Diabetes mellitus: Pathology review

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Case Study0:00–1:07

In the emergency department, two individuals came in. One of them is 12-year-old Timmy, who is severely dehydrated, presents with rapid and deep breaths, abdominal pain, nausea, and vomiting.
On the clinical examination, his breath actually smells fruity and sweet. Timmy's parents said that he had been eating a lot lately, but he actually lost weight.
Also, they said that Timmy is also drinking water all the time and going to the bathroom a lot. The other person is 55-year-old Oliver, who also came in with severe dehydration, lethargy, and his family said he had a seizure about 2 hours ago, and in the past month he had lost some weight, although he had been eating.
Both individuals underwent several investigations, including glucose levels, ketones, BMP, and an ABG. OK.
Based on both individuals' symptoms, we can assume that both suffer from diabetes mellitus. Diabetes mellitus is a condition where glucose can't be properly moved from the blood into the cells.

Physiology1:07–2:36

This leads to high levels of glucose in the blood and not enough of it inside cells. Since cells need glucose as a source of energy, not letting 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 with two hormones, insulin and glucagon. Both of these hormones are produced in the islets of Langerhans of the pancreas.
Insulin is secreted by the beta cells, while glucagon is secreted by the alpha cells. Insulin reduces blood glucose levels.
It does that by binding to insulin receptors embedded in the cell membrane of 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.
OK, now there are 2 types of diabetes mellitus, type 1 and type 2, and the main difference between them is the underlying mechanism that causes the blood glucose levels to rise.
Let's start with type one diabetes mellitus, which is an autoimmune condition. See, autoimmune conditions sometimes happen together, so on the exam, the past medical history might include a history of autoimmune thyroid disease like Hashimoto's thyroiditis, or vitiligo, or lupus.

Type 1 Diabetes2:36–6:16

In type one diabetes, the immune system targets and destroys the beta cells of the pancreas. A common target is an enzyme inside beta cells called glutamic acid decarboxylase, which helps make gamma aminobutyric acid or gamba, which among others, increases insulin release, and also has a protective and regenerative effect on the beta cells.
The high yield fact to remember is that the antibodies against glutamic acid decarboxylase are called GAD antibodies. In addition, other antibodies like anti-illet cell antibodies can also be present.
Without the protective and regenerative effect of GABA, the beta cells progressively decrease. Losing beta cells means less insulin, and less insulin means that glucose builds up in the blood because it can't enter the body's cells.
Now, there is a gene complex involved in the regulation of the immune response, and this is called the human leukocyte antigen system or HLA system.
These genes code for 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 where antigens are presented to the immune cells. Interestingly, people with type 1 diabetes often have specific HLA genes in common, HLA-DR3 and HLADR4, both of which are high yield for your exams.
In diabetes mellitus type 1, destruction of beta cells usually starts early in life, and individuals present with symptoms of diabetes before the age of 30.
In type 1 diabetes, the tissues are very sensitive to insulin, but since there are less beta cells, insulin levels are low.
On histology, there is usually an islet leukocyte infiltrate. There are 4 clinical symptoms of uncontrolled diabetes.
There's polyphagia, glucosuria, 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 called proteolysis.
Both of which result in weight loss for someone with uncontrolled diabetes. This cattabolism leads to polyphagia.
Now, with high glucose levels, when blood gets filtered through the kidneys, some of it starts to spill into the urine. This is called glycosuria.
Since glucose is osmotically active, water tends to follow it, resulting in an increase in urination or polyuria. Finally, because there is so much urination, people with uncontrolled diabetes become dehydrated, resulting in polydipsia.
Now, let's move on to type 2 diabetes mellitus. In type 2 diabetes, 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 the membrane.
This is called insulin resistance. The most important risk factor for insulin resistance is obesity.

Type 2 Diabetes6:16–8:28

Apart from this, there are also some genetic factors involved. 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.
This works for a while, and by keeping insulin levels higher than normal, blood glucose levels can be kept normal. This beta cell compensation though, isn't sustainable, and over time, these overworked beta cells get exhausted and eventually die off.
When this happens, insulin levels will start decreasing. So, remember that the serum levels of insulin in type 2 diabetes are variable, depending on when it's diagnosed.
Now, along with insulin, beta cells also secrete islet amyloid polypeptide, so while beta cells are cranking out insulin, they also secrete an increased amount of amyloid polypeptide.
Over time, amyloid polypeptide builds up and aggregates in the islets, so on histology, there will be amyloid polypeptide deposits in the pancreas, along with a variable number of beta cells, depending on when it's diagnosed.
Now, type 2 diabetes usually appears after the age of 40, and presents similarly to type 1 diabetes with polydipsia, polyuria, polyphagia, and sometimes weight loss.
Diagnosing type 1 or type 2 diabetes is done by getting a sense of how much glucose is floating around in the blood. Very commonly, a fasting glucose test is taken, where the person doesn't eat or drink, except water, that's OK, for 8 hours, and they're blood tested for glucose levels.
A level of 126 mg per deciliter or higher indicates diabetes. A non-fasting or random glucose test can be done at any time, with 200 mg per deciliter or higher, being diagnostic for diabetes, if the individual has symptoms.

Diagnosis8:28–10:02

Another test is called an oral glucose tolerance test, where a person is given glucose, and then blood samples are taken at time intervals, to figure out how well it's being cleared from the blood.
A glucose level over 200 mg per deciliter after 2 hours indicates diabetes. OK, so, 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 the HbA1c test, which tests for the proportion of hemoglobin and red blood cells that have glucose stuck to it, or glycated hemoglobin.
An HbA1c level of 6.5% or higher indicates diabetes. This proportion of glycated hemoglobin doesn't change day to day, so a high yield fact is that this test gives a sense for whether the blood glucose levels have been high over the past three months, which is the lifespan of a typical red blood cell.
Regarding treatment in type 1 diabetes, insulin is always necessary because of decreased endogenous production. While in type 2 diabetes, lifestyle modifications like exercise and dietary changes are first line.
In addition, other medications like metformin, SGLT-2 inhibitors, and GLP-1 receptor agonists are the first line pharmacologic intervention in type 2 diabetes, with insulin being an option if other medications fail to control glucose levels.

Treatment10:02–10:58

It's also important to treat and prevent complications in diabetes. For example, ACE inhibitors and ARBs have been shown to decrease the risk of diabetic nephropathy in individuals with diabetes and hypertension.
In addition, yearly eye exams, urine microalbumin testing, and foot exams should be done. Now, let's go over one very high yield acute complication of diabetes, that usually happens with type one diabetes, and it's called diabetic ketoacidosis or DKA.
This usually happens when individuals aren't rigorous with their insulin therapy, or when the body is really stressed and needs more insulin, like during an infection.

Diabetic ketoacidosis10:58–15:18

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 acetoacidic acid and beta hydroxybutyric acid.
These ketones 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 ketoacidosis, which is a type of metabolic acidosis.
This doesn't typically happen in type 2 diabetes, because there's usually some level of endogenous insulin that prevents lipolysis.
Clinically, individuals with DKA are dehydrated, because a lot of glucose is lost through urine, and they can developkusol respirations, which is a deep and rapid breathing as the body tries to move carbon dioxide out of the blood, in an effort to reduce its acidity.
Their breath also smells sweet and fruity, because ketones break down into acetone, which escapes as a gas during exhalation.
Abdominal pain, nausea, vomiting, and in severe DKA, mental status changes like obtundation and coma can occur. Complications of DKA include acute cerebral edema, which is when there's too much fluid in the intra or extracellular space.
In the case of DKA, there's too much fluid in the extracellular space of the brain, because glucose basically drags water out of cells.
Other complications include cardiac arrhythmias, due to potassium imbalance, which can lead to sudden cardiac death. Finally, since people with DKA have poorly controlled diabetes, their immune system is also likely to be compromised.
This means they are more vulnerable to common infections, like candida, but also some that only affect people with immune deficiencies.
One of these is muomycosis, a life-threatening fungal infection caused by rhizopus species that starts in the sinuses, but can spread to the brain.
Lab results show hyperglycemia and metabolic acidosis, which is demonstrated by low pH levels and low levels of bicarbonate or HCO3.
The anion gap is high, which reflects a large difference in the unmeasured negative and positive ions in the serum, largely due to this buildup of ketoacids.
Blood ketone levels are also high, and if there's a concomitant infection, then leukocytosis can also be present. Now, let's focus a bit for the next part.
Cells have a transporter that exchanges hydrogen ions for potassium. When the blood gets acidic, there's a lot of positively charged hydrogen ions floating around.
Cells will exchange these extracellular protons with intracellular potassium, so at first, there will be hyperkalemia. Next, in addition to helping glucose enter cells, insulin also stimulates the sodium potassium ATP aces, which help potassium get into cells, and so without insulin, more potassium stays in the extracellular fluid.
Since all this potassium is eventually excreted, even though the blood potassium levels remain high, overall stores of potassium in the body starts to run low, and in this way, total body potassium is depleted.
Treatment of DKA relies on IV fluids to correct dehydration, IV insulin, and potassium. Sometimes to prevent overcorrecting the hyperglycemia, a small amount of dextrose is given with the insulin.
One high yield acute complication that usually happens with type 2 diabetes is hyper osmolar hyperglycemic state, which is when levels of glucose are really high, and it leads to extreme dehydration.
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.

Hyperosmolar hyperglycemic state15:18–16:44

So when levels of glucose are super high in the blood, That means it's in a hyper osmolar state, so water begins to leave the body's cells and enter the blood vessels, leaving the cells relatively dry and shriveled.
The excess glucose is filtered into the urine, and the water osmotically follows it, leading to polyuria and dehydration.
And this is a very serious situation because severe dehydration affects the brain, leading to various symptoms like lethargy and seizures, which can progress to coma and death if left untreated.
Labs show hyperglycemia, often over 600 mg per deciliter, high serum osmolarity, often over 320 milliosmoles per kilogram, and unlike DKA, there's no acidosis, because ketone production is limited by the endogenous insulin.
Treatment relies on a lot of IV fluids, potassium replacement, and insulin therapy. Another important complication associated with the treatment of diabetes is hypoglycemia.
This is usually related to insulin, but can also be caused by oral medications, like sulfonylureas. Recall that the brain depends on glucose for its energy, so hypoglycemia is extremely dangerous, as it can lead to irreversible damage to neurons.

Hypoglycemia16:44–18:22

The symptoms of hypoglycemia include symptoms of autonomic system activation such as palpitations, sweating, shaking, nausea, and of course hunger.
The more dangerous symptoms are called neuroglyccopenic symptoms, which include dizziness, lethargy, confusion, and coma.
Now, exams like to test your ability to differentiate hypoglycemia caused by injecting insulin from that caused by insulinomas or sulfonylureas.
To do this, we measure serum levels of insulin and C peptide, an endogenous byproduct of insulin production in the beta cells.
High insulin levels but low C peptide means the hypoglycemia is caused by exogenous insulin. On the other hand, high insulin and high C peptide levels indicate that the problem is either coming from an insulinoma, an insulin producing beta cell tumor, or sulfonylurea use.
In the case of sulfonylurea use, serum or urine testing can detect the drug, confirming drug-induced hypoglycemia. Now there are some chronic complications of diabetes which can happen with both type 1 and type 2 diabetes.
The two basic mechanisms are non-enzymatic glycosylation, or NEG, and osmotic cellular damage. Non-enzymatic glycosylation occurs when glucose covalently attaches to cell proteins and lipids without the help of an enzyme.

Non-enzymatic glycosylation18:22–20:46

These sugar-coated molecules are pro-inflammatory and can cause damage to the cell. NEG in small blood vessels like arterials cause hyaline arteriosclerosis, where the walls of arterials develop protein deposits that make them hard and inflexible.
In addition, the basement membrane can thicken and make it hard for oxygen to easily move to the tissues, causing hypoxia.
In the eyes, it can lead to retinopathy. A fundoscopic exam will show cotton wool spots, flame hemorrhages, and microaneurysms.
In the kidneys, the afferent and efferent arterials, as well as the glomerulus itself, can get damaged, which can lead to nodular glomerulus sclerosis.
On histology, there's Kimmelsteel Wilson nodules, which are clumps of hyaline material found in glomerular capillaries. In the early stages of diabetic nephropathy.
Small amounts of albumin leak through the glomerular basement membrane and into the urine. This is called microalbuminuria, and it's the earliest sign of diabetic nephropathy, which can eventually progress to chronic kidney disease.
When any G occurs in medium and large arterial walls, it can lead to atherosclerosis, which can affect multiple vessels like the coronary arteries of the heart, causing coronary artery disease or CAD.
This is the major cause of death in people with diabetes. It can also affect the arteries in the legs, causing peripheral vascular occlusive disease, which can lead to gangrene and even limb loss.
Finally, it can affect the tiny arteries in the brain, leading to cerebrovascular disease and strokes. The next mechanism is osmotic cellular damage.
Normally when glucose enters cells, it can be converted to an alcohol called sorbitol by the enzyme aldose reductase. The problem is that sorbitol is an osmotic agent, meaning it attracts water, but here the water is going into the cells.
As a protective mechanism, some cells are able to convert sorbitol to fructose with the enzyme sorbitol dehydrogenase. But the cells of the lens, the parasites in the retina, Schwann cells, and renal epithelial cells lack this enzyme.

Osmotic cellular damage20:46–22:18

So, in the lens, sorbitol builds up and causes cataracts. Damage to the Schwann cells decreases the myelination of sensory and autonomic nerve fibers, causing diabetic neuropathy, which manifests in a stocking glove distribution.
This makes these parts of the body more prone to injury, and they can often develop foot ulcers as a result of chronic damage.
This is made worse by the fact that they will also have impaired healing due to hyperglycemia. Autonomic neuropathy can cause diabetic gastroparesis, which is weakness of the gastric peristalsis that results in vomiting after meals and constipation.
Besides type 1 and type 2 diabetes, there are also a couple of other subtypes of diabetes mellitus. An important one that's commonly tested is gestational diabetes, which is when pregnant patients have increased blood glucose, especially during the 3rd trimester.
This occurs because the placenta releases large amounts of human placental lactogen, which is thought to induce insulin resistance.
Some individuals might not be able to produce enough insulin to overcome the effect of this placental hormone, so blood glucose goes up and signs of diabetes manifest.
Diabetes can also occur secondary to some systemic disorders like Cushing's syndrome and medications like glucocorticoids.

Subtypes of diabetes22:18–23:06

This is because corticosteroids also cause insulin resistance. All right, as a quick recap, type 1 diabetes mellitus is an autoimmune condition that's associated with HLADR3 and DR4.
It causes the destruction of beta cells by autoantibodies, and this usually starts before the age of 30. The tissues are very sensitive to insulin, but insulin levels are low.
In type 2 diabetes mellitus, there's insulin resistance. Risk factors for type 2 diabetes are obesity and various genetic factors.
Insulin levels are increased at the start, but as the islet cells tire out and die, the levels drop. Type 2 diabetes usually manifests after the age of 40 and presents similarly as type 1 diabetes, with symptoms like glucosuria, polyuria, polydipsia, polyphagia, and unintentional weight loss.

Review23:06–25:31

To diagnose diabetes, a fasting glucose, a non-fasting glucose, or an oral glucose tolerance test can be done. However, HbA1C gives a better sense of blood glucose over the past three months.
One important acute complication of type one diabetes is DKA, which presents with dehydration, small respiration, sweet and fruity breath, abdominal pain, nausea, vomiting, and mental status changes like obtundation and coma can occur.
These people will have metabolic acidosis and ketosis. An acute complication of type 2 diabetes is hyper osmolar hyperglycemic state, characterized by dehydration due to high serum osmolarity.
The cause is severe hyperglycemia, but there's no metabolic acidosis, since ketones are not generated. Some of the important chronic complications of diabetes include small vessel disease, which can affect the eyes or the kidneys.
Atherosclerosis, which can lead to CAD, peripheral vascular occlusive disease, and cerebrovascular disease, and neurological problems like paresthesia in a glove and stocking distribution.
OK, back to our cases. Timmy came in severely dehydrated, and he had rapid and deep breaths, which are indicative of Kusal respiration.
His breath had a sweet and fruity odor due to acetone from ketone body metabolism. All of these points to DKA.
The lab results showing high levels of glucose, low pH with low bicarbonate levels, and a high anion gap. Increased blood ketone levels and hyperkalemia confirm this.
His parents said that he has been eating a lot lately but actually lost weight, meaning he has polyphagia and weight loss.
He also had polydipsia and polyuria, and these are all symptoms of diabetes mellitus. Due to his age and the presence of DKA.
He most likely has a case of previously undiagnosed type one diabetes. Now, Timmy has received a lot of fluids and insulin, and after making him feel better, more tests have been done, like a fasting glucose and GAD antibodies test to confirm the diagnosis.

Summary25:31–26:30

Next we have Oliver, who came in with severe dehydration, lethargy, and seizures. Labs show really high levels of glucose, above 600 mg per deciliter, but no acidosis or ketones.
His serum osmolarity was over 320 miliosmoles per kilogram. All this indicates hyper osmal or hyperglycemic state, which is usually a complication of type 2 diabetes.
Oliver has been treated with IV fluids and insulin. Further tests like fasting glucose and HbA1c need to be done to confirm type 2 diabetes.
Diabetes mellitus: Pathology Review: Video, Causes | Osmosis