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Diabetes Mellitus

Pathology || Signs and Symptoms || Complications || Diagnosis || Treatment || Overview || Related Articles || References and Resources
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Pathology





Diabetes mellitus, or "sugar" diabetes, is a disease where the body inappropriately manages blood sugar levels. In order to understand this disease, we have to first understand the hormone insulin.

Insulin is responsible for managing blood sugar levels. It is a protein secreted by specialized cells in the pancreas. When there is lots of sugar floating around in the blood (ie: after eating a candy bar), insulin is secreted by cells in the pancreas known as β-cells.

Insulin then travels in the blood stream where it binds to receptors on many different tissue types. For example, if insulin binds to hepatocytes (ie: liver cells) it instructs them to remove glucose from the blood and store it in a polymerized form known as glycogen. The goal of all insulin's effects is to bring the blood sugar level back within normal limits.

The problem in diabetes mellitus is that insulin is either not secreted by the pancreas, or does not perform its function appropriately. Either way, glucose is not removed from the blood stream. The result is a higher than normal blood sugar concentration.

There are two distinct forms of diabetes mellitus:

- Type 1 diabetes (aka: juvenile onset and/or insulin dependent diabetes)
- Type 2 diabetes (aka: adult onset and/or insulin in-dependent diabetes)

Type 1 diabetes mellitus is an auto-immune disorder, which means that the bodies immune system attacks itself. In this case, the body attacks the β-cells in the pancreas. Once enough β-cells are destroyed the pancreas can no longer secrete insulin.

The pathology of type 2 diabetes mellitus is more complicated. There is no single "cause" of type 2 diabetes, and as such, it is believed to be the result of a combination of factors. Genetics, lifestyle, and diet all play an important role in the development of this form of the disease.

In type 2 diabetes the pancreas is still able to produce insulin. However, the problem is that insulin does not have its normal effect on other body tissues. This is known as "insulin resistance." In an effort to combat this resistance the pancreas secretes more insulin. Eventually the insulin resistance becomes too severe; the pancreas can not keep up, and blood sugar levels begin to rise. If the levels rise beyond a specific laboratory threshold the diagnosis of diabetes is made.

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Signs and Symptoms

High blood sugar levels lead to the symptoms of diabetes mellitus. One of the most common symptoms of diabetes is a frequent need to urinate. The reason this occurs is because the large amounts of sugar in the blood exceed the kidney's ability to re-absorb it. As a result glucose leaks into the urine. The body is forced to dilute this excess solute load by secreting more water into the urine.

Since diabetics are unable to use sugar as a fuel they often lose weight. Diabetes, in metabolic terms, is similar to starving. The body is unable to utilize sugar appropriately. Normally, excess sugar gets converted to fat (ie: for you "need-to-know it all types" glucose is converted into acetyl-CoA fragments. If these are not "burned" by the Krebs cycle they get polymerized into long chain fatty acids, which get stored in fat tissue). However, in diabetics the sugar is "lost" in the urine and not used for metabolic purposes.

Diabetes, in metabolic terms,
is equivalent to starving
If blood sugar levels become ridiculously high severe complications, and potentially death can result. These patients become dehydrated and they often have electrolyte abnormalities. These factors can lead to coma, heart arrhythmias, and potentially death if left untreated. These severe complications usually occur during periods of "stress." Conditions like infections and certain drugs (both prescription and recreational) can cause the "stress" needed to induce a diabetic crisis.

This diabetic crisis is known as "diabetic ketoacidosis" if it occurs in a patient with type 1 diabetes. It is known as "non-ketotic hyperosmolar syndrome" if it occurs in a patient with type 2 diabetes.

Complications

There are many complications of diabetes mellitus. These complications are the result of years of high sugar levels in the blood. Over time the excess sugar undergoes a metabolic transformation known as "glycosylation". Glycosylated sugar is toxic to nerves and blood vessels.

Diabetic Ulcer

Diabetic foot ulcer

If damage occurs to the nerves that innervate the stomach a condition known as "gastric paresis" can occur, which is a fancy term for the stomach not being able to contract as well as it used to.

In addition, nerves that carry sensory information can also be damaged, especially at the finger tips and toes. Patients with this type of nerve damage may not feel cuts and blisters on their toes. These areas can become secondarily infected resulting in gangrenous digits that are often amputated (see image to left). This is part of the reason why all diabetics should see a foot specialist regularly.

Perhaps the most frightening complication of diabetes is the havoc it wreaks on the cardiovascular system. Diabetics have a much larger risk of heart attack and stroke.

Patients with diabetes are at risk for retinopathy, or damage to the retina of the eye. This can lead to blindness if not regularly checked. Damage to the kidney's filtering area known as the glomerulus can also occur. After years of damage, chronic kidney disease can occur. If severe enough, patients may need permanent dialysis or kidney transplantation.

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Diagnosis

The diagnosis of diabetes is made by measuring the amount of sugar in the blood. This can be done either "fasting" or via a "blood glucose tolerance test." There are three possible results:

- Normal
- Impaired (ie: "pre-diabetes" or "borderline" diabetes)
- Diabetic

"Fasting" blood glucose levels are usually taken in the morning before breakfast. It is considered "normal" if the blood glucose levels are between 60 and 100 mg/dL. Impaired is between 100 and 126 mg/dL. Diabetes is diagnosed if there are two fasting blood glucose levels greater than 126 mg/dL.

If fasting is not an option, or the patient ate breakfast, the clinician can do a "glucose tolerance test." In this test the patient drinks a liquid that is rich in sugar (75 grams of sugar is used for most adults). The blood sugar levels are then tested two hours later. If the blood sugar level at two hours is less than 140 mg/dL the test is "normal." If the level falls between 140 and 200 mg/dL the patient is impaired or pre-diabetic. And if the levels are greater than 200 mg/dL the diagnosis of diabetes is made.

Diagnosing Diabetes Mellitus

  Fasting blood glucose levels Glucose tolerance test levels at 2 hours after a 75g sugar load
Normal < 100 mg/dL < 140 mg/dL
Impaired 100-126 mg/dL 140-200 mg/dL
Diabetes > 126 mg/dL > 200 mg/dL

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Treatment

Treatment of diabetes involves either replacing insulin, or improving insulin sensitivity.

Type 1 diabetics require insulin since their bodies no longer produce it. This is why type 1 diabetes was previously referred to as "insulin dependent diabetes".

Treatment Options:
(1) Replace insulin
(2) Improve insulin
       sensitivity

There are numerous medicines used to control blood sugar levels in type two diabetics. One option is a class of medications known as the sulfonylureas. These medications work by increasing pancreatic production of insulin.

A second category of medications, known as the thiazolidinediones, improve the ability of insulin to act on peripheral tissues like fat, muscle, and liver.

The third category of medications known as the biguanides perform a similar function to the thiazolidinediones, and also inhibit liver cells from secreting stored sugar into the blood stream.

Regardless of which medication(s) is (are) used the ultimate goal of medical therapy is to maintain the blood glucose levels within a specified range. Fasting blood glucose levels should ideally be kept between 90 and 130 mg/dL; post-meal glucose levels should ideally be less than 180 mg/dL. Maintaining glucose values within these ranges helps keep glycosylated hemoglobin (aka: hemoglobin A1C) less than 7%, which decreases the risk of microvascular complications.

In addition to replacing insulin, or increasing insulin sensitivity, patients with diabetes should also be treated for other comorbid conditions. For example, statins are often started to control hyperlipidemia. Dialysis might be necessary to control severe kidney disease. Frequent foot and neurological exams are also necessary to prevent complications of diabetic neuropathy (ie: foot ulcers, gastric paresis, etc).

It is currently recommended that patients with diabetes have a blood pressure goal of 130/80 or better. In addition the LDL cholesterol level should be maintained below 100 mg/dL, HDL should be above 40 mg/dL, and triglycerides should be kept below 150 mg/dL.

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Overview

Diabetes is classified as type 1 or type 2. In type 1 diabetes destruction of the pancreatic cells responsible for insulin secretion occurs through an auto-immune process. In type 2 diabetes, insulin sensitivity is lost by peripheral body tissues causing the pancreas to secrete more and more insulin until it "burns out". Diagnosis is based off of blood sugar levels, usually measured when the patient is fasting (although other methods exist). Treatment is with insulin or insulin-sensitizing medications.

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Related Articles

- Diabetes insipidus

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References and Resources

(1) Swanson A, Watrin K, Wilder L. Clinical Inquiries: How can we keep impaired glucose tolerance and impaired fasting glucose from progressing to diabetes? J Fam Pract. 2010 Sep;59(9):532-3.

(2) Judge EP, Phelan D, O'Shea D. Beyond statin therapy: a review of the management of residual risk in diabetes mellitus. J R Soc Med. 2010 Sep;103(9):357-62.

(3) Fowler GC, Vasudevan DA. Type 2 diabetes mellitus: managing hemoglobin A(1c) and beyond. South Med J. 2010 Sep;103(9):911-6.

(4) Kumar V, Abbas AK, Fausto N. Robbins and Cotran Pathologic Basis of Disease. Seventh Edition. Philadelphia: Elsevier Saunders, 2004.

(5) Le T, Bhushan V, Grimm L. First Aid for the USMLE Step 1. New York: McGraw Hill, 2009.

(6) Flynn JA. Oxford American Handbook of Clinical Medicine (Oxford American Handbooks of Medicine). First Edition. Oxford University Press, 2007.

(7) Champe PC. Lippincott's Illustrated Reviews: Biochemistry. Second Edition. Lippincott-Ravens Publishers, 1992.

(8) American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2004 Jan;27 Suppl 1:S15-35.

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The most widely used biguanide is metformin.
The thiazolidinediones include rosiglitazone (Avandia®), pioglitazone (Actos®), and troglitazone.

Rosiglitazone was withdrawn from the market in Europe because of an increased risk of heart attacks.

The first generation sulfonylureas include: acetohexamide, chlorpropamide, tolbutamide, and tolazamide.

Second generation sulfonylureas include: glipizide, gliclazide, and glyburide.

Third generation sulfonylureas include: glimepiride.