It’s important to note that the second generation is more commonly associated with severe hypoglycemia since these medications are more potent!
Furthermore, sulfonylureas can cause allergic reactions, such as rash; but on rare occasions, they can also cause a severe skin condition called Stevens-Johnson syndrome.
For generation-specific side effects, the first generation sulfonylureas can cause disulfiram-like reactions, also known as alcohol intolerance.
In other words, individuals taking alcohol while on first generation sulfonylureas can experience hangover-like symptoms, such as nausea, vomiting, flushing, dizziness, and headache.
Finally, as far as the contraindications go, sulfonylureas should not be used to treat diabetes mellitus type 1 or diabetic ketoacidosis!Another group of medications called meglitinides also prevent the ATP-sensitive potassium pumps from opening.
These medications include repaglinide and nateglinide, and just like sulfonylureas, they are taken orally. Although they have the same mechanism as the sulfonylureas, they are more rapid-acting, but have a shorter duration; so, they are usually taken before each meal to control postprandial glucose levels.

Meglitinides6:21–6:58

The side effects are hypoglycemia and weight gain; thus, if a meal is missed, individuals on meglitinides should not take the medication to avoid hypoglycemia.
Next up are the incretins, which are a group of hormones that aid in lowering blood glucose levels by stimulating insulin release after a meal.
One specific type of incretin is glucagon-like peptide 1, or GLP-1, and it is from the gut in response to increased glucose levels.

Incretins6:58–8:03

In fact, incretins account for 60 to 70% of postprandial insulin secretion. GLP-1 receptor agonists, such as exenatide and liraglutide act on the same receptors as GLP-1; and they are given subcutaneously to lower glucose levels by increasing insulin secretion, reducing glucagon release, slowing down gastric emptying and enhancing satiety.
Common side effects of these medications include gastrointestinal disturbance, such as nausea and vomiting; decreased appetite, weight loss, and fatigue; but also hypoglycemia, when used in combination with other hypoglycemics.
Finally, incretins are associated with the potential risk for acute pancreatitis.Dipeptidyl Peptidase 4 inhibitors, or DPP-4 inhibitors include medications such as SITagliptin and sAXagliptin.
DPP-4 breaks down is GLP-1. As we've mentioned, GLP-1 is released from the gut in response to spikes of glucose levels during mealtime and they help stimulate insulin release.

Dipeptidyl peptidase 4 inhibitors8:03–9:17

DPP-4 inhibitors therefore inhibit DPP-4 from inactivating GLP-1 and allow GLP-1 to exert its effects for longer, thus lowering glucose levels.
So, just like incretins, DPP-4 inhibitors eventually increase insulin secretion, reduce glucagon release, slow down gastric emptying, and enhance satiety!
But, in contrast to incretins, these medications are taken orally. Some of the side effects include GI disturbance, headache, nasopharyngitis, and mild urinary or respiratory infections.
It’s important to note that DPP-4 inhibitors do not cause weight gain or weight loss, therefore we can say that they are weight neutral!
Finally, since most of the insulin secretagogues are metabolized by the liver and excreted by the kidneys, these medications should be used with caution in individuals with hepatic or renal impairment.
Also, the usage of these medications is not recommended during pregnancy or breastfeeding. Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharm facts!

Contraindications9:17–9:35

So let’s have a large castle gate with “insulin” above it to help you remember we’re talking about insulin secretagogues.

Memory Palace9:35–13:33

On the left side of the gate, we’ll put a sewer entrance that’s blocked by a large banana. This is where we’ll put the drugs that block the potassium pump.
On the right side of the gate, we’ll have magical glyphs carved into the wall that spells out “one” and this is where we’ll put the drugs that increase the activity of GLP-1.Okay, so first, let’s look at the left side of the gate.
To the left of the sewer, we have the sulfonylureas. We’ll put the more commonly used 2nd generation drugs here, and since they all start with the letter G, we’ll represent them with Gnomes.
First is a lady gnome dressed as a bride for glyBURIDE. Next is a gnome kissing her with his big lips for glipiZIDE.
Finally, we have a gnome cutting limes for margaritas and he represents glimepiride. All the gnomes are pretty fat, representing weight gain, and they are surrounded by empty candy wrappers for hypoglycemia.
The gnome bride’s white wedding dress has very large red spots on it to represent allergic reactions and Stevens-Johnson syndrome.
For 1st generation sulfonylureas, you need to remember they can cause disulfiram-like reactions, so let’s have a vomiting gnome with a giant, old-timey beer mug with the number “1” on it.
Finally there’s an area next to the wedding that’s been quarantined off, and this is where we’ll put the contraindications.
First, there’s a barrel full of acid that’s melting through a large key, representing ketoacidosis. There’s a big warning sign above the barrel with the word “DM1” crossed out, so you know type one diabetes is also contraindicated.
Moving on to the right side of the sewer. We have the meglitinides, which end in “glinide” so we’ll have a jealous goblin watching the gnomes’ wedding.
He’s also rather chubby since he stole a bunch of candy as can be seen by the empty candy wrappers around him. So meglitinides also cause weight gain and hypoglycemia.
Okay, onto the drugs that affect GLP-1. Now, besides increasing insulin secretion, GLP-1 also decrease glucagon release, so under the glyph, we’ll put an almost empty sugar bowl, since all the “glucose is gone.” Next to the bowl, there’s a possum who ate all the sugar.
His belly is full and plump, representing delayed gastric emptying; and he’s looking super satisfied, for enhanced satiety.
We can put the GLP-1 receptor agonists on the left of the glyph. Since these drugs end in “tide,” we can have a maid “tidying” things up by cleaning the glyph with a feather duster.
This should also help you remember these drugs act directly on the GLP-1 receptors. In her other hand, she’s holding a frying pan that’s on fire since these drugs can cause pancreatitis, one of the more serious side effects.
Now, for the more common side effects, let's give her a pet raccoon. This poor guy is very skinny, representing weight loss.
He’s wearing a muzzle, so he can’t eat, and that’s decreased appetite. He can still vomit though and he’s holding his stomach to represent nausea, vomiting and other GI side effects.
On the right of the glyph, we have the DPP-4 inhibitors. This will be represented by a tea party with a Duke, a Prince, and a Princess, for DPP.
There’s also an empty seat for a 4th person, which represents the 4 in DPP-4. Now since all the drugs in this class end in “gliptin,” we’ll give them a big teapot of Liptin tea.
For side effects, the princess has a runny nose, representing nasopharyngitis and respiratory infections; and a bandage on her head for headache.
The duke and prince didn’t tolerate the tea very well and they’re vomiting profusely to represent the GI distress. Also, the prince is thinking about the toilet to remind you of urinary infections.
Finally, on the table, let’s put a balanced scale with a dumbbell on each side since these medications are weight neutral.All right, as a quick recap.
Insulin secretagogues are a large group hypoglycemics used to treat type II diabetes. Sulfonylureas and meglitinides work by inhibiting the ATP-sensitive potassium channel, which increases insulin release from pancreatic beta cells.
GLP-1 receptor agonists such as exenatide and liraglutide are incretins that have a variety of effects including increasing insulin secretion, reducing glucagon release, and slowing down gastric emptying.

Review13:33–14:15

DPP-4 inhibitors, such as SITagliptin and sAXagliptin prevent the breakdown of GLP-1.But wait, there’s more: Here’s a mind map with all of the mnemonics.
Go ahead and pause the video so you can test yourself to see what you remember. Stay tuned for the answers after the credits.
insulin. Secretion reducing glucagon release and slowing down, gastric emptying dpp-4 Inhibitors such as sittig Lipton and saxagliptin prevent the breakdown of glp-1.
But wait, there's more, here's a mind map with all of the demonics. Go ahead and pause the video.

Mind Map14:15–14:28

So you can test yourself to see what you remember. Stay tuned for the answers after the credits.