AssessmentsHypoglycemics: Insulin secretagogues
Hypoglycemics: Insulin secretagogues
Content Reviewers:Yifan Xiao, MD
Contributors:Evan Debevec-McKenney, Jake Ryan, Ursula Florjanczyk, MScBMC, Robyn Hughes, MScBMC, Alaina Mueller
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 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.
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.
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.
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.
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.
In Type 2 diabetics, the ATP-sensitive potassium channel is not as sensitive to ATP. Thus, there is less beta cell depolarization, which results in decreased insulin release. This is where sulfonylureas come into play.
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.
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!
Another group of medications called meglitinides also prevent the ATP-sensitive potassium pumps from opening.
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.
- "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
- "Rang and Dale's Pharmacology" Elsevier (2019)
- "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
- "Sulfonylurea versus metformin monotherapy in patients with type 2 diabetes: a Cochrane systematic review and meta-analysis of randomized clinical trials and trial sequential analysis" CMAJ Open (2014)
- "Ion Transporters, Channelopathies, and Glucose Disorders" International Journal of Molecular Sciences (2019)
- "Meglitinide analogues: a review of clinical data focused on recent trials" Diabetes & Metabolism (2006)
- "CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM – 2019 EXECUTIVE SUMMARY" Endocrine Practice (2019)