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.

A 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).

A 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.

10-year Study Proves High Blood Sugar Linked With Retinopathy Risk

Here is more evidence that uncontrolled blood sugar (hyperglycemia) increased the risk of diabetic retinopathy (blindness). Individuals who have poorly controlled type 1 or type 2 diabetes may be at greater risk of developing retinopathy, according to a new study from a team of French researchers. They found that persistently high levels of blood sugar are a strong indicator of future retinopathy risk.

In a cohort study, the risk of the condition shot up markedly when fasting plasma glucose and glycated hemoglobin (HbA1c) reached levels that are used to indicate diabetes risk, according to Beverley Balkau, PhD, of the Institut National de la Santé et de la Recherche Médicale in Villejuif, France, and colleagues.

The finding allows physicians to set threshold values that define patients at risk of the eye condition, they argued in the February issue of Archives of Ophthalmology. They said the information helps clear up some debate over the role that blood sugar levels play in the development of retinopathy and could provide medical professionals with a way of measuring a patient's risk for the condition.

For the study, Balkau and colleagues studied more than 700 men and women taking part in the DESIR study, which enrolled volunteers ages 30 to 65 in western France from 1994 to 1996. At the outset, doctors examined participants' retinas and took blood sugar readings. The individuals were then followed for a period of ten years.

The goal was to study the frequency of retinopathy in individuals 10 years after measuring baseline levels of fasting plasma glucose and HbA1c and to evaluate positive predictive values for retinopathy at various levels of the glycemic variables.

After a baseline health exam, all participants were asked to return for subsequent examinations three, six, and nine years later. Those who were diagnosed with diabetes or who had had a fasting glucose level of at least 126 mg/dL at any point during the study were asked to undergo testing for retinopathy using a nonmydriatic digital retinal camera.

For comparison, two groups of matched participants also had the retinal exam ‒ those who had had an impaired fasting glucose level (from 110 through 125 mg/dL) at any time during the study and those whose glucose levels had always been below 110 mg/dL.

By the end of the study period, the researchers noted a strong correlation between initial blood sugar readings and the development of retinopathy. Participants with the condition had 22 percent higher fasting blood sugar levels and 12 percent higher HbA1c levels at the start of the study compared to participants who did not develop retinopathy.

All told, the researchers found 44 participants with retinopathy, including 19 of 237 in the diabetes group, another 19 of 246 with impaired glucose levels, and six of 249 in the normal glucose group.

Those with retinopathy had higher baseline fasting glucose and HbA1c levels on average -- 106 versus 130 mg/dL and 6.0% versus 6.4%, respectively (P<0.001).

And a higher percentage were treated for hypertension ‒ 36.4% of those with retinopathy compared with 19.6% (P=0.008), and they had a trend toward higher systolic blood pressure.

Analysis also showed that:

• Fasting plasma glucose levels of 108 and 116 mg/dL had positive predictive values of 8.4% and 14.0%, respectively, for retinopathy.

• HbA1c levels of 6.0% and 6.5% had positive predictive values of 6.0% and 14.8%, respectively.

Because of the sharp increase, they argued, the lower levels of each marker should be used as thresholds to identify those at risk of retinopathy 10 years down the road. "We propose that thresholds of 108 milligrams per deciliter for fasting plasma glucose concentration and 6.0 percent for HbA1c level could be used to define those who are at risk of retinopathy," they wrote.

Balkau and colleagues noted that the study's strengths included a large sample size and long follow-up.

However, they cautioned that the study participants were self-selected individuals who volunteered for the study after a free health checkup and the sample size of those with retinopathy was small, allowing evaluation only of risk factors strongly associated.

Preventing Diabetes And Literacy Key To Beat Dementia

According to a BBC report, preventing diabetes and depression could have a dramatic impact on cutting cases of dementia, a study suggests. Boosting levels of education and upping fruit and vegetable consumption would also have a big effect, the British Medical Journal said. It comes as another study showed dementia patients are missing out on vital early treatments because GPs are being slow to diagnose them.

Several risk factors for the disease have been identified, including obesity, high blood pressure and high cholesterol. But British and French researchers wanted to assess what public health interventions could have the biggest impact on reducing the burden of dementia in the population.

They took a group of 1,400 elderly people and tested them for signs of dementia after two, four and seven years. Alongside this they recorded height, weight, education level, monthly income, mobility, dietary habits, alcohol consumption, and tobacco use and asked participants to do a reading test as a measure of intelligence.

Eliminating depression and diabetes and increasing fruit and vegetable consumption were estimated to lead to an overall 21% reduction in new cases of dementia. Increasing education would also lead to an estimated 18% reduction in new cases of dementia across the general population over the next seven years, they reported. By contrast, removing a gene linked with the disease would only cut new cases by 7%.

The team concluded that early screening for diabetes and treatment of depression would be the most useful approach for trying to reduce the future burden of dementia. And they added that encouraging literacy at all ages and trying to increase population intake of fruit and vegetables would also have an important effect but admitted that these aims were harder to achieve. Further studies including younger adults are needed to test the impact of such approaches, they added.

In the second study also in the BMJ, analysis of health records of over 135,000 people in the UK found that people with dementia were three times more likely to die in the first year after diagnosis than those without the condition.

That suggests that diagnoses are being made in the later stages of the disease.

Study leader Dr Greta Rait from the Medical Research Council said: "GPs are going to be dealing with more and more dementia cases in future and primary care must get better at detection."

Rebecca Wood, chief executive of the Alzheimer's Research Trust, said the links between depression, diabetes and dementia were well known. "Any policy that urges clear diagnosis and monitoring of these conditions could help make an impact on dementia.

"What is painfully evident from the study is the gaping hole that remains in our understanding and ability to diagnose or treat dementia effectively, a hole that can only be filled by more research."

Professor Clive Ballard, director of research at the Alzheimer's Society said a healthy lifestyle is key. "Effective prevention of diabetes, depression and heart disease could potentially improve the lives of millions of people affected by this cruel condition and reduce the billions spent on dementia care each year."

Dr Victoria King, head of research at Diabetes UK, said there is a growing body of evidence suggesting links between diabetes and Alzheimer's disease. "Finding ways to stop the type 2 diabetes epidemic in its tracks can only be seen as a good thing - especially as this could prevent millions of people developing the serious complications of the condition, which include heart disease, stroke, kidney failure, blindness and amputation."