Monday, February 11, 2008

Diabetes Explained: Part 1

The medical world is abuzz regarding the recent revelation that driving blood sugar to its lowest theoretical level may not be the optimal treatment regimen. PalMD of WhiteCoat Underground has already addressed the issue in a short post, noting wisely that this whole issue just raises more questions about the nature of diabetes and how it should be treated.

But what is diabetes, anyway? There are a lot of misconceptions, perhaps the most popular being that diabetes is a disease you contract as a result of eating too much sugar. My own mother was convinced that a diet proportionally high in carbohydrates was likely to cause diabetes until I made an attempt to explain otherwise. It also gets likened to a sort of food intolerance--the idea that diabetics can't eat sugar because it will cause acute damage. Naturally, the truth is far more complicated; patients with diabetes won't keel over and die in minutes if they eat cake.

Diabetes is often conceptualized as a problem with glucose metabolism. When you or I eat, the body breaks down complex carbohydrates into simple glucose units. Certain amino acids, the building blocks of proteins, are converted into glucose by complex pathways in the liver (the big, scientific word for this is "gluconeogenesis"). Glucose then circulates through the blood and is delivered to various sites; it is the preferred fuel for every cell type in the body, especially neurons. Something like 80% of the glucose in your body is utilized by the brain and nerve tissue.

The issue is that glucose is unable to enter cells unless the drawbridge is down, because glucose molecules are too big to freely pass through cell membranes. In order for glucose to enter cells, special pores on the cell surface need to open. And the trigger that opens those pores is insulin. Without insulin, most of the body's cells have no way to utilize glucose--and therefore, they are unable to fuel themselves efficiently.

It isn't that sugar is somehow toxic to patients with diabetes--the problem is more like having a blocked fuel line in your car. No matter how much gas you put in, your car can't get the gas because of the obstruction. And if you keep filling the tank anyway, you're going to cause it to overflow and spill gas onto the street, harming the environment with damaging emissions.

There are two types of diabetes. Type I diabetics are unable to make insulin; this could be because of a genetic defect, damage to the pancreas by infection or trauma, etc. The net effect is that no matter how much the type I diabetic eats, he is essentially starving, because his body's cells have no way to use glucose. Instead, they rely on far less efficient fuel sources like ketone bodies, which is sort of like putting the lighter fluid-soaked charcoal remnants from last night's bonfire into your car's gas tank and expecting it to operate well. The typical untreated type I diabetic is thin and malnourished. There is tons of glucose floating around in the bloodstream and none of it is accessible, so it gets excreted in the urine.

Type II diabetics make insulin--in fact, they frequently make tons of insulin, especially in the early stages of the disease. The problem is that their cells are less responsive to the effect of insulin, so they use glucose very inefficiently. If type I diabetes is an obstructed fuel line, type II diabetes is a leaky gas tank. Type II diabetics are commonly overweight--having large amounts of fat cells decreases the body's response to insulin. Fat doesn't just sit there; it secretes hormones that regulate glucose usage and appetite, among other things. The bizarre thing is that from a metabolic standpoint, your type II diabetic, despite being overweight, is functionally starving.

If I were stranded on a desert island with nothing to eat, my body's metabolic machinery would switch gears in less than 24 hours. We're starving, it would say, and the pancreas would release a hormone called glucagon to remedy the situation. Glucagon would tell my body to break down my fat stores (the few that I have), cannibalize muscle tissue, and instruct the liver to release its glucose hoard to feed the brain. Eventually, the stores would run out and my brain, cut off from its supply of necessary glucose, would shut down, taking the rest of the body with it. My heart, ever a trooper, would keep on truckin' until the autonomic nervous system crashed, because it is perfectly happy to feed on metabolic scraps.

An untreated diabetic's body is doing this all the time, and the only reason it doesn't kill them is that the brain, kidneys, and nerves don't need insulin to take in glucose. They're the exception to the rule, and if they weren't, diabetes would be fatal a lot more quickly than it actually is.

The reason sugar is harmful to diabetics has less to do with the essential properties of sugar itself and more to do with the effects of wildly fluctuating glucose levels on those three tissues. When glucose levels are high, glucose rushes into the big three--the nerves, the nephrons (the functional units of the kidney), and the retina of the eye. When blood glucose finds its way back down, frequently by being excreted in the urine, there is a huge disparity between the amount of glucose in the nerves and in the blood.

Those of you who remember basic chemistry will recall that such concentration differences are considered unfavorable in accordance with physical law. If we put a tablespoon of sugar in a glass of water, the sugar molecules would slowly spread out throughout the glass (though more slowly than we might like, which is why most people opt to stir the glass). Given enough time, the concentration of the sugar will be uniform throughout the water, and we will have a solution.

But what if we put a barrier in the glass dividing it in half from top to bottom, and the barrier permitted the passage of water, but not sugar? If we put sugar in one partition, the sugar-water on that side will be much more concentrated. Physics doesn't especially like this scenario; equal concentrations on both sides would be preferable. Sugar can't move through the barrier, but water can. As a result, water is going to pass through the no-sugar side to the sugar side in an attempt to equalize the concentrations.

This is the precise scenario that takes place in the human body. Once sugar concentrations in the bloodstream go down, the sugar concentration inside cells (retina, nephron, and neuron) is higher than the sugar concentration outside the cells. Since the sugar can't come out, water goes in. But the cells are limited in size by the boundaries of their membranes. When enough water rushes into the cells, they burst and are destroyed like overfilled water balloons.

So the big problem with sugar and diabetes has less to do with sugar itself being harmful and more to do with osmotic pressure, the situation described above with the barrier that will permit water to cross but not glucose. This is why diabetics with poorly-controlled blood sugar--blood glucose that fluctuates from low to high with great frequency--are more likely to suffer nerve damage, blindness, or kidney failure.

The recent study suggests that type II diabetics (NOT type I diabetics) were just as likely to die from their condition if they maintained low blood glucose levels than if they didn't (this isn't the whole story, so nobody panic). This is a surprise mostly because prior research has fairly conclusively confirmed that controlling blood sugar reduces the risk of those three problems I mentioned earlier in addition to reducing the likelihood of heart attacks, strokes, and other cardiovascular complications.

Why might this be? To understand this issue, we'll need to look at the way diabetes is treated, which will make absolutely no sense without an understanding of what diabetes is. Next post, we'll explore the issue of treatments for diabetes, how they work, and what this new research might mean.


PalMD said...

Thanks for the start!

daedalus2u said...

You should check out these papers.

The "important" glucose level is the level adjacent to the individual cell that is taking it up. Not the glucose concentration in bulk blood. Only the endothelium gets glucose from bulk blood, and endothelium mostly gets ATP via glycolysis anyway.

I see hyperglycemia as a mechanism to get more glucose to the peripheral tissues farthest from a capillary before all of it is consumed by the cells between the capillary and that farthest cell(s). Similarly I see insulin resistance as a mechanims to get more insulin to those cells farthest from a capillary.