How does glucose cause damage?

[REDLAN]

I ask because I've been reading, and trying to understand how this happens. The current explanations I've heard are that...

1) glucose is sharp and in high concentrations it cuts holes in cell walls and structures causing damage.

2) when glucose levels are high - glucose enters the cell and builds up causing osmotic stress and the cell becomes damaged as it swells.

trouble is I find both these explanations don't sit very well with how glucose is transported through the body...

firstly glucose can't get into cells on it's own it has to diffuse through a special protein called GLUT which sits on the cell wall. Also on the cell wall are insulin receptors - when insulin binds to this receptor it starts a chain reaction, which causes the GLUT protein to open and allow glucose into the cell.

So what happens in a normal person after a meal high in carbs - the body responds by increasing insulin production, which binds to insulin receptors, which opens up more GLUT receptors, and glucose diffuses into the cell down the concentration gradient thereby lowering the BG

so now explanation no 1) - glucose is sharp and damages cells - what is so special about glucose compared to the myriad of other small molecules circulating in our bodies which don't cut holes in cell walls - I find this really hard to get my head round... first off glucose can only get into the cell via GLUT - if high concentrations cause damage, then surely wouldn't damage be likely to occur at places with the most intimate bonding i.e. on the GLUT protein, and ergo cell transport would be self-limiting. If we assume that glucose can leak across cell walls then we need to know at what concentrations this effect occurs and more importantly becomes significant - does anyone know of any research where they have demonstrated this effect?

2) osmotic stress - I have more difficulty with this one than number 1) - if diabetes works the way I think it does, then actually diabetes should provide some protection against osmotic stress - so the hypothesis is that high blood sugar allows glucose to build up in the cells, this then causes them to swell and so become damaged - except that high blood sugar occurs because there is not enough insulin in the body, ergo there is too much glucose OUTSIDE the cells - be really interested to hear an explanation of this one. if the hypothesis is correct then people who eat very large amounts of carbohydrates should get diabetic complications due to osmotic stress - where do you think all that glucose is going to end up?

I do have a what if question, but maybe later...

[JediSkipdogg]

Well, I can say when it comes to diabetic retinopathy that it is from the vessel walls swelling inside the eye. They then swell so much that they burst and depending on how severe of a burst is how severe the retinopathy will be. So in that sense, there is not enough insulin to open the cells therefore putting the pressure in the blood vessel walls.

[xMenace]

And proliferative vessels, which are typically the ones that hemm, have no supporting tissues around them. They are inherently weak.

[Cyborg]

Certain cells in the body do not require insulin to absorb glucose. Some of these cells exist in the eyes and kidneys. When bg levels are elevated extra glucose is absorbed into these cells causing problems.

[June91]

no 1) - glucose is sharp and damages cells - what is so special about glucose compared to the myriad of other small molecules circulating in our bodies which don't cut holes in cell walls

It is as simple as you stated: glucose is sharp - pretty much like a crystal of table sugar, with sharp, angular edges that can literally cut through.

[Injecto]

2) when glucose levels are high - glucose enters the cell and builds up causing osmotic stress and the cell becomes damaged as it swells.
2) osmotic stress - I have more difficulty with this one than number 1) ...

REDLAN, this explanation is applicable only to those cells that do not require insulin, such as eyes, nerves, kidneys.

[Emm]

Sharp bits? Really?

I've only heard simplified explanations, along the lines of: The blood is thick & gooey like syrup because of the glucose, and has a hard time moving around, thus areas of the body are 'starved' of oxygen etc from the blood.

Surely there's something in that. Or have I been fed simplified ****? Sharp bits?? For real?

[JediSkipdogg]

From How Does Diabetes Affect My Body? (http://www.genetichealth.com/DBTS_Consequences_of_Diabetes.shtml)

How does Blood Sugar Cause Damage?

In people with diabetes, sugar (glucose) accumulates in the blood to very high levels. The excess glucose can attach to proteins in the blood vessels and alter their normal structure and function. One effect of this is that the vessels become thicker and less elastic, making it hard for blood to squeeze through.

Diabetic eye disease starts when blood vessels in the back of the eye (the retina) balloon out into pouches. Although this stage — called nonproliferative retinopathy — generally does not affect vision, it can progress to a more serious form called proliferative retinopathy. This occurs when damaged blood vessels close off and new, weaker vessels take their place. These new vessels can leak blood, which blocks vision. They can also cause scar tissue to grow and distort the retina.

Because the retina can be irreversibly damaged before you notice any change in vision, and because retinopathy can be effectively treated with lasers to minimize vision loss, the American Diabetes Association recommends screening for retinopathy yearly.

Kidney disease starts when the blood vessels in the kidney become leaky. These leaky vessels allow protein from the blood to be excreted with urine. (It's this protein that doctors detect when they test for kidney function.) Eventually, some vessels collapse and place more pressure on those that remain. Under this increased load, the remaining blood vessels are also damaged and the kidney may fail. If the disease progresses to this point, a person may have to go on dialysis — where a machine performs the role of the kidney — or receive a kidney transplant.

Because of the serious consequences of kidney disease, the American Diabetes Association recommends screening for protein in the urine every year starting at the time of diagnosis, or five years after the diagnosis in Type 1 diabetics.

High blood sugar damages blood vessels and can lead to blockage. In the heart, this blockage can cause heart attacks. In fact, people with diabetes have two to four times the risk of developing heart disease or stroke than the general population. Blocked vessels in the legs can cause pain and can also impair circulation. With poor circulation, small cuts or infections are less likely to heal. Eventually, 0.6 percent of all diabetics have lower limb amputations because of damage to the feet or lower legs.

In diabetes, the nerves that become damaged are the ones that allow you to sense temperature, pressure, texture, or pain on your skin. In most people with diabetes, nerve disease (neuropathy) effects the feet and lower legs, causing numbness or tingling. The real problem arises when numbness allows injuries to the foot to go unnoticed. For this reason, the American Diabetes Association recommends that all people with diabetes have a thorough foot exam every year.

[REDLAN]

I found what I was looking for....

The excess glucose can attach to proteins

this is the main theory for why elevated glucose causes damage - it's not sharp or any of the other stuff. The problem is that it binds to proteins in the serum and plasma, altering their function a process called glycosylation

Glycosylation - Wikipedia, the free encyclopedia (http://en.wikipedia.org/wiki/Glycosylation)

presumably this process goes on all the time - HbA1C is measurement of the glycosylation of hemaglobin, and must occur at normal BG levels

it these glycosylated proteins that cause all the damage. There is some jargon for these abnormal glycosylated proteins - they're called Advanced Glycation End Products or AGEs, and they are even testing AGE inhibitors (Pyridoxamine) at the moment on lab animals - and it appears to slow the development of retinopathy

The AGE Inhibitor Pyridoxamine Inhibits Development of Retinopathy in Experimental Diabetes -- Stitt et al. 51 (9): 2826 -- Diabetes (http://diabetes.diabetesjournals.org/cgi/content/full/51/9/2826)

in the article they compared vitamin E (VE), Pyridoxamine (PM), and R-alpha-lipoleic acid (LA) - the interesting bit is that (PM) treated rats showed no difference than the nondiabetic controls at the end of the study period (29 weeks), while the VE and LA treated groups did.

so there you go AGE inhibitors coming to clinical trial near you soon - if the side effects are tolerable and this drug works as well as the rat study suggests then it will be quite a breakthrough in treatment.

this is of course vitamin b6...

[REDLAN]

from my last post, I was just a bit curious as to why if B6 vitamins were so good at slowing diabetes complications we weren't all on them, so I did some maths....

the rats were on approximately 155mg of the vitamin B6 precursor Pyridoxamine. Now then your average rat weighs about 500g, sooooo....

if we scale this up for an 80 kg human (i.e. me) then to replicate the experiment I would need to take 24g of vitamin B6 each day - boots sell B6 in 10mg tabs, soooooo...

that means 2400 tablets per day! And they come with a handy warning saying "do not exceed stated dose" coz....

there are studies that have shown that daily intakes of B6 above 400 mg can lead to other problems.

And to replicate the experiment I need to take 60 times more than this.

think I'll be holding off on the vitamin supplements for now (",)

[Cyborg]

Sharp bits? Really?

I've only heard simplified explanations, along the lines of: The blood is thick & gooey like syrup because of the glucose, and has a hard time moving around, thus areas of the body are 'starved' of oxygen etc from the blood.

Surely there's something in that. Or have I been fed simplified ****? Sharp bits?? For real?

I agree... The other damage comes by glycosylation of the cells in the body, including the red blood cells, a measure of which is your a1c. As you stated, this affects the ability to do their job. Glycosylation of other things such as tendons can cause such ailments as frozen shoulder.

[REDLAN]

I've only heard simplified explanations, along the lines of: The blood is thick & gooey like syrup because of the glucose, and has a hard time moving around, thus areas of the body are 'starved' of oxygen etc from the blood.

In my reading to find out how glucose damaged the body - I found the answer to this one as well - for a simplified explanation it's almost right - the official answer is...

high concentrations of glucose, glycosylate proteins in the blood, including hemaglobin (and apparently this one is involved in this effect), these adnormal proteins bind to NO (nitric oxide) - Nitric oxide is produced by the arterial walls as an anti-coagulant. So you increase the risk of clots forming - clot formation is believed to be the main mechanism by which atherosclerotic plaques grow - hence the cause of heart disease - heart attack are caused when a clot forms above an atherosclerotic plaque in an artery in the heart - blocking blood flow - this is why diabetics are around 4 times more likely to suffer Coronary Heart Disease than the normal population.

so no there aren't any sharp bits (",)

[BlueSky]

.... diabetics are around 4 times more likely to suffer Coronary Heart Disease than the normal population. ...
T2 diabetics and people with Metabolic Syndrome seem to have a much higher heart disease risk than T1 diabetics. It also seems that T2 diabetics get complications at lower BG levels than T1s. Why is this?

[JediSkipdogg]

T2 diabetics and people with Metabolic Syndrome seem to have a much higher heart disease risk than T1 diabetics. It also seems that T2 diabetics get complications at lower BG levels than T1s. Why is this?

For a few reasons....

1) They are generally running higher levels for years before diagnosis. If say a type 2 develops diabetes by running an average of 100 mg/dl higher each year, and they don't discover they are diabetic till they are in the 400s constantly (because remember, the body will adapt to steadily high numbers) then they have done 3 years of damage to the body. This is where the organ damage comes in. And remember, organs do have a shelf life so to speak and running high is shortening their life.

2) When a type 2 on meds or diet or exercise alone runs high they have no way to bring it down. They have to just sit high until it comes down damaging their body. A T1 can generally bring that down within 2-3 hours.