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A 50-year-old man comes to the office for a review of his laboratory studies. He has a history of diabetes mellitus, and his current medications include glipizide and metformin. He says that he takes his medications regularly, but his wife is concerned about his diabetes control. His health maintenance labs show a hemoglobin A1c of 9%, increased from 7% at his last visit. Which of the following labs would best indicate a need for insulin to control this patient's blood sugar?
Content Reviewers:Rishi Desai, MD, MPH
Contributors:Tanner Marshall, MS
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.
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 transporters 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.
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 that 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. “Glycos” refers to glucose, “uria” the urine.
Since glucose is osmotically active, water tends to follow it, resulting in an increase in urination, or polyuria. “Poly” 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.
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.