Diabetes Forecast

High Blood Glucose and Diabetes Complications

The buildup of molecules known as AGEs may be the key link

By Erika Gebel, PhD ,

If you have diabetes, you probably spend plenty of time thinking, talking, and worrying about blood glucose. Keeping it under control through diet, exercise, and medication can feel like a full-time job. It may seem odd that such a small, sweet thing can be such a big bother.

Ever wonder what it is about high blood glucose that leads to the serious complications of diabetes? So have scientists. They think the key link may be molecules known as advanced glycation end products, or AGEs. As blood glucose rises, these substances increase in the body, and when too many AGEs accumulate, they may be hazardous to your health. The evidence is not all in yet, but here's a peek at what research has shown so far.

The AGE-ing Process

As the concentration of glucose in the blood increases, there's a shift in the body's chemical balance that allows glucose to attach to other molecules, often vital proteins that, for example, make up body structures like blood vessels. And when glucose coats proteins like a sickly sweet glaze, an AGE is created. AGEs can damage proteins "in very important ways that contribute to cell dysfunction and the complications of diabetes," says Paul Thornalley, PhD, a professor at Warwick Medical School in England.

AGEs are apparently regarded by the body as cellular junk; normally, the body takes out the trash. Yet in people with diabetes, the sheer number of AGEs may overwhelm the system for clearing them out of the body. "We are producing these [AGEs] all the time, even those without diabetes, but most people excrete the AGEs in their urine. But a person with diabetes may have 10 times as much in their urine," says Thornalley.

The buildup of AGEs is likely to cause damage that leads to complications in people with diabetes. Researchers aren't sure how this happens, but they are focusing on the one thing all diabetes complications have in common: damage to blood vessels. Tiny blood vessels in the eye can swell and leak, leading to retinopathy. Injured blood vessels in the kidney can cause its delicate filters to thicken and become less adept, resulting in nephropathy. When blood vessels that supply nutrients and oxygen to nerves become affected, neuropathy can result. And lesions on blood vessel walls cause atherosclerosis, which raises the risk of heart attack and stroke.

The evidence that AGEs are a link among complications is scattered but compelling. Researchers have found heavy AGE buildup in organs of the body that are prone to diabetes-related injury: the kidneys, eyes, and nerves. In one study, the level of AGEs in the eyes of people with type 2 diabetes was found to correlate with the severity of retinopathy. AGEs may be linked to cardiovascular disease, too. The lining of the blood vessels becomes stiffer as AGEs accumulate; stiff blood vessels are a cause of high blood pressure. AGEs may also interfere with the body's natural mechanism for removing LDL ("bad") cholesterol. And there's evidence that AGEs increase blood vessel inflammation, which is believed to be a central factor in heart disease.

Collagen, a protein in the body, provides an example of how AGEs can affect blood vessels. This chain-like protein is like a scaffold for the cells that make up the blood vessels. "If collagen becomes glycated by an AGE, it is damaged at the site where the cell binds to this protein," says Thornalley. "The cells become detached and float around in the blood and die. This leaves a gap in the vessel wall and can cause thrombosis [blood clot formation], which down the line can trigger heart disease or stroke."

Food for Thought

Some research, though not widely accepted, offers a quite different explanation of AGEs: It suggests that most AGEs are not formed in the body at all but come from what people eat and may be the underlying cause of not only the complications of diabetes but diabetes itself.

"Glucose is important, but we have been missing another important part: Most of the AGEs in humans, diabetics or not, come from food," says Helen Vlassara, MD, a professor at the Mount Sinai School of Medicine in New York. Her hypothesis is that AGEs from food cause oxidative stress and inflammation in the body, leading to insulin resistance, diabetes, and its complications. Evidence from Vlassara's lab, among others, has supported the link, such as studies that connected dietary intake of AGEs to their levels in the body and markers of inflammation.

The chemical reactions that create AGEs in the body also occur in food. The way food is prepared affects how many AGEs are present. "Highly processed foods contain more AGEs than minimally processed foods," says Vlassara. And the more AGEs a person consumes, the theory goes, the greater the risk of type 2 diabetes. So, the apparent connection between the obesity epidemic and the rising rate of diabetes would be explained by this: People are eating more processed (and fattening) foods and, hence, more AGEs.

But this theory hasn't won many converts in the scientific community. "This is a very controversial area," says Thornalley. He has measured AGE absorption by the intestine and concluded that dietary sources could not be a significant source of AGEs in the body. "Dr. Vlassara has a point that many of the foods we eat contain AGEs and we do absorb some of them. However, when the kidneys are working well, [AGEs] have a very short lifetime in the body."

Crafting Countermeasures

No matter the source, AGEs are widely considered a health hazard, and researchers are searching for medicines to combat them. A growing body of research is measuring the impact of anti-AGE agents on the health of animals and even humans.

Some potential therapies prevent the formation of AGEs, while others break them up once they've formed. A 2008 study found that diabetic rats given LR-90, a compound that helps keep glucose from binding to other molecules and forming AGEs, had healthier kidneys than those that weren't given the experimental drug. So-called AGE breakers, which chemically disassemble AGEs, have shown promise in several studies of animals with diabetes and in a few early human clinical trials.

Another potential therapeutic agent being tested is already available: thiamine (vitamin B1). "We know from animal studies that one of the benefits of taking thiamine is it decreases AGEs," says Thornalley, who is helping run a clinical trial of thiamine in people. "The nice thing about thiamine, and similar interventions, is they work independently from glucose control."

That's right: An anti-AGE therapy would not rely on lowering blood glucose levels, and it would benefit even people with diabetes who already successfully maintain tight glucose control. This would be especially important because researchers have found in clinical trials that diabetic complications can occur in people who have achieved near-normal blood glucose levels. "I spent most of my life pushing for glucose control only to find that it wasn't enough," says Vlassara. Even so, Thornalley says good blood glucose control will help prevent the buildup of AGEs and continue to be important: "Any AGE-lowering agent that is developed will not take the place of any existing therapy."

There's much work left to do in AGE research, but understanding advanced glycation end products and their role in diabetes may add an entirely new dimension to the disease's prevention and treatment.



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