Insulins

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Introduction0:00–0:26

Insulin is a type of peptide hormone that reduces the amount of glucose in the blood. It is produced in the pancreas by beta cells.
These cells are found within clusters of endocrine cells called the Islets of Langerhans, which are distributed across the pancreas.
If the body is unable to produce enough insulin, then insulin therapy is used to keep the blood glucose low. Insulin’s main function is to facilitate the transport of glucose from the blood into the various insulin-responsive tissues like muscle cells and adipose tissue.

Physiology0:26–2:25

This hormone binds to insulin receptors on the surface of the cell membrane. Now, these receptors have two alpha and two beta subunits.
Alpha subunits are located outside of the cell and they bind insulin; while two beta subunits are located within the cell and they have tyrosine kinase activity which carries signals into the cell.
Once stimulated, insulin receptors cause intracellular storage vesicles, which contain glucose transport proteins called GLUT4, to fuse with the cell membrane.
Next, the GLUT4 proteins embed themselves into the membrane and allow glucose to move into the cell. As a result, insulin promotes glucose uptake and glycogenesis, which is the conversion of glucose to glycogen.
Glycogenesis is the process that takes place in the liver and skeletal muscles. When glycogen storage capacity is reached, insulin promotes glycolysis, which is the breakdown of glucose to pyruvate.
It also stimulates lipogenesis, the synthesis of fatty acids and triglycerides in the liver and adipose tissue; and amino acid uptake and protein synthesis in skeletal muscles.
Finally, insulin activates Na+/K+- ATPase pumps and shifts potassium into intracellular space, thereby decreasing potassium levels in the blood.
On the flip side, insulin inhibits glycogenolysis, which stands for the breakdown of glycogen; and gluconeogenesis, which is glucose production from lactic acids and noncarbohydrate molecules.
Finally, insulin inhibits lipolysis, the breakdown of lipids; and proteolysis, the breakdown of proteins. Type 1 diabetes mellitus, which most commonly affects children and adolescents, arises when a person’s own T cells attack the pancreas.
Normally, maturing T cells in our body go through a process called “self-tolerance” where the T cells that would attack our own body are eliminated.

Pathology2:25–3:29

In type 1 diabetes, there is a genetic abnormality which causes the loss of self-tolerance among T cells that target the beta cells.
The result is the destruction of the beta cells which leads to decreased insulin production and hyperglycemia, or increased blood glucose.Type 2 diabetes is caused by insulin resistance in the cells of the body.
When blood glucose rises after a meal, the pancreas produces insulin as a response. Since the peripheral cells are resistant to insulin, they do not take in the glucose, so the pancreas has to produce even more insulin.
Eventually, the poor pancreas gets so overworked that the beta cell starts to atrophy, which leads to decreased insulin production and high blood glucose levels.
In order to correct the insulin deficiency found in Type 1 diabetes and later stages of type 2 diabetes, exogenous insulins can be used.

Administration route3:29–4:08

Insulin is administered subcutaneously because they can be broken down in the GI tract. Insulin is typically administered through syringes or insulin pens.
When injected into the abdominal region, the absorption is the quickest, followed by arms, thighs, and buttocks. Some diabetics prefer the insulin pump since insulin dosages are programmed into the device and will be delivered subcutaneously throughout the day, thus preventing the need for multiple daily insulin injections.
Now, there are multiple categories of insulin therapies, more commonly referred to as insulin preparations. These preparations are categorized according to their onset of action and duration of effect; and they include rapid-acting, short-acting, intermediate-acting, long-acting, and ultra long-acting insulins.

Insulin preparations4:08–5:33

Rapid-acting and short-acting insulins are used for bolus insulin regimen, where they are taken before each meal to counteract the post-meal increase in blood glucose.
Intermediate-acting, long-acting, and ultra long-lasting insulins are used for basal insulin regimen to maintain a steady background level of insulin throughout the day.
They are given once or twice daily to regulate the basal, or fasting blood glucose, level. Next, there's a basal-bolus regimen where a basal insulin is used to maintain fasting blood glucose levels, and a bolus insulin is taken before meals.
Lastly, is the sliding-scale regimen. This regimen is typically reserved for hospital settings where a person’s blood glucose level could fluctuate rapidly due to metabolic stressors like infections or other illnesses.
In this regimen, every 4-6 hours, the person’s glucose level is measured and an appropriate dosage of short acting insulin is given.
Finally, it’s important to note that insulins are the preferred medications in managing diabetes in pregnancy and breastfeeding.Now let’s look at each class of insulin, starting with rapid-acting insulins, which include insulin aspart, lispro, and glulisine.
These medications are given subcutaneously and they are actually modified versions of regular insulin with different sequences of amino acids.

Rapid-acting insulins5:33–6:18

This makes them less stable, and they break down into single monomers soon after injection. Rapid-acting insulins begin working within 5 to 15 minutes of administration, with a peak effect at 1 hour.
Their effects last for 3 to 4 hours. These insulins are injected right before a meal or they can be used in insulin pumps.
They are also the preferred insulin for treating diabetic ketoacidosis.Next are the short-acting insulins, or regular insulin, which is the only type of insulin that could be given subcutaneously and intravenously.
Regular insulin in the body is generally produced and stored as a hexamer, which is simply a term used to describe a single unit of 6 insulin molecules.

Short-acting insulins6:18–7:03

This structure allows insulin to remain stable within the body, and break down into individual monomers in order to become active.
Thus, regular insulin only begins working 30 minutes after administration and its effect peaks at 2-3 hours. Its duration of action lasts between 5-8 hours and, besides diabetes melitus, it can be used to treat hyperkalemia.Next up is the intermediate-acting insulin known as NPH insulin, which stands for neutral protamine hagedorn.
It’s created through the addition of protamine and zinc to regular insulin. These additional elements cause NPH insulin to become less soluble in the blood than regular insulin.

Intermediate-acting insulins7:03–7:39

As a result, NPH insulin only becomes active around 1-2 hours after administration, with a peak effect after 4 hours, and lasts for 16 to 24 hours.
Due to its long duration of action, it’s used as a basal insulin. Moving on, we have the long-acting insulins which include insulin glargine and detemir.
Glargine is unique because once it’s injected, it forms a precipitate of microcrystals at the site of injection which significantly stabilizes insulin's natural hexamer structure.
This allows it to slowly and steadily release insulin monomers into the bloodstream. On the other hand, detemir has a fatty acid side chain which allows it to bind to albumin for a time before dissociating again and becoming active.

Long-acting insulins7:39–8:28

Both of these long acting insulins begin to work within 1 to 2 hours of administration. Detemir typically lasts for around 20 hours, whereas glargine lasts up to 24 hours.
These medications do not have a peak effect.A relatively new preparation of insulin is insulin degludec, which is considered an ultra long acting insulin, and is formed by the deletion of a single amino acid from regular insulin.
Degludec is a depot injection, meaning the medication is deposited beneath the skin. It forms hexamers like regular insulin, but multiple hexamers combine to form a long chain which slowly breaks down into a monomer.

Ultra long-acting insulins8:28–9:04

Its onset of action is between 1 to 2 hours with no peak effect. Its duration of action lasts up to 48 hours.
The main side effect of insulin therapy is the risk of hypoglycemia, or low blood glucose, due to the administration of too much insulin.
This is more common with insulins that have a peak effect. Some symptoms of hypoglycemia include headache, weakness, hunger, sweating, dizziness, anxiety, and tachycardia.
It’s important to note that individuals with renal impairment, the elderly, and children younger than 7 years of age are at increased risk for hypoglycemia!

Side effects9:04–10:06

In addition, these medications can also cause hypokalemia since insulin shifts potassium into intracellular space; but this is more common with regular intravenous insulin.
Repeated injections in the same area could cause lipodystrophy, which is a local atrophy or hypertrophy of subcutaneous fat near the injection area, causing a depression beneath the skin.
This is why it’s important to switch between injection sites frequently. Lastly, insulin can cause moderate weight gain.
Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharmacology facts! Let’s imagine an athletic event where each contestant represents a class of insulin.There’s a dwarf for rapid acting insulin, a regular boy for short acting, a man of average height for intermediate acting, a tall man with abnormally long legs for long acting, and an ogre for ultra long acting.

Memory palace10:06–12:53

The height of the contestants corresponds with the duration of action for each of these classes of insulin, so the rapid acting dwarf has the shortest duration and the ultra long acting ogre has the longest.To remember the 3 rapid acting insulins, let’s give the dwarf an asparagus for aspart, and a seagull, for glulisine, is trying to steal it from him.
The dwarf has a lisp for lispro so he’s yelling “thtupid gullth!” Short acting is pretty simple since it’s just a regular boy representing regular insulin.
The man representing intermediate acting insulin is a Person of Normal Height, so NPH. The long legged man is holding detergent for detemir, in fact, he’s gargling it for glargine, which can’t be too healthy.
The ogre is carrying his igloo on his back which represents degludec.To remember their onset of action, let’s have the insulins run on a 3 mile track where each mile represents an hour.
The dwarf didn’t make it to the half-mile mark before giving up, so the onset of action for rapid acting insulin is less than 30 minutes.
The boy collapsed at the 1/2 mile mark so the onset of short acting insulin is around 30 minutes. Next, is a 3 way tie between the normal height man, the long legged man, and the ogre.
They are half way between the 1 and 2 mile mark, since intermediate acting, long acting, and ultra long acting insulin’s onset of action is between 1 and 2 hours.The next event will represent when the peak effect takes place, so let’s make the insulins climb a large ladder where each bar represents an hour.
The taller insulins like long acting and ultra-long acting are banned from this event since they do not have peak effects.
So first, we have the dwarf dangling off the first bar since its peak effect happens around 1 hour. The boy is climbing between the 2nd and 3rd bar so its peak effect is around 2-3 hours.
Finally, we have the normal height man who’s standing victoriously at the top of the 4th bar since its peak effect happens after 4 hours.
For side effects, let’s have an obese boy representing weight gain. He’s holding a large, empty candy wrapper to represent hypoglycemia; and an empty juice can with K+ on it to represent hypokalemia.
His big tummy is caved inwards to represent lipodystrophy. All right, as a quick recap… Insulins are given to people with diabetes to lower blood glucose.
Bolus insulins like rapid acting and short acting insulins are given before a meal to control post-meal hyperglycemia. Basal insulins like intermediate acting, long acting, and ultra long acting insulins are given to control the fasting glucose level throughout the day.
Rapid acting insulins have the fastest onset at 15 to 30 minutes, followed by short acting insulin which starts working at 30 minutes.

Review12:53–13:49

Intermediate acting, long acting, and ultra long acting starts working between 1 to 2 hours. Only intermediate, short, and rapid acting insulins have peak effects at over 4 hours, between 2 and 3 hours, and 1 hour respectively.
Major side effects of insulin include hypoglycemia, weight gain, and lipodystrophy at the injection site. "But wait - there's more.
Here's a mind map with all of the mnemonics from the video. Go ahead and pause the video so you can test yourself to see what you remember."
short and rapid acting insulins have peak effects at over four hours between two and three hours and one hour respectively Major side effects of insulin include hypoglycemia weight gain and lipodystrophy at the injection site but wait there's more here's a mind map with all of the demonic from the video go ahead and pause the video so you can test yourself to see what

Mind map13:49–13:59