Diabetes Mellitus: Sugar Pee and A1C

Diabetes mellitus, or “sugar” diabetes, occurs when the body inappropriately manages its blood sugar levels. The key player in diabetes mellitus is a hormone called insulin. For simplicity we will use the term “glucose” as a relatively generic term for “sugar” going forward, but remember that glucose is actually one type of sugar.

Insulin is a protein secreted by specialized cells in the pancreas known as β-cells. When the body senses a high level of glucose floating around in the blood it causes the pancreas to secrete insulin. Many individual insulin molecules then travel throughout the body where it binds to receptors on many different tissue types. For example, if insulin binds to hepatocytes (liver cells) it instructs those cells to remove glucose from the blood and store it in a polymerized form known as glycogen. Insulin’s goal is to bring blood sugar levels to within normal limits.

The problem in diabetes mellitus is that insulin is either not secreted by the pancreas, or it does not perform its functions 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 (sometimes referred to as juvenile onset or insulin dependent diabetes) and type II diabetes (sometimes referred to as adult onset or insulin independent diabetes).

Type 1 diabetes 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. I like to think of type 2 diabetes as a slew of factors that have beaten down the bodies ability to properly manage blood sugar levels.

In type 2 diabetes the pancreas is still able to produce insulin. However, the problem is that insulin does not cause its normal effect on body tissues. This is known as "insulin resistance." In an effort to combat this resistance the pancreas secretes more insulin. Once 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.

How Does Diabetes Mellitus Present?

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 excess blood sugar exceeds 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. Hence more urine production –> increased trips to the bathroom!

Since diabetics have difficulty using sugar as a fuel they often lose weight (although most type II diabetics are overweight or obese secondary to excessive caloric intake). Diabetes, in metabolic terms, is similar to slowly starving. The body is unable to utilize sugar appropriately, which is the main “fuel” for most people. 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 similar to slowly starving.
If blood sugar levels become ridiculously high severe complications, and potentially death can result. These patients can become very dehydrated and will often have significant electrolyte abnormalities. These factors can lead to coma, heart arrhythmias, and death if left untreated. These severe complications usually occur during periods of "stress." Conditions like infections and certain drugs (both prescription and illicit) can cause the "stress" needed to induce a diabetic crisis.

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

What Else Can Happen to People with Diabetes?

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, especially poorly controlled 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. Damage to the kidney’s filtering area known as the glomerulus can also occur; this can lead to chronic kidney disease. If severe enough, patients may need permanent dialysis or kidney transplantation.


The diagnosis of diabetes is made by measuring the amount of sugar in the blood. There are three common ways to diagnose diabetes today. The first is by checking a molecule known as hemoglobin A1C. Diabetes can also be diagnosed with fasting blood sugar levels or by a glucose tolerance test. There are three possible results of these tests: normal, impaired (pre-diabetic), or diabetic.

Hemoglobin A1C levels are drawn from the blood. Two separate results above 6.5% indicate diabetes. Levels between 5.7 and 6.4% indicate pre-diabetes. Levels below 5.7% are normal.

"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

  Hemoglobin A1C Fasting blood glucose levels Glucose tolerance test levels at 2 hours after a 75g sugar load
Normal Less than 5.7% < 100 mg/dL < 140 mg/dL
Impaired 5.7% to 6.4% 100-126 mg/dL 140-200 mg/dL
Diabetes 6.5% or greater > 126 mg/dL > 200 mg/dL

Heal Me Doctor

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”. Insulin as a treatment is discussed in a separate article.

Treatment Options:
(1) Replace insulin
(2) Improve insulin
A healthy diet and exercise are very important treatments in managing diabetes. However, many patients require medications.

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 medications 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) levels below 7%, which decreases the risk of the diabetic complications.

In addition to replacing insulin, or increasing insulin sensitivity, patients with diabetes should also be treated for other co-morbid 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.

The Replay…

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.

Just Keep Learning, Just Keep Learning (That’s a Dory Reference)…

References and Resources

  • 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.
  • 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.
  • Fowler GC, Vasudevan DA. Type 2 diabetes mellitus: managing hemoglobin A(1c) and beyond. South Med J. 2010 Sep;103(9):911-6.
  • Kumar V, Abbas AK, Fausto N. Robbins and Cotran Pathologic Basis of Disease. Seventh Edition. Philadelphia: Elsevier Saunders, 2004.
  • Le T, Bhushan V, Grimm L. First Aid for the USMLE Step 1. New York: McGraw Hill, 2009.
  • Flynn JA. Oxford American Handbook of Clinical Medicine (Oxford American Handbooks of Medicine). First Edition. Oxford University Press, 2007.
  • Champe PC. Lippincott’s Illustrated Reviews: Biochemistry. Second Edition. Lippincott-Ravens Publishers, 1992.
  • American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2004 Jan;27 Suppl 1:S15-35.

Too Much Pee! Understanding Diabetes Insipidus

In order to understand diabetes insipidus we have to understand a little about how the kidneys reabsorb water. Water absorption in the kidney is dictated by a hormone known as vasopressin (aka: antidiuretic hormone). This hormone is synthesized in the hypothalamus of the brain, transported down the pituitary stalk, and excreted into the blood stream by the posterior portion of the pituitary gland.

Once in the blood stream vasopressin goes to the kidney where it binds to receptors on cells in the collecting ducts of the nephron. This interaction sets off a series of reactions that allows the kidney to reabsorb water from urine. The end result is that the body retains water and the urine becomes more concentrated (“Look mom my pee is yellow!”).

With this background, we can now discuss diabetes insipidus (DI). Diabetes insipidus occurs when the hypothalamus, or pituitary gland fail to communicate effectively with the kidneys. This can happen in one of two ways: the hypothalamus or pituitary can fail to send a signal (ie: vasopressin) to the kidney, or the kidney can fail to respond to that signal. The first case is known as “central” diabetes insipidus, and the second case is known as “nephrogenic” diabetes insipidus.

In either case, the kidney fails to reabsorb water. The end result is dehydration and a steadily rising blood sodium level, which can cause numerous signs and symptoms.

Signs and Symptoms

Patients with diabetes insipidus pee like crazy! This is because the kidney is unable to reabsorb water. Patients can urinate over a liter of fluid per hour! Because of this, the serum sodium level can increase precipitously. The resulting hypernatremia (ie: elevated sodium level) can cause seizures, altered mental status, and coma if not recognized and treated aggressively.

In addition, patients with diabetes insipidus are usually very thirsty. They typically ask for “ice water”, and will drink large volumes in an attempt to keep up with their urinary losses.


Diagnosis is based on several clinical markers. Urine output greater than 250 mL/hour in the setting of a low urine osmolarity (50-150 mOsm/L) or specific gravity (1.001-1.005), a high normal or above normal blood sodium concentration, and a higher than normal blood osmolarity are indicators of diabetes insipidus.

Often times the diagnosis may still be difficult to make when only one, or a few of the above are present. If this is the case, a “water deprivation test” can be performed. This test is exactly what it sounds like: don’t allow the patient to receive any form of fluid (either intravenous or oral). You must monitor their condition carefully!

Under conditions of water deprivation, a normal person’s kidneys will start to retain water, and because of this, the urine will become more concentrated (usually to greater than 600 mOsm/L). However, in patients with diabetes insipidus the kidneys are unable to absorb water and the urine osmolality remains lower than expected (ie: the urine remains dilute).

If the water deprivation test is positive then the next step is to determine if central or nephrogenic diabetes insipidus is present. The easiest way to do this is to provide synthetic vasopressin (“thank god for the pharmaceutical companies!”). If the patient has central DI then the urine output will decrease, and the urine concentration will increase; in other words, the kidney is responding to the synthetic vasopressin.

However, in nephrogenic diabetes insipidus the patient will continue to have increased urine output and the urine concentration will fail to increase. In other words the kidney is unable to respond to vasopressin either in natural, or synthetic form.


Treatment is dependent on what form of diabetes insipidus is present and how severe it is. Some patients with DI are capable of drinking enough water to compensate for their urinary losses and therefore require no specific intervention.

However, other patients may not be able to drink enough to keep up with their losses. This can occur in patients who are urinating so much that they can not possibly keep up orally, or in patients who are unable to drink for other reasons (ie: coma, swallowing problems, etc.). If this is the case, then a patient with central diabetes should be given artificial vasopressin, also known as desmopressin (DDAVP).

Patients with nephrogenic diabetes insipidus are treated with a combination of medications depending on the severity of their disease. Thiazide diuretics such as hydrochlorothiazide can decrease the urine output. Interestingly, non-steroidal anti-inflammatory medications like ibuprofen and indomethacin can decrease urine output by blocking the formation of prostaglandins, which normally inhibit the effects of vasopressin.


Diabetes insipidus occurs when the kidney fails to respond to vasopressin, either because vasopressin is not secreted by the pituitary, or because of an intrinsic defect in the kidney’s ability to sense vasopressin.

In either situation the kidney fails to reabsorb water, which causes dehydration and hypernatremia (ie: elevated sodium level in the blood). If the patient is unable to drink enough fluids the condition can be fatal. If oral rehydration is not enough, then patients with central diabetes insipidus can be treated with synthetic vasopressin analogues. In patients with nephrogenic diabetes insipidus diuretics such as hydrochlorothiazide and non-steroidal anti-inflammatory medications may  help decrease urine output. 

References and Resources

  • Trepiccione F, Christensen BM. Lithium-induced nephrogenic diabetes insipidus: new clinical and experimental findings. J Nephrol. 2010 Nov-Dec;23 Suppl 16:S43-8. Review.
  • Noda Y, Sohara E, Ohta E, et al. Aquaporins in kidney pathophysiology. Nat Rev Nephrol. 2010 Mar;6(3):168-78. Epub 2010 Jan 26. Review.
  • Ranadive SA, Rosenthal SM. Pediatric disorders of water balance. Endocrinol Metab Clin North Am. 2009 Dec;38(4):663-72.
  • Knepper MA, Verbalis JG, Nielsen S. Role of aquaporins in water balance disorders. Curr Opin Nephrol Hypertens. 1997 Jul;6(4):367-71.
  • Robertson GL. Regulation of arginine vasopressin in the syndrome of inappropriate antidiuresis. Am J Med. 2006 Jul;119(7 Suppl 1):S36-42.