How is diabetes mellitus treated using drugs?
A story called “why does diabetes mellitus happen?” has three main characters: the pancreas, insulin and glucose. It’s a very long story, but it has a short version, as follows. The pancreas is a tadpole-shaped organ behind the stomach. Beta cells in the pancreas release a hormone called insulin, which floats around the bloodstream, telling all body cells to take up glucose from the blood. People develop ‘type 1’ diabetes mellitus (DM) if their pancreases fail to create insulin, or ‘type 2’ DM if their body cells fail to respond to insulin. People with DM have tonnes of glucose in their blood, and not enough glucose in their cells – so their cells get really tired because cells need glucose to make energy, and their blood gets really sticky because glucose is a sticky sugary substance, a bit like honey.
This story, called “how is diabetes mellitus treated using drugs?” has six main characters with ridiculously long names:
- Adenosine Mono Phosphate Kinase
- Glucagon Like Peptide 1
- Dipeptidyl Peptidase 4
- Peroxisome Proliferation Activation Receptor Gamma
- Adenosine Triphosphate Sensitive Potassium Channels
- Alpha Glycosidase
Each character corresponds to a drug that decreases the amount of glucose in the blood in order to treat type 2 DM. Read on to meet the characters!
Character #1: Adenosine Mono Phosphate Kinase (nickname – AMPK)
AMPK is an enzyme that floats around in the cytoplasm of a cell doing absolutely nothing, unless it gets activated. AMPK gets activated in cells who don’t have enough energy. Activated AMPK encourages cells to break down their fat stores and take up more glucose from the blood, in order to gain more energy.
Question 1: if you were designing a drug to treat DM, would you want it to encourage or discourage AMPK from getting activated?
Answer: encourage. Metformin is the first choice drug for type 2 DM, it’s taken as a tablet, and it lowers blood glucose by activating AMPK.
Character #2: Glucagon Like Peptide 1 (nickname – GLP1)
GLP1 is a hormone released into the bloodstream by cells in the walls of the small intestine when half-digested food from the stomach arrives in the small intestine. GLP1 does tonnes of things, all of which make you feel full. For example, GLP1 makes food stay in the stomach for longer before reaching the small intestine (so you feel full because your stomach can’t fit any more food in it), and it also encourages the pancreas to release more insulin (so your cells get more glucose for making energy which makes you feel less hungry).
Question 2: if you were designing a drug to treat DM, would you want it to increase or decrease the amount of GLP1 in the bloodstream?
Answer: increase. Liraglutide is the name of the injection of GLP1 given to treat type 2 DM. Liraglutide lowers blood glucose because GLP1 makes the pancreas release more insulin.
Character #3: Dipeptidyl Peptidase 4 (nickname – DPP4)
DPP4 is an enzyme that breaks down GLP1 to stop it from working. If you did not have DPP4, you would finish eating a meal and feel full for weeks instead of hours because there would be tonnes of GLP1 in your bloodstream.
Question 3: is there a difference between increasing GLP1 and decreasing DPP4?
Answer: not really. There will be more active GLP1 in your blood if you decrease DPP4 or if you increase GLP1. There’s a drug called Sitagliptin which stops DPP4 from working.
Character #4: Adenosine Triphosphate Sensitive Potassium Channels (nickname – K-ATP channels)
K-ATP channels are found on the cell membranes of beta cells in the pancreas. If there’s lots of ATP in a beta cell, it’s K-ATP channels will close. This traps potassium in the beta cell, which makes a bunch of chemical reactions happen, which eventually allows the beta cell to release insulin.
It’s actually pretty clever of the K-ATP channels to provide a link between ATP content and insulin release in pancreas beta cells, and here’s why. ATP, adenosine triphosphate, is the chemical energy that cells require for many of their daily activities. ATP is made by cells when they perform lots of chemical reactions which break down glucose. Pancreas beta cells and brain cells are the only body cells which are allowed to take up as much glucose from the blood as they like, regardless of whether insulin is telling them to. The amount of glucose taken up (and promptly converted into ATP) by a pancreas beta cell is proportional to the level of blood glucose. If there’s lots of ATP in a pancreas beta cell, it means that there is lots of glucose in the blood.
Question 4: if you designed a drug to treat DM, would it close or open K-ATP channels?
Answer: close. Sulfonylureas are a type of drug that close K-ATP channels in pancreas beta-cells – which makes the beta-cells release insulin.
Character #5: Peroxisome Proliferator Activated Receptor Gamma (nickname – PPARg)
PPARg lives in the nucleus of cells and it’s a transcription factor (i.e. a molecule controlling which proteins a cell makes from its genes). PPARg gets activated when the blood contains too many molecules of fat (such as triglycerides or cholesterol). Active PPARg encourages adipocytes (special cells that store fat) to take up molecules of fat and glucose from the blood. This enables adipocytes to do more cell division, and prevents the blood from having too much fat and glucose in it – which can be dangerous.
Question 5: if you were designing a drug to treat DM, would you want it to increase or decrease the activation of PPARg?
Answer: increase. Pioglitazone is a drug that activates PPARg.
Character #6: Alpha Glycosidase (nickname: aG)
aG is an enzyme found inside the small intestine. It breaks down big complex carbohydrate molecules into glucose molecules which are small enough to slide out through tiny gaps in the walls of the small intestine and into the bloodstream through even tinier gaps in the walls of blood vessels. Without aG, your cells would not get any energy from the bowl of pasta that you just ate, because all the carbohydrates from the pasta would be trapped as macromolecules inside your intestines!
Question 6: why do alpha glycosidase inhibitors make you fart?
Answer: there are bacteria inside your large intestine which digest and then metabolise all of the undigested carbohydrates which should have been digested by your aG enzyme. This process releases lots of gas (such as carbon dioxide). Acarbose is a drug that inhibits aG. It’s great for reducing blood glucose (by preventing the digestion of complex carbohydrates into glucose in the small intestine), but it does make you fart!
So how do you treat type 2 DM using drugs?
Well, it depends on the patient. They can get an increasing number of different drugs as their type 2 DM gets worse. All of the drugs have side effects, so it’s up to the patient to complain if they feel really bad, and then they can change which drug they get. It’s also up to the doctor to know that the patient may have health conditions that will determine which drugs they MUST NOT HAVE. For example, Metformin is dangerous for people with severe kidney failure, and Pioglitazone is dangerous for people with heart failure.
In conclusion, these drugs are amazing!
100 years ago, people died of type 2 Diabetes Mellitus pretty quickly because their cells ran out of energy and their blood got too sticky (this causes blood clots). We are really lucky in the 21st century that just by eating tablets or having injections, we can allow our cells to get the glucose that they need from the blood, if our cells do not respond to insulin as much as they should.