Mystery Mechanism Protects Some Diabetics From Developing Complications

WHY are some diabetics free of complications? Researchers are now asking the question the other way around. They want to know why some diabetic patients do not develop complications. What is protecting them? It seems some people with diabetes possess yet-unidentified factors that reduce the risk for and even prevent them from developing diabetes-related complications, despite living with the disease for decades.

If researchers can identify the mechanisms protecting these individuals ‒ who are clearly different because something protects them from devastating complications ‒ then it might be possible to develop drugs that can do the same thing.

I had reported end January that what current research provides is an admission that the fundamental mechanisms that create the environment for the development of diabetes complications are still very much unknown.

One aspect of the disease though that is very well documented is the damage that the disease wreaks on an individual’s blood vessels. Diabetes does not kill the individual but the complications often do.

Among the top of the list of complications is cardiovascular disease, as diabetics have three times of the risk compared to non-diabetics. The small blood vessels are also damaged. Nearly 70 percent of patients would have suffered from kidney damage leading to end stage renal failure. Many others suffer from eye complications, with nearly two percent of these diabetics going blind eventually.

Still, despite decades of intensive research on diabetes complications, the fundamental mechanisms are not yet fully known. Neither it is possible to prevent or treat the damage of the blood vessels that affects a majority of all diabetics.

“The blood vessels and other organs of the body are sugar coated and become stiff. It is reminiscent of a premature biological aging,” says Peter Nilsson of the Lund University Diabetes Centre in Sweden who isstudying diabetics with no complications in Sweden.

just-published study conducted by the Joslin Diabetes Center on people who have lived with type 1 diabetes for more than 50 years presents a strong case for the existence of a protective mechanism in some individuals that allows them to live relatively free of the problems typically associated with long-term duration of diabetes. These mechanisms, the study found, may be different for microvascular (such as kidney, nerve and eye disease) than macrovascular complications (such as heart disease).

press release issued by the American Diabetes Association yesterday quotes lead researcher George King, Chief Scientific Officer of the Joslin Diabetes Center and Professor of Medicine at Harvard Medical School saying: “If we can identify what constitutes this protective mechanism, we have the potential to induce such protections in others living with diabetes…That’s huge.”

The Joslin researchers looked at 351 U.S. residents known as the “Medalist” cohort and found that a subgroup of people who had lived with type 1 diabetes for more than 50 years remained free from such complications as proliferative diabetic retinopathy (PDR), a serious eye disease that can lead to blindness (42.6 percent of them); nephropathy, or kidney damage (86.9 percent of them); neuropathy, or nerve damage (39.4 percent); and cardiovascular disease (51.5 percent). Of those who did not develop PDR, 96 percent with no retinopathy progression in the first 17 years of their disease never experienced a worsening of symptoms, meaning that they likely possessed some type of protection specific to this complication.

Surprisingly, glycemic control was not a factor in providing this protective mechanism.

“That doesn’t mean of course that glycemic control doesn’t help to prevent complications. Numerous other studies have shown that it unquestionably does. In this case, it means only that there is a separate, protective mechanism in play that is not related to glycemic control that also helps to protect against diabetes-related problems. We are still working on identifying just what that is,” King said.

It’s important to note that most of the people in this study developed type 1 diabetes before strict glycemic control was even possible or used as the standard of medical care, the researchers write. The people in this study likely lived for several decades, therefore, without maintaining strict control.

The study also found that those with high plasma carboxyethyl-lysine and pentosidine, or advanced glycation end products (AGEs), were 7.2 times more likely to have some kind of complication than those who had low levels of this combination of AGEs. (AGEs are compounds that develop in the body after long exposure to high glucose levels and have generally been regarded as playing a role in diabetes-related complications.)

However, those with other types of AGE molecules exhibited protective features. Thus, this study suggests that not all AGEs are alike in their actions and raises the exciting possibility that some AGEs may be markers for protection against one or more diabetic complications.

In an accompanying editorial titled The Question Is, My Dear Watson, Why Did the Dog Not Bark?, Dr. Aaron Vinik, Director, Eastern Virginia Medical School Diabetes Research Center, writes that “the accumulation of AGEs may be one of the important factors in metabolic memory,” a phenomenon in which an initial period of good glycemic, lipid and blood pressure control results in a prolonged period of health benefits that last beyond the period of control.

However, while it is clear that for some there is a protective mechanism at play, it’s unclear whether metabolic memory is playing a role because glycemic control was not considered important until 1993, long after the study began.

What’s most interesting, Vinik points out, is that sRAGE (the circulating soluble receptor for AGEs) is deficient in those who have the most severe complications, and is present at high levels in those with the most longevity. “If this is the missing link, it is huge for the possible emergence of a new biomarker and the potential for therapy that might increase circulating sRAGE or sRAGE itself,” he said.

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