Researchers Close to Developing a Drug to Prevent Diabetic Peripheral Neuropathy
DATE: October 15, 2010
A drug developed at the University of Kansas has the potential to stop a debilitating condition of diabetes that often leads to pain in the extremities and even amputations, KU researchers have found. The researchers recently published an article showing that KU-32 can stop and even reverse diabetic peripheral neuropathy, or DPN, in mice. The condition leads to death of nerves in the extremities of individuals with diabetes.
“People with DPN can be very sensitive to light touch, which can cause significant pain,” said Rick Dobrowsky, professor of pharmacology and toxicology and one of the paper’s authors. “The other side is eventually diabetes causes death of the nerves. DPN often leads to loss of feeling in the hands and feet, which can make diabetics susceptible to wounds and infections and often leads to amputations of toes and feet.” DPN is the second leading cause of amputations, after injuries. Dobrowsky co-authored the paper with Brian Blagg, professor of medicinal chemistry; Roger Rajewski, professor of pharmaceutical chemistry; Joanna Krise and Michelle McIntosh, research associates with the Biotechnology Innovation and Optimization Center; Cuijuan Yu, research associate with the Higuchi Biosciences Center; postdoctoral researcher Yuanming Lu; and graduate students Michael Urban and Cuijuan Yu. It was published in the American Society of Neurochemistry’s journal, ASN Neuro.
The researchers administered KU-32 to diabetic mice. The compound stopped DPN and showed it could restore sensory neuron function to damaged nerve tissue. KU-32 inhibits a specific member of a family of proteins called molecular chaperones. “These studies provide the first evidence that targeting molecular chaperones reverses the sensory hypoalgesia associated with DPN,” the authors wrote. There are approximately 24 million diabetics in the United States. Dobrowsky said nearly 60 percent of them suffer from DPN at some point. The researchers hope that eventually the drug could be used to help to treat the condition in humans. Their research shows KU-32 can be administered orally as infrequently as once a week and still be effective. It has been shown to have long-term efficacy, meaning it could be administered in small doses, potentially reducing severity of side effects. “Our tests so far indicate that KU-32 is completely nontoxic and is absorbed in the blood stream very well,” said Blagg. “It has long-term efficacy. It is a promising treatment.”
There are only two FDA-approved drugs used for treatment of DPN, Blagg said. However, one is an anticonvulsant and the other is an antidepressant, and neither has the potential to reverse nerve degeneration. The research, funded by grants from the Juvenile Diabetes Research Foundation and the National Institutes of Health, is ongoing. The team is hoping to discover how long the drug can be effective in combating DPN. People often find out they have diabetes when they are suffering from the nerve-degenerating condition. “The idea is to try to determine at what point in nerve degeneration will be most effective and at what point the drug will not be efficacious,” Dobrowsky said. “We’d like to know at what stage in the progression of DPN a window of opportunity exists for the beneficial use of KU-32.” The researchers also hope to determine exactly how the drug stopped and reversed DPN in mice. It’s not immediately evident if it improved existing nerve fibers or generated new ones. The drug is still in pre-clinical development. It will likely need another year or two of study, then the researchers hope it could be advanced to clinical trials in humans. Dobrowsky said the collaboration of researchers with different areas of expertise was key to the study. “This is an excellent example of how collaboration allows us to achieve one of the School of Pharmacy’s goals, to discover medications that enhance and extend life,” he said.
Even Well-Controlled Diabetes May Present Post-Surgery Risk
MONDAY, Oct. 18 (HealthDay News) — People with diabetes who had normal blood sugar levels before non-heart surgery had a higher risk of death in the year following surgery compared to people without diabetes, researchers have found.
And, patients who hadn’t been diagnosed with diabetes but had high blood sugar readings before surgery had a higher risk of death in the year after a surgical procedure compared to people with lower blood sugar readings, they noted.
“When we looked at blood sugar levels and the likelihood of complications after surgery, we didn’t see a significant difference between diabetics and non-diabetics. But, when we looked at the long-term outcomes, we found significant differences between diabetics and non-diabetics,” said Dr. Basem Abdelmalak, director of anesthesia for bronchoscopic surgery at the Cleveland Clinic in Ohio.
Findings from the study were scheduled to be presented Monday at the Anesthesiology 2010 meeting in San Diego.
The researchers collected information from one preoperative blood test to assess fasting blood sugar levels before 61,536 non-cardiac surgeries. Abdelmalak said the surgeries were varied, and included all surgeries that weren’t related to the heart.
From this large sample, about 16 percent of the surgical patients had either type 1 or type 2 diabetes.
The average age of the patient population overall was 57, according to Abdelmalak. The average age of the non-diabetic patient was 56, and the diabetic group was slightly older, with an average age of 63, he said.
The researchers compared the one preoperative blood sugar reading to short- and long-term postoperative complications and death.
The investigators found that people with diabetes had between an 8 percent and 11 percent risk of dying in the year following surgery. But those with lower blood sugar levels before surgery — in the range of about 60 milligrams to 90 milligrams per deciliter (mg/dL), according to Abdelmalak — had a risk of death between 10 percent and 18 percent.
In people without diabetes, another interesting relationship emerged. Those with a blood sugar level of more than 200 mg/dL had more than an 11 percent risk of death in the year after surgery compared to just 3 percent to 5 percent for non-diabetics with lower blood sugar levels.
Abdelmalak said that one reason the non-diabetics with high blood sugar levels had an increased risk of death might be because they have undiagnosed diabetes. Diabetes, especially type 2 diabetes, can go unrecognized for long periods, but at the same time is still causing damage to the body. So, these people may have already been at a higher risk from complications related to undiagnosed diabetes.
As for the finding that people with a low blood sugar level are more likely to die in the year after surgery, Abdelmalak hypothesized that the body may get used to living with higher blood sugar levels — in essence, resetting the body’s metabolism. If you then try to maintain “normal” blood sugar levels, these may then be too low for you.
“We are still looking for the best way to give advice for managing diabetes during surgery. We’re hoping that this study will stimulate further research, and that hopefully, we’ll reach agreement on what is the better, or even optimal level of blood glucose,” said Abdelmalak.
“We have abundant data that achieving good blood sugars without causing hypoglycemia has many benefits that are still worth striving for,” explained Dr. Richard Bergenstal, president of medicine and science for the American Diabetes Association.
“Initially, it seemed that the lower the blood sugars could be recommended for everybody. But, now it looks as if we might need to individualize target blood sugars. However, we are still trying to sort out what are the right targets for which patients,” said Bergenstal.
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In the meantime, both experts suggested that people who haven’t been diagnosed with diabetes, but who have high blood sugar levels before surgery, may need to be followed more closely after surgery since they have a higher risk of death. And, the same holds true for people with diabetes who have lower blood sugar levels.
