In diabetes mellitus, your body has trouble moving glucose, which is a type of sugar, from
your blood into your cells. This leads to high levels of glucose in your blood
and not enough of it in your cells, and remember that your cells need glucose
as a source of energy, so not letting the glucose enter means that the cells
starve for energy despite having glucose right on their doorstep.
In general,the body controls how much glucose is in the blood relative to how much gets into the cells with two hormones: insulin and glucagon. Insulin is used to
reduce blood glucose levels, and glucagon is used to increase blood glucose
levels. Both of these hormones are produced by clusters of cells in the
pancreas called islets of Langerhans. Insulin is secreted by beta cells in
the center of the islets, and glucagon is secreted by alpha cells in the
periphery of the islets. Insulin reduces the amount of glucose in the blood by
binding to insulin receptors embedded in the cell membrane of various
insulin-responsive tissues like muscle cells and adipose tissue. When
activated, the insulin receptors cause vesicles containing glucose transporter
that are inside the cell to fuse with the cell membrane, allowing glucose to
be transported into the cell. Glucagon does exactly the opposite, it raises
the blood glucose levels by getting the liver to generate new molecules of
glucose from other molecules and also break down glycogen into glucose so
that it can all get dumped into the blood. Diabetes mellitus is diagnosed
when the blood glucose levels get too high, and this is seen among 10% of the
world population. There are two types of diabetes - Type 1 and Type 2, and the
main difference between them is the underlying mechanism that causes the
blood glucose levels to rise. About 10% of people with diabetes have Type 1,
and the remaining 90% of people with diabetes have Type 2. Let's start with
Type 1 diabetes mellitus, sometimes just called type 1 diabetes. In this
situation, the body doesn't make enough insulin. The reason this happens is
that in type 1 diabetes there is a type 4 hypersensitivity response or a
cell-mediated immune response where a person's own T cells attack the
pancreas. As a quick review, remember that the immune system has T cells that
react to all sorts of antigens, which are usually small peptides,
polysaccharides, or lipids, and that some of these antigens are part of our
own body's cells. It doesn't make sense to allow T cells that will attack our
own cells to hang around, and so there's this process to eliminate them
called self-tolerance. In type 1 diabetes, there is a genetic abnormality
causes a loss of self-tolerance among T cells that specifically target the
beta cell antigens. Losing self-tolerance means that these T cells are allowed
to recruit other immune cells and coordinate an attack on these beta cells.
Losing beta cells means less insulin, and less insulin means that glucose piles
up in the blood, because it can't enter the body's cells. One really
important genes involved in regulation of the immune response is the human
leukocyte antigen system, or HLA system. Although it's called a system, it's
basically this group of genes on chromosome six that encode the major
histocompatibility complex, or MHC, which is a protein that's extremely
important in helping the immune system recognize foreign molecules, as well as
maintaining self-tolerance. MHC is like the serving platter that antigens are
presented to the immune cells. Interestingly, people with type 1 diabetes
often have specific HLA genes in common with each other, one called HLA-DR3
and another called HLA-DR4. But this is just a genetic clue right? Because
not everyone with HLA-DR3 and HLA-DR4 develops diabetes. In diabetes mellitus
type 1, destruction of beta cells usually starts early in life, but sometimes
up to 90% of the beta cells are destroyed before symptoms crop up. Four
clinical symptoms of uncontrolled diabetes, that all sound similar, are
polyphagia, glycosuria, polyuria, and polydipsia. Let's go through them one by
one. Even though there's a lot of glucose in the blood, it can't get into
cells, which leaves cells starved for energy, so in response, adipose tissue
starts breaking down fat, called lipolysis, and muscle tissue starts breaking
down proteins, both of which results in weight loss for someone with
uncontrolled diabetes. This catabolic state leaves people feeling hungry, also
known as polyphagia. Phagia means eating, and Poly means a lot. Now with
high glucose levels, that means that when blood gets filtered through the
kidneys, some of it starts to spill into the urine, called glycosuria.
Glucose refers to glucose, uria the urine. Since glucose is osmotically
active, water tends to follow it, resulting in an increase in urination, or
polyuria. Polye again refers to a lot, and uria again refers to urine
again. Finally, because there is so much urination, people with uncontrolled
diabetes become dehydrated and thirsty, or polydipsia. Poly means a lot, and
dipsia means thirst. Even though people with diabetes aren't able to produce
their own insulin, they can still respond to insulin, so treatment involves
lifelong insulin therapy to regulate their blood glucose levels and basically
enable their cells to use glucose. One really serious complication with type
1 diabetes is called diabetic ketoacidosis, or DKA. To understand it, let's
go back to the process of lipolysis, where fat is broken down into free fatty
acids. After that happens, the liver turns the fatty acids into ketone bodies,
like acetoacetic acid and beta hydroxybutyric acid, acetoacetic acid is a
ketoacid because it has a ketone group and a carboxylic acid group. Beta
hydroxybutyric acid on the other hand, even though it's still one of the ketone
bodies, isn't technically a ketoacid since its ketone group has been reduced to
a hydroxyl group. These ketone bodies are important because they can be used
by cells for energy, but they also increase the acidity of the blood, which
is why it's called keto-acid-osis. If the blood becoming really acidic can
have major effects throughout the body. Patients can develop Kussmaul
respiration, which is a deep and labored breathing as the body tries to move
carbon dioxide out of the blood, in an effort to reduce its acidity. Cells
also have a transporter that exchanges hydrogen ions (or protons”H+) for
potassium. When the blood gets acidic, it is by definition loaded with
protons that get sent into cells while potassium gets sent into the fluid
outside cells. Another thing to keep in mind is that in addition to helping
glucose enter cells, insulin stimulates the sodium-potassium ATPases which
help potassium get into cells, and so without insulin, more potassium stays in
the fluid outside cells. Both of these mechanisms lead to increased potassium
in the fluid outside of cells which quickly makes it into the blood and
causes hyperkalemia. The potassium is then excreted, so over time, even
though the blood potassium levels remain high, overall stores of potassium in
the body”which includes potassium inside cells”starts to run low. Patients
will also have a high anion gap, which reflects a large difference in the
unmeasured negative and positive ions in the serum, largely due to this build
up of ketoacids. Diabetic ketoacidosis can happen even in people who've
already been diagnosed with diabetes and currently have some sort of insulin
therapy. In states of stress, like an infection, the body releases
epinephrine, which in turn stimulates the release of glucagon. Too much
glucagon can tip the delicate hormonal balance of glucagon and insulin in favor
of elevating blood sugars and can lead to a cascade of events we just
described”increased glucose in the blood, loss of glucose in the urine, loss
of water, dehydration, and in parallel a need for alternative energy,
generation of ketone bodies, and ketoacidosis. Interestingly, both ketone
bodies break down into acetone and escape as a gas by getting breathed out
the lungs which gives a sweet fruity smell to a person's breath. In general
though, that's the only sweet thing about this illness, which also causes
nausea, vomiting, and if severe, mental status changes and acute cerebral
edema. Treatment of a DKA episode involves giving plenty of fluids, which
helps with dehydration, insulin which helps lower blood glucose levels, and
replacement of electrolytes, like potassium; all of which help to reverse the
acidosis. Now, let's switch gears and talk about Type 2 diabetes, which is where the body makes insulin, but the tissues don't respond as well to it.
The exact reason why cells don't respond isn't fully understood, essentially
the body's providing the normal amount of insulin, but the cells don't move
their glucose transporters to their membrane in response, which remember is
needed for glucose to get into the cell, these cells therefore they have
insulin resistance. Some risk factors for insulin resistance are obesity,
lack of exercise, and hypertension, and the exact mechanisms are still being
explored. For example, an excess of adipose tissue”or fat”is thought to cause
the release of free fatty acids and so-called adipokines, which are
signaling molecules that can cause inflammation, which seems related to
insulin resistance. However, many people that are obese are not diabetic, so
genetic factors probably play a major role as well. We see this when we look
at twin studies as well, where having a twin with type 2 diabetes increases
the risk of developing type 2 diabetes, completely independent of other
environmental risk factors. In Type 2 diabetes, since tissues don't respond
as well to normal levels of insulin, the body ends up producing more insulin
in order to get the same effect and move glucose out of the blood. They do
this through beta cell hyperplasia, an increased number of beta cells, and beta
cell hypertrophy, where they actually grow in size, all in this attempt to pump
out more insulin. This works for a while, and by keeping insulin levels
higher than normal, blood glucose levels can be kept normal, called
normoglycemia. Now, along with insulin, beta cells also secrete islet amyloid
polypeptide, or amylin, so while beta cells are cranking out insulin they
also secrete an increased amount of amylin. Over time, amylin builds up and
aggregates in the islets. This beta cell compensation, though, 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. As beta cells are lost and insulin levels decrease,
glucose levels in the blood start to increase, and patients develop
hyperglycemia, which leads to similar clinical signs that I mentioned before,
like polyphagia, glycosuria, polyuria, and polydipsia. But unlike type 1
diabetes, there is generally some circulating insulin in type 2 diabetes from
the beta cells that are trying to compensate for the insulin resistance. This
means that the insulin/glucagon balance is such that diabetic ketoacidosis
doesn't usually develop. Having said that, a complication called hyperosmolar
hyperglycemic state (or HHS) is much more common in type 2 diabetes than type
1 diabetes - and it causes increased plasma osmolarity due to extreme
dehydration and concentration of the blood. To help understand this, remember
that glucose is a polar molecule that cannot passively diffuse across cell
membranes, which means that it acts as a solute. So when levels of glucose
are super high in the blood (meaning it's a hyperosmolar state), water begins
to leave the body's cells and enter the blood vessels, leaving the cells
relatively dry and shriveled rather than plump and juicy. Blood vessels that
are full of water lead to increased urination and total body dehydration. And
this is a very serious situation because the dehydration of the body's cells
and in particular the brain can cause a number of symptoms including mental
status changes. In HHS, you can sometimes see mild ketonemia and acidosis,
but not to the extent that it's seen in DKA, and in DKA you can see some
hyperosmolarity, so there is definitely overlap between these two syndromes.
Besides type 1 and type 2 diabetes, there are also a couple other subtypes of
diabetes mellitus. Gestational diabetes is when pregnant women have increased
blood glucose which is particularly during the third trimester. Although
ultimately unknown, the cause is thought to be related to pregnancy hormones
that interfere with insulin's action on insulin receptors. Also, sometimes
people can develop drug-induced diabetes, which is where medications have
side effects that tend to increase blood glucose levels. The mechanism for
both of these is thought to be related to insulin resistance (like type 2
diabetes), rather than an autoimmune destruction process (like in type 1
diabetes). Diagnosing type 1 or type 2 diabetes is done by getting a sense
for how much glucose is floating around in the blood and has specific
standards that the World Health Organization uses. Very commonly, a fasting
glucose test is taken where the person doesn't eat or drink (except water,
that's okay) for 8 hours and has their blood tested for glucose levels.
Levels of 100 110 milligrams per deciliter to 125 milligrams per deciliter
indicates prediabetes and 126 milligrams per deciliter or higher indicates
diabetes. A non-fasting or random glucose test can be done at any time, with
200 milligrams per deciliter or higher being a red flag for diabetes. Another
test is called an oral glucose tolerance test, where a person is given glucose,
and then a blood samples are taken at time intervals to figure out how well
it's being cleared from the blood, the most important interval being 2 hours
later. Levels of 140 milligrams per deciliter to 199 milligrams per deciliter
indicate prediabetes and 200 or above indicates diabetes. Another thing to
know is that when blood glucose levels get high, the glucose can also stick
to proteins that are floating around in the blood or in cells. So that brings
us to another type of test that can be done which is the HbA1c test, which
tests for the proportion of hemoglobin in red blood cells that has glucose
stuck to it - called glycated hemoglobin. HbA1c levels of 5.7% to 6.4%
indicates prediabetes, and 6.5% or higher indicates diabetes. This proportion
of glycated hemoglobin doesn't change day to day, so it gives a sense for
whether the blood glucose levels have been high over the past 2 to 3 months.
Finally, we have the C-peptide test, which tests for this byproduct of insulin
production. If the level of C-peptide is low or absent, it means the pancreas
is no longer producing enough insulin, and the glucose can't enter the cells.
For type I diabetes, insulin is the only treatment option. For type II
diabetes, on the other hand, lifestyle changes, like weight loss and exercise,
along with a healthy diet and oral antidiabetic medications, like metformin
and several other classes, can sometimes be enough to reverse some of that
insulin resistance and keep blood sugar levels in check. However, if oral
antidiabetic medications fail, type II diabetes can also be treated with
insulin. Something to bear in mind is that insulin treatment comes with a risk
of hypoglycemia, especially if insulin is taken without a meal. Symptoms of
hypoglycemia can be mild, like weakness, hunger, shaking, but they can progress
to loss of consciousness and seizures in severe cases. In mild cases,
drinking juices, or eating candy, or sugar, may be enough to bring blood sugar
up. But in severe cases, intravenous glucose should be given as soon as
possible. The FDA has also recently approved intranasal glucagon as a
treatment for severe hypoglycemia. Ok, now, over time, high glucose levels
can cause damage to tiny blood vessels, called the microvasculature. In
arterioles, a process called hyaline arteriolosclerosis where the walls of
arterioles where they develop hyaline deposits, these deposits of proteins,
and these make them hard and inflexible. In capillaries, the basement
membrane can thicken and make it hard for oxygen to easily move from the
capillary to the tissues, causing hypoxia. One of the most significant
effects is that diabetes increases the risk of medium and large arterial wall
damage and subsequent atherosclerosis, which can lead to heart attacks and
strokes, major causes of morbidity and mortality for patients with diabetes.
In the eyes, diabetes can lead to retinopathy and evidence of that can be seen
on a fundoscopic exam that shows cotton wool spots or flare hemorrhages - and
can eventually cause blindness. In the kidneys, the afferent and efferent
arterioles, as well as the glomerulus itself can get damaged which can lead
to a nephrotic syndrome that slowly diminishes the kidney's ability to filter
blood over time - and can ultimately lead to dialysis. Diabetes can also
affect the function of nerves, causing symptoms like a decrease in sensation
in the toes and fingers, sometimes called a stocking-glove distribution, as
well as causing the autonomic nervous system to malfunction, and that system
controls a number of body functions - everything from sweating to passing
gas. Finally, both the poor blood supply and nerve damage, can lead to ulcers
(typically on the feet) that don't heal quickly and can get pretty severe,
and need to be amputated. These are some of the complications of uncontrolled
diabetes, which is why it's so important to, diagnose and control diabetes
through a healthy lifestyle, medications to reduce insulin resistance and
even insulin therapy if beta cells have been exhausted. While type 1 diabetes
can not be prevented, type 2 diabetes can. In fact, many people with diabetes
can control their blood sugar levels really effectively and live a full and
active life without any of the complications.
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