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.

Diabetes: Autonomic Neuropathy Far Worse Than ‘Pins & Needles’ in the Feet

For around 50 percent diabetics, living with diabetic peripheral neuropathy ‒ that "pins and needles" feeling you get after your foot falls asleep, along with a burning sensation, and possibly numbness and loss of balance and no way to relieve it ‒ is a daily reality. When the peripheral nervous system fails, the patient becomes a vegetable.

Diabetic neuropathy is categorized as autonomic and peripheral diabetic neuropathy, depending on which particular nervous system it affects. The third category, focal diabetic neuropathy, affects individual nerves, not a system.

Diabetes can cause dysfunction of any or every part of the autonomic nervous system, leading to a wide range of disorders. And these are serious. Among the most troublesome and dangerous of the conditions linked to autonomic neuropathy are known: silent myocardial infarction (MI), cardiac arrhythmias (abnormal heart rhythm), ulceration (formation or development of an ulcer), gangrene, and nephropathy (damage to or disease of the kidney).

The prognosis is bleak: While treatment relieves pain and can control some symptoms, the disease generally continues to get worse.

What is Autonomic Neuropathy?

The peripheral nervous system controls the sensory and motor functions. This helps us to become aware of our environment and to control muscular activity. Patients with diabetic neuropathy might also develop autonomic neuropathy, leading to incontinence, constipation, diarrhea, acid reflux, difficulty breathing, sexual dysfunction (impotence) and inability to regulate blood pressure.

This happens because autonomic neuropathies affect the nerves that regulate vital functions, including the heart muscle and smooth muscles. Indeed, the autonomic nervous system is at the very core of our existence. It controls the vital life functions like heartbeat and respiration. So, when the autonomic nervous system fails, the patient dies.

In other words, autonomic neuropathy is a form of peripheral neuropathy. It is a group of symptoms, not a specific disease. There are many causes. Damage to the autonomic nerves affects the function of areas connected to the problem nerve. For example, damage to the nerves of the gastrointestinal tract makes it harder to move food during digestion (decreased gastric motility). Damage to the nerves supplying blood vessels also causes problems with blood pressure and body temperature.

Essentially, diabetic autonomic neuropathy impairs the ability to conduct activities of daily living and lowers quality of life. Autonomic neuropathy is also associated with an increased risk of sudden death. It also accounts for a large portion of the cost of care. (See my earlier related post 'Don't Ignore Diabetic Nerve Pain' here.)

Remember, diabetic autonomic neuropathy is a stealthy complicationof diabetes, developing slowly over the years and quietly robbing diabetic patients of their ability to sense when they are becoming hypoglycemic or having a heart attack. It can affect any organ of the body, from the gastrointestinal system to the skin, and its appearance portends a marked increase in the mortality risk of diabetic patients.

Eventually, autonomic neuropathy damages the nerves that run through a part of the peripheral nervous system and are used for communication to and from the brain and spinal cord (central nervous system) and all other parts of the body, including the internal organs, muscles, skin, and blood vessels.

Telltale Signs
Clinical symptoms generally do not develop for many years after the onset of diabetes. However, subclinical autonomic neuropathy can often be identified by quantitative functional testing within 1 year of diagnosis in patients with type 2 diabetes and within 2 years in those with type 1 diabetes. The most important causative factors are poor glycemic control, long duration of diabetes, increasing age, female sex, and higher body mass index. (See my earlier related post 'All Eyes on Research That May Provide Cure for Diabetic Neuropathy' here.)

Leading causes of death in diabetic patients with either symptomatic or asymptomatic autonomic neuropathy are heart disease and nephropathy. Increased urinary albumin excretion is related to autonomic neuropathy in diabetic patients.

Impairments in the autonomic nervous system may also contribute to the pathogenesis of diabetic nephropathy and cardiovascular disease. Autonomic neuropathy is also an independent risk factor for stroke.

Consequences
The cardiovascular manifestations of autonomic neuropathy appear to be the most widely studied ones and justifiably so because they are likely to be potentially lethal. Postural giddiness and syncope (temporary loss of consciousness and posture, described as "fainting" or "passing out") are the only autonomic symptoms referable to the cardiovascular systems.

Undeniably, the cardiovascular system bears the brunt of autonomic neuropathy in diabetics and this may be responsible for certain disabling symptoms, painless myocardial infarction and even sudden death during surgery. (It is therefore desirable to evaluate in detail the cardiovascular and autonomic status of all diabetics before major surgery.)

Cardiovascular autonomic neuropathy causes abnormalities of heart-rate control and vascular dynamics. It has been linked to postural hypotension, exercise intolerance, enhanced intraoperative cardiovascular lability (susceptible to change, error or instability), increased incidence of asymptomatic ischemia (showing no evidence of inadequate blood supply), myocardial infarction (heart attack), and decreased likelihood of survival after myocardial infarction.

Besides, failure to recognize symptoms in a diabetic as due to autonomic neuropathy may lead to a lot of unnecessary investigations and sometimes to wasteful treatment such as testosterone in sexual impotence. Indeed, sexual impotence is now recognized to be a common and sometimes the only manifestation of autonomic neuropathy followed closely by nocturnal polyuria (passing large volumes of urine at night but normal amounts during the day).

Gastrointestinal manifestations of autonomic neuropathy also include nausea and vomiting due to diminished gastric motility (the ability to move spontaneously); diarrhea and nocturnal fecal incontinence (bedwetting) due to exaggerated sympathetic hypofunction (a diminished or inadequate level of activity of an organ system or its parts) during sleep; and asymptomatic, functional disturbances of the gall bladders and the esophagus. Localized bouts of sweating on the face during eating are also reported to be diagnostic of diabetic autonomic neuropathy.

Outlook (Prognosis)
Once autonomic abnormalities are present, they are permanent, sometimes showing progressive deterioration but rarely, if ever, improving. They can affect multiple organ systems in the body, can cause disabling symptoms and have a lethal potential. It is therefore, necessary to be constantly aware of them and to screen the diabetics periodically, and most certainly pre-operatively. Therein lies their safety.

Of patients with symptomatic autonomic dysfunction, 25% to 50% die within 5 to 10 years of diagnosis. The 5-year mortality rate in patients with diabetic autonomic neuropathy is three times higher than in diabetic patients without autonomic involvement.

Undeniably, neuropathy is one of the most common complications of diabetes. And when it affects the autonomic nervous system, it can damage the cardiovascular, gastrointestinal, and genitourinary (reproductive and urinary) systems and impair metabolic functions (necessary for the maintenance of a living organism) such as glucose counter-regulation (unrestrained eating).

This is because the autonomic nervous system is primarily efferent (conveying away from a center), transmitting impulses from the central nervous system to peripheral organs. However, it also has an afferent (carrying toward the center) component. Its two divisions—the parasympathetic (part of nervous system that serves to slow the heart rate, increase intestinal and gland activity, and relax the sphincter muscles) and the sympathetic (that accelerates the heart rate, constricts blood vessels, and raises blood pressure) nervous systems— work in balanced opposition to control the heart rate, force of cardiac contraction, dilatation and constriction of blood vessels, contraction and relaxation of smooth muscle in the digestive and urogenital systems, the secretions of glands, and pupillary (affecting the pupil of the eye) size.

Ipso facto, the reported prevalence of diabetic autonomic neuropathy varies, with community-based studies finding lower rates than clinic-based and hospital-based studies, in which the prevalence may be as high as 100%.

Prevention
Intensive glycemic control is critical in preventing the onset and slowing the progression of diabetic autonomic neuropathy. The Diabetes Complications and Control Trial (DCCT) showed that intensive glycemic control reduced the prevalence of autonomic dysfunction by 53%.

It is also the first therapy to be considered when diabetic autonomic neuropathy is diagnosed. In addition, a variety of pharmacologic and nonpharmacologic therapies are available to treat the symptoms of autonomic neuropathy.

In addition, regular foot care can prevent a small infection from getting worse. This is why no appointment for diabetes care is complete without a thorough foot examination.

Treatment
For patients with both type 1 or type 2 diabetes, glycemic control is important, although methods to achieve target levels may differ. The methods for achieving euglycemia (normal glucose content of the blood) and the target blood glucose and HbA1c levels are given in a position statement from the American Diabetes Association.

The goals of treating diabetic neuropathy are to prevent the disease from getting worse and to reduce the symptoms of the disease. Tight control of blood sugar (glucose) is important to prevent symptoms and problems from getting worse.

Medications may be used to reduce the symptoms in the feet, legs, and arms. These medications include antidepressant drugs, such as amitriptyline (Elavil), doxepin (Sinequan), or duloxetine (Cymbalta); antiseizure medications, such as gabapentin (Neurontin), pregabalin (Lyrica), carbamazepine (Tegretol), and valproate (Depakote); drugs that block bladder contractions may be used to help with urinary control problems.

Erythromycin, domperidone (Motilium), or metoclopramide (Reglan) may help with nausea and vomiting. Pain medications (analgesics) may work for some patients on a short-term basis, but in most cases they do not provide much benefit. Capsaicin can be used topically to reduce pain.

Phosphodiesterase type 5 (PDE-5) drugs, such as sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) are safe and effective for treating impotence in patients with diabetes.

Regular foot exams are important to identify small infections and prevent foot injuries from getting worse. If foot injuries go unnoticed for too long, amputation may be required.

Possible Complications
Injury to the feet due to loss of feeling; muscle breakdown and imbalance; poor blood sugar control due to nausea and vomiting; skin and soft tissue breakdown (ulceration) that may require amputation.

In addition, neuropathy may mask angina, the warning chest pain for heart disease and heart attack.

When to Contact a Medical Professional
Promptly call your health care provider if you develop symptoms of diabetic neuropathy.

Sources: American Diabetes Association (ADA), Neurology, National Institute of Health (NIH), Aaron I Vinik, National Diabetes Information Clearinghouse (NDIC)