- [Voiceover] Type II diabetes receives a lot of attention
in the laypress as a public health threat,
as it affects about 10% of the global population,
and is currently the eighth most
common cause of death worldwide.
As such, understanding how to treat type II diabetes
is very important because if it's treated properly,
one can avoid nearly all of the complications
of type II diabetes and live a happy and healthy life.
Now before we dive into the specific treatments,
let's first discuss the glucose regulation pathway
as it will help us to better understand
the pharmacokinetics or the mechanisms of action
for the different treatments of type II diabetes.
Now in the center here is the blood glucose level,
and as blood glucose levels increase,
say after eating a meal, this is sensed by the pancreas,
and the beta cells within the pancreas secrete insulin
which acts on cells throughout the body
to lower the blood glucose level.
Then as blood glucose levels decrease,
this is also sensed by the pancreas,
and then the alpha cells secrete glucagon
which acts to raise the blood glucose levels.
And one of the mechanisms by which it does so
is by promoting the conversion of
glycogen to glucose in the liver
which is then released into the blood stream.
Now diabetes mellitus is a group of disorders
that's caused by dysfunction of the insulin pathway
resulting in an inability to lower blood glucose levels.
And as you can see by this diagram,
there are two main steps that must occur
for this pathway to work properly.
First, insulin must be secreted by
the beta cells of the pancreas.
Then second, the cells throughout the body
must respond to insulin for it to have an effect.
And this glucose regulation pathway can be
thought of as similar to that of
the temperature regulation in a building.
The thermostat is analogous to the pancreas
in that it senses the changes in temperature
and sends different signals accordingly.
If the temperature increases, then it sends
a signal to the air conditioner to turn on,
which then lowers the temperature.
Conversely, if the temperature decreases,
this is also sensed by the thermostat
and it sends a signal to the boiler and radiator
to turn on, which then raises the temperature.
Now once again, there are two important steps.
The thermostat must sense the change in temperature
and send a signal, which is similar to the first step
in the insulin pathway, and second, the air conditioner
must be able to act upon this signal
in order to have an effect.
So let's go back to our insulin pathway.
When we think of the types of diabetes,
in general we think of type I diabetes
as dysfunction of the first step,
and type II diabetes as occurring
due to dysfunction of the second step.
So it would make sense that the treatment
of the different types of diabetes will be different
as their underlying mechanisms are different.
In the treatment of type II diabetes,
some medications are given to increase insulin secretion,
to help overcome the resistance,
and others are given to directly decrease
the insulin resistance in the second step.
So let's now discuss the specific treatments
for type II diabetes and the mechanisms by which they work.
And we'll begin with lifestyle modifications.
The first lifestyle intervention is that of
proper nutrition and weight loss.
Regardless of one's initial weight,
proper nutrition and associated weight loss
improves the body's ability to
regulate blood glucose levels.
And proper nutrition for type II diabetes
includes a well-balanced low-calorie
and low-carbohydrate diet.
Admittedly, this can be a very difficult change
for many people with type II diabetes.
As it takes a great deal of dedication and self-control.
However, it is extremely important
because a proper diet and weight loss have been shown
to both increase insulin secretion
and decrease insulin resistance.
The other lifestyle modification is physical activity.
Independent of weight loss, increased physical activity
has been shown to improve glycemic control
through reducing insulin resistance.
And the benefits of exercise begin almost immediately,
however they can be short lived
if physical activity is not maintained.
Persisting only about three to six days after
the cessation of routine exercise.
So the recommendations for routine exercise
include 30 minutes a day, five days a week,
of moderate intensity aerobic activity
such as walking, jogging, or biking.
And the great thing about these lifestyle modifications
is they don't just treat type II diabetes.
A proper diet and routine physical activity
will also improve one's cardiovascular function,
lipid profile, as well as their general mental wellbeing.
In addition to lifestyle modifications,
there are many different medications
available to treat type II diabetes,
however it can be confusing to keep them all straight.
Instead of discussing each of the medications
individually, let's classify the different medications
into groups based on their mechanism of action
and how it relates to our diagram of glucose regulation.
And we'll start with a group of medications
known as the biguanides,
and I know I just said we won't be discussing
the individual medications, however there is one exception,
and that is with metformin.
And this is because metformin is by far
the most common biguanide prescribed for type II diabetes.
And it's also the first line medication for the disease.
Now, metformin has three mechanisms of action
that improve glucose regulation.
Most importantly, metformin directly increases
the peripheral insulin sensitivity.
It also acts by decreasing the action
of glucagon in the liver.
So instead of just augmenting the insulin pathway,
metformin also inhibits the opposing glucagon pathway.
Then lastly, although not shown in this diagram,
metformin reduces intestinal absorption of glucose
which then decreases the amount of glucose
available to enter the blood stream.
And fortunately, metformin is also very effective.
On average, metformin can reduce someone's
hemoglobin A1c by about 1%, however it is important
to note that individuals with liver failure
can not take metformin and a small percentage
of individuals who take the medication
will need to stop taking it due to
an adverse side effect known as lactic acidosis.
The next group of medications have
a somewhat difficult name.
They are the thiazolididiones or TZDs for short.
Similar to metformin, TZDs also work to increase
type II diabetes by acting on the second step
to increase insulin sensitivity,
however the means by which they do so is different.
TZDs activate a receptor known as the
peroxisome proliferator-activated receptor gamma
or PPAR gamma for short.
And PPAR gamma is a transcription factor
for multiple genes that increase insulin sensitivity
in adipose, muscle, and liver cells.
As such, by activating PPAR gamma,
TZDs indirectly increase insulin sensitivity.
Now the next group of medication is the sulfonylureas
which are another common group of anti-diabetic medication.
Sulfonylureas inhibit the potassium channels
on the beta cells within the pancreas
and by inhibiting these channels,
potassium builds up within the cell
and this depolarizes the cell membrane
which opens voltage gated calcium channels.
This causes an influx of calcium into the beta cells
which triggers the release of insulin into the blood stream.
So instead of decreasing insulin resistance,
sulfonylureas treat type II diabetes by
overcoming the insulin resistance
through increased insulin secretion.
The last two groups of type II diabetes medications
act upon the incretin pathway,
and are therefore known as incretins.
And they are the glucagon-like peptide one
or GLP-1 agonists and the dipeptidyl peptidase four
or DPP-4 antagonists.
Incretins such as GLP-1 are hormones that have
two synergistic effects that result in
the lowering of blood glucose levels.
First, they directly stimulate the release of insulin
from the beta cells in the pancreas.
And second, they inhibit the release of glucagon.
DPP-4, on the other hand, is an enzyme
that inhibits the action of GLP-1.
Therefore GLP-1 agonists can be given
to directly stimulate this incretin pathway
to augment the insulin pathway
and treat type II diabetes.
Similarly, DPP-4 inhibitors can be given
to indirectly augment the insulin pathway
by inhibiting the inhibition of the incretin pathway.
So it's important to know that any of the treatments
for type II diabetes that act upon this first step
in the insulin pathway, and therefore
increase insulin secretion, will therefore
also carry a risk of inducing hypoglycemia
or low blood sugar levels.
And the treatments that act upon this step
and carry this risk include lifestyle modifications,
sulfonylureas, and the incretins.
And one way to decrease this risk is
to take the medications with a meal.
Now this is just an overview of
the pharmacokinetics of the different interventions
used to treat type II diabetes
and this is helpful for understanding
how we can use medications to reverse
and treat the underlying mechanisms that cause the disease,
however just understanding the mechanisms
does not convey a very practical approach
to treating this disease.
For most individuals, treating type II diabetes
requires a combination of lifestyle modifications,
potentially multiple medications,
and routine care by a primary care provider
to achieve a happy and healthy life
free of the complications of type II diabetes.