Spring 1996 Volume 5, Number 2

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BY SHAI GOZANI, M.D., PH.D.

What rare nervous system disorder afflicts J.M.? Actually, she suffers from one of the most common diseases in the United States: J.M. is one of an estimated 14 million Americans with diabetes mellitus, often referred to simply as diabetes. The abnormal sensations she experiences are characteristic of a relatively common complication called diabetic neuropathy.

What is diabetes and how does it affect the nervous system? Can it be treated and what does the future hold? These are questions that diabetics, as well as scientists, physicians and biomedical engineers, ask themselves daily.

Diabetes occurs in two predominant forms: Insulin-dependent diabetes mellitus (IDDM, type I) accounts for about 5 to 15 percent of cases and tends to arise in children and teenagers. However, the vast majority of individuals with diabetes --about 12 million --have Non-insulin-dependent diabetes mellitus (NIDDM, type II) which often develops in the fourth or fifth decades of life.

The cardinal feature of diabetes is an abnormal metabolism of the blood sugar known as glucose. Insulin, a hormone normally produced by the pancreas, is largely responsible for the regulation of glucose levels in the blood. Diabetics either lack insulin or have a resistance to the action of the hormone. This absolute or relative insulin deficiency prevents them from properly metabolizing glucose and leaves them with chronically high concentrations of glucose in their blood, or "hyperglycemic." Most evidence indicates that the long-term health consequences of diabetes are caused by persistent hyperglycemia.

Damaging the nervous system
Long-term complications of diabetes are numerous. One of the most characteristic is called retinopathy, or disease of the retina. In fact, diabetic retinopathy is the leading cause of blindness in the United States. Another, nephropathy, or kidney disease, occurs in a significant number of diabetics; about 25 percent of individuals with kidney failure requiring dialysis and/or kidney transplantation have diabetic nephropathy. Diabetics also suffer from a greater than normal rate of heart attacks and stroke.

Many individuals who have had either type of diabetes for more than five to 10 years will suffer from diabetic neuropathy. Those who experience symptoms of diabetic neuropathy often consider these the most distressing manifestations of their diabetes.

The most common expression of diabetic neuropathy is a loss of sensation in the feet and occasionally in the hands. Beyond the disturbing and troublesome numbness, a lack of sensory feedback from the feet can trigger a sequence of dangerous events. In particular, the malfunction of nerves carrying sensory information from the feet may lead to an altered foot architecture that increases the probability of injuries of which the individual is unaware. These injuries may develop into foot ulcers, or craterlike lesions of the skin that are often infected. In some cases, the ulcers do not heal and amputation of damaged toes, or even the entire foot, is required --a devastating situation striking all too many individuals who have had diabetes for many years.

Another common target of diabetic neuropathy is the autonomic nervous system where it can produce highly disruptive alterations in basic functions, including the digestive, bladder and sexual functions. In fact, impotence eventually affects more then 50 percent of men with diabetes.

Getting tough on the disease
While there is no cure for any form of diabetes and few effective treatments for its specific complications, a fairly effective treatment paradigm is emerging. The recently completed Diabetes Control and Complications Trial (DCCT) validated what many endocrinologists have believed for years. It demonstrated that very aggressive attempts to normalize blood glucose levels reduce the likelihood or rate of progression of several long-term complications of diabetes.

For nerve disease, the study showed that participants whose blood glucose levels were intensively managed had a greater than 50 percent reduction in all manifestations of diabetic neuropathy after five years. Although the DCCT was limited to individuals with insulin-dependent diabetes, the results are believed extensible to non-insulin-dependent diabetes.

It is important to say that normalization of blood glucose levels in diabetics has risks. Intensive blood glucose management such as that utilized in the DCCT tends to increase the probability of severe hypoglycemia, characterized by rapid drops on the blood glucose concentration. Hypoglycemic events are dangerous and may result in coma if not rapidly reversed. As a result, intensive blood glucose management requires increased medical supervision and attention by the diabetic.

The whole purpose of managing and improving blood glucose levels is to lower the chronically high amounts of glucose that diabetics tend to have in their blood. This reduction in glucose concentration is accomplished through regulation of diet, exercise, weight loss if appropriate, and the administration of therapeutic agents such as insulin. To insure treatment efficacy and safety, especially with intensive management, frequent determinations of blood glucose levels are required. As a result, "self blood glucose monitoring" by diabetics has become a fundamental component of diabetes management. Diabetics who attempt to aggressively normalize their blood glucose require three or more glucose checks a day.

Fighting the "ouch" factor
In the past ten years, technologies that facilitate blood glucose monitoring have advanced significantly. Today, diabetics can carry a small device, not much larger than a credit card, that allows them to check their glucose level by placing a drop of blood on a special test strip inserted into the "glucose meter." The blood droplet is usually obtained by pricking one's finger tip with a small lancet. This technology has revolutionized blood glucose monitoring, but for patients whose diabetes might most demand it, multiple "finger pricks" extract a significant toll.

Many diabetics consider the finger prick painful and highly onerous, and compliance with the recommended monitoring frequency is quite low. In fact, many individuals refuse to use the monitors at all. Children and the elderly have a particularly difficult time with the compliance and use of the current technology. As a result, tremendous efforts have been directed at creating a "noninvasive" and painless blood glucose monitor. Unfortunately, the development landscape for such a device has been repeatedly littered with the dashed hopes of diabetics. No such instrument is presently approved for public use.

Yet, there is cause for optimism. Several different noninvasive blood glucose monitoring technologies are under investigation, and there is good reason to believe that within five years the FDA will approve a truly effective and safe device. In addition, other approaches to treating the disease have made gains. Improvements in pancreatic organ transplants have led to their increasing role in the treatment of diabetes; recent advances in the design of an artificial pancreas have been encouraging, as have been improvements in automated insulin-delivery systems.

Beyond these developments, great strides are being made in understanding the fundamental causes of the various forms of diabetes and attendant complications, including diabetic neuropathy. Insights gained from this research may lead to new treatments and, possibly in the future, a cure. Hopefully, this knowledge will help J.M. sleep a little more peacefully. *