Root of Diabetic Disorder Found, Scientists Say : Medicine: Painful peripheral neuropathy leads to gangrene and amputations. Researchers say funds are needed for clinical study that could lead to treatment.
Colorado State University researchers say they have identified the root cause of peripheral neuropathy, the crippling nerve disease that afflicts 10% to 15% of the 14 million American diabetics, causing intense pain and amputation of limbs.
The discovery could lead to the first effective treatment for the disorder if the researchers can raise the money for clinical trials, said Colorado molecular biologist Douglas N. Ishii. Physicians currently have only supportive therapy to alleviate symptoms.
Working with rats, Ishii and his colleagues found that animals with peripheral neuropathy had low levels of two hormones, called insulin-like growth factors I and II (IGF-I and IGF-II), in their affected nerves. Indirect evidence suggests that a similar process occurs in primates and humans, he said.
More important, they report today in the journal Brain Research Review, giving IGF to the animals dramatically reduced pain and led to the regeneration of the nerves, even though the animals’ diabetes careened on unchecked.
“We hope these very encouraging laboratory studies will be similarly promising in clinical research,” said Zach W. Hall, director of the National Institute of Neurological Disorders and Stroke, which funded Ishii’s research.
But Ishii cautioned: “Even if clinical trials began tomorrow, it would still be five to seven years before a drug was available for wide use.”
Richard Kahn, chief scientific and medical officer of the American Diabetes Assn., was even more cautious. “We have to confirm this in humans in some fashion . . . for it to be considered a real breakthrough,” he said.
Diabetes is caused by the body’s inability to produce enough insulin to regulate the storage and use of sugars in the blood. About 1 million Americans with Type 1 diabetes require insulin injections two to four times per day because their pancreases produce no insulin at all. About 13 million Americans with Type 2 diabetes produce below-normal amounts of insulin and are typically treated with drugs that stimulate its production.
With either type of diabetes, blood sugar levels go through wide variations during the course of the day and researchers believe that these variations cause the complications that arise after a patient has had the disease for many years, including eye damage, kidney damage and peripheral neuropathy. These complications can be minimized by very tight control of blood sugar levels, a rigorous process that involves multiple small injections of insulin (for Type 1), exercise and a strict diet.
“But it is the hardest thing in the world to get people to change their behavior and their diets,” Ishii said.
In the early stages of peripheral neuropathy, patients develop severe, unremitting pain in their limbs. Patients often cannot even stand the weight of a bedsheet on their bodies. Later, their limbs go numb, causing patients to injure themselves when they inadvertently step on or run into objects.
Wounds often do not heal properly, leading to the development of gangrene, followed by amputations--as many as 50,000 per year in the United States. Men become impotent and both sexes lose control of their bladders and bowels.
In previous research, Ishii had found that insulin growth factors support the survival and regeneration of peripheral nerves. The current research was triggered when he observed that the IGFs had the greatest effect “in precisely those nerves that are most affected in diabetic neuropathy.”
He studied rats made diabetic by injecting a chemical that destroys insulin-secreting cells in the pancreas, a standard animal model. Researchers have long known that IGF levels in the blood of such animals are below normal, but the significance of that observation was unknown. Using newly devised techniques, Ishii showed that levels were also below normal in the spinal column and in the peripheral nerves of the animals. He speculated that high levels of sugar in the blood somehow inhibit normal production of the hormones.
The team administered IGF-II under the skin of the animals and found that it significantly reduced pain and prevented neuropathy. “It did so, to our astonishment, even though blood sugar levels remained sky high,” Ishii said.
Ishii noted that IGF-II is currently very expensive--a supply to treat one rat costs $1,000.
The next step, he added, is clinical trials in humans, but the funding for such trials is problematic. The development costs for a new drug typically average $230 million, and the National Institute of Neurological Disorders and Stroke, which has supported his research for 15 years, does not have the funds to back such a project. He hopes a drug company will license the university’s patents and support the trials.
Such an outcome is very possible, added Dr. Aaron Vinik of the Diabetes Research Institutes in Norfolk, Va.
“Some companies have already invested a lot of money in approaches that aren’t nearly as promising as this,” he said. And would he have his patients participate in such a trial? “I’d like to run it,” he responded.
