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's produced in the pancreas by beta cells. These cells are found within clusters of endocrine cells called islets of Langerhans, which are distributed across the pancreas.
When the pancreas is unable to produce enough insulin, insulin therapy can be used to maintain the blood glucose within normal range.
Insulin's main function is to facilitate the transport of glucose from the blood into various insulin responsive tissues, like muscle or adipose tissue.

Physiology0:26–2:25

Now, after insulin is secreted from the pancreas, it travels in the blood to the cell membrane where it binds to insulin receptors.
These receptors have 2 alpha and 2 beta subunits. Alpha subunits are located on the outside of the cell membrane and bind insulin, causing conformational change to the beta subunits, which are located inside the cell membrane.
These changes activate tyrosine kinase activity, which carries signals into the cell, causing intracellular storage vesicles, which contain glucose transport proteins called glute-4, to fuse with the cell membrane.
Once fused, glute-4 proteins provide a channel for glucose to move into the cell, through facilitated diffusion. Insulin also promotes glycogenesis, which is the conversion of glucose to glycogen in the liver and skeletal muscles.
Glycolysis, which is the breakdown of glucose to pyrivate, lipogenesis, which is the synthesis of fatty acids, and triglycerides in the liver and adipose tissue, and amino acid uptake and protein synthesis in skeletal muscles.
Insulin also activates sodium potassium ATPace pumps, and shifts potassium into cells, decreasing potassium levels in the blood.
On the flip side, insulin inhibits glycogenolysis, or the breakdown of glycogen, and gluconeogenesis, which is glucose production from non-carbohydrate molecules, such as lactic acid.
Finally, insulin inhibits lipolysis, the breakdown of lipids, and proteolysis, the breakdown of proteins. Type 1 diabetes mellitus, which most commonly is diagnosed in children and adolescents, arises when a person's T cells attack the pancreas.

Pathology2:25–3:29

Usually, maturing T cells undergo a process called self-tolerance, where T cells that attack our own body are eliminated.
In type 1 diabetes, genetic, molecular, and environmental abnormalities cause the loss of self-tolerance in T cells that target pancreatic beta cells, resulting in the destruction of beta cells, reduced insulin production, and hyperglycemia.
Type 2 diabetes is caused by insulin resistance, meaning cells don't respond well to insulin, leading to less glucose being transferred into cells and causing increased production of insulin by the pancreas.
Eventually, the pancreas gets so overworked that beta cells start to die, leading to decreased insulin production and hyperglycemia.
In order to correct the insulin deficiency found in type 1 diabetes and later stages of type 2 diabetes, exogenous insulin can be used.
Insulin is typically administered subcutaneously, because if taken orally, it would be broken down in the GI tract. Insulin can be given intravenously during severe hyperglycemic episodes, and there's also a newer formulation of insulin that can be inhaled.

Administration route3:29–4:08

The quickest way to absorb insulin is by injecting it into the subcutaneous tissue of the abdominal region, followed by the arms, thighs, and buttocks.
People with diabetes typically use syringes or pre-filled insulin pens, although some prefer an 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.

Insulin preparations4:08–5:33

Now, there are multiple classes 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.
Rapid-acting and short-acting insulins are used for a bolus insulin regimen, where they're taken before each meal to counteract the post-meal increase in blood glucose.
Intermediate-acting, long-acting, and ultra-long-acting insulins are used for a basal insulin regimen, to maintain a steady background level of insulin throughout the day.
They're given once or twice daily to regulate the basal or non-prandial blood glucose level. Combining these creates a basal bolus regimen, where a basal insulin is used to maintain steady blood glucose levels throughout the day, and a bolus insulin is taken before meals to counteract the post-meal increase in blood glucose.
Another type of insulin regimen is the sliding scale regimen. This is typically reserved for hospital settings, where a person's blood glucose level may fluctuate rapidly due to metabolic stressors like infections or other illnesses.

Rapid-acting insulins5:33–6:18

In this regimen, every 4 to 6 hours, the person's blood glucose level is measured. And an appropriate dosage of rapid-acting or short-acting insulin is administered.
It's important to note that insulin is the preferred medication for 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 glulazine. These medications are given subcutaneously, and they're modified versions of regular insulin with different sequences of amino acids, which prevent hexamer formation, leading to more rapid monomer absorption.
Rapid-acting insulins begin working within 30 minutes of administration, with a peak effect around 30 to 90 minutes after injection.

Short-acting insulins6:18–7:03

Their effect generally lasts for 3 to 5 hours. These insulins are injected right before meals, or can be used in insulin pumps.
Next is the short-acting insulin or regular insulin, which is a type of insulin that can be given either subcutaneously or intravenously.
Regular insulin is generally produced and stored as a hexamer, which is simply a term used to describe a single unit of 6 insulin molecules.
Hexamers must break down into monomers before being absorbed. Regular insulin generally starts working within 60 minutes after administration, and its effects peak around 2 to 5 hours.

Intermediate-acting insulins7:03–7:39

Its duration of action lasts between 5 and 8 hours. Because it can be given intravenously, it's the preferred insulin for treating diabetic ketoacidosis, hyper-osmolar hyperglycemic state, and hyperkalemia.
Next up is the intermediate-acting insulin, known as NPH insulin, which stands for neutral protamine hagedorn. It's created by adding protamine and zinc to regular insulin, causing a lowering of insulin solubility in the blood.

Long-acting insulins7:39–8:28

NPH insulin becomes active around 1 to 2 hours after administration, with a peak effect between 4 and 12 hours, and lasts 18 to 24 hours.
Due to its longer duration of action, it's used as a basal insulin. Moving on, we have long-acting insulins, which include insulin glargine and dedimer.
Insulin glargine is unique because once injected, it forms a precipitate of microcrystals at the site of injection, which significantly stabilizes insulin's hexamer structure.
This allows it to slowly and steadily release insulin monomers into the bloodstream. On the other hand, insulin dedimer has a fatty acid side chain, which allows it to bind to albumin for a time before dissociating and becoming active.
Both of these long-acting insulins start to work between 1 and 2 hours of administration, but neither have a peak effect.

Ultra long-acting insulins8:28–9:04

Insulin dedimer has a duration of action up to 24 hours, whereas insulin glargine has a duration of action between 20 and 24 hours.
A relatively new preparation of insulin is insulin Deglidec. Which is considered an ultra long acting insulin, and is formed by the deletion of one amino acid and addition of a fatty acid side chain to regular insulin.
Insulin Deglidec is a depot medication injected and stored beneath the skin. Insulin Deglidec is made up of multiple hexamers in a long chain that slowly break down into insulin monomers and is used for basal glucose control.

Side effects9:04–10:06

Its onset of action is between 1 to 2 hours with no peak effect. Its duration of action is greater than 24 hours.
The main side effect of insulin therapy is the risk of hypoglycemia or low blood glucose. 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.
In addition, these medications can also cause hypokalemia, since insulin shifts potassium into the intracellular space. But this is more common with intravenous administration of regular insulin.

Memory palace10:06–12:53

Repeated injections in the same area may lead to lipodystrophy, which is a local atrophy or hypertrophy of subcutaneous fat near the injection site, causing a depression or lump beneath the skin.
This is why it's important to alternate injection sites frequently. Lastly, insulin can cause moderate weight gain.
Now, let's make a simple and fundamonic that'll help you efficiently memorize these pharmacology facts. Let's imagine an athletic event where each contestant represents one of the classes of insulin.
There's a toddler 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.
The height of the contestants corresponds with the duration of action for each of these classes of insulin. So, the rapid-acting toddler has the shortest duration, and the ultra long acting ogre has the longest.
To remember the three rapid-acting insulins, let's give the toddler an asparagus for aspart, and a seagull for glulazine is trying to steal it from him.
The toddler has a lisp for Lispro, so he's yelling, stupid gull. 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 Dedemir.
In fact, he's gargling it for glargine, which probably isn't very healthy. The ogre has a deck glued to his back, which represents Deglue deck.
To remember their onset of action, let's have the insulins run on a 3-mile track where each mile represents an hour. The toddler didn't make it to the 0.5 mile mark before giving up, so the onset of action for rapid-acting insulin is less than 30 minutes.
The boy collapsed between the 0.5 mile and 1 mile mark, so the onset for short-acting insulin is less than 60 minutes. Next is a three-way tie between the normal height man, the long-legged man, and the ogre.
They are halfway 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.

Review12:53–13:49

So first, we have the toddler between the floor and the second bar, since its peak effect is about 30 to 90 minutes after administration.
The boy climbed to the 5th bar, because short-acting insulin's peak effect is between 2 and 5 hours. Finally, we have the normal hype man, who's standing victoriously at the top of the 12th bar, since NPH insulin's peak effect is up to 12 hours after administration.
For side effects, there's a boy with obesity, representing weight gain. There's an empty candy wrapper nearby to represent hypoglycemia, and an empty juice with a K on it to represent hypokalemia.
His tummy is bumpy to represent lipodystrophy. All right, here's 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.

Mind map13:49–14:45

Basal insulins like intermediate acting, long acting, and ultra long acting insulins are given to control the baseline glucose level throughout the day.
Rapid-acting insulins have the fastest onset within 30 minutes, followed by short-acting insulin, which starts working within 60 minutes.
Intermediate acting, long-acting, and ultra-long acting start working between 1 and 2 hours. Rapid-acting insulins have a peak effect between 30 and 90 minutes.
Short-acting insulins peak between 2 and 5 hours, and intermediate-acting insulins peak between 4 and 12 hours. Major side effects of insulin include hypoglycemia, weight gain, and lipodystrophy at the injection