July 31, 2000
One of the quiet miseries of long-term diabetes is a condition called gastroparesis --a failure of the stomach to empty after a meal because the valve-like pyloric muscle won't relax. Gastroparesis affects nearly 75 percent of people who've had diabetes more than five years, causing bloating, pain, loss of appetite and, on occasion, vomiting and dehydration.
Now researchers at Johns Hopkins have shown the immediate problem stems from a lack of the gaseous nerve transmitter nitric oxide (NO) in key tissues --the same basic molecular mishap that takes place in impotence. In an article in this week's Journal of Clinical Investigation, the scientists also report that both insulin and Viagra, impotence's uplifting therapy, reverse gastroparesis in diabetic mice.
"The study not only suggests a different approach to relieve gastroparesis, but it also could offer ways for diabetics to keep their insulin and blood sugar levels on an even keel," says neuroscientist Christopher Ferris, M.D., Ph.D., who led the study. "Having gastroparesis slow the progress of food through the digestive tract can dramatically alter blood sugar levels," Ferris says. "Yet being able to predict those levels is critical for diabetics on insulin. We think this work is useful, in part," he adds, "because it could result in a way to keep digestion -- and diabetes therapy --on track."
In the study, the researchers studied standard mouse models of diabetes at molecular, tissue and organ levels. In one model, STZ mice develop apparent diabetes when an injected toxin destroys insulin-producing cells of the pancreas. In another model, NOD mice develop an especially realistic version of diabetes when the animals' primed immune systems attack their own insulin cells. The researchers also examined otherwise normal "knockout" mice lacking the gene that triggers nitric oxide production. Finally, they studied the ability of live preparations of pyloric valves in the various mouse models to contract or relax.
Both the diabetic mice and the knockout mice showed all the symptoms of gastroparesis. They also produced significantly lower levels of nitric oxide --or none at all in the knockout mice-- than normal mice. "That strongly suggests that lowered NO is the immediate cause of gastroparesis in diabetes," says Ferris.
An important part of the study focused on the role of insulin in reversing the disorder. When the researchers injected the mouse models with insulin, NO production returned to normal, as did emptying of the stomach after eating. The normal emptying also returned when the researchers treated the diabetic mice with sildenafil (Viagra).
"Somehow," Ferris says, "increasing insulin leads to increased NO, which brings about muscle relaxation. So does Viagra. We already knew that Viagra affects specific muscle in the penis that needs to relax before an erection can occur," says Ferris. "Apparently it also has that muscle relaxing effect in the diabetic mice."
Viagra works one step "downstream" from NO, fooling muscles into behaving as though plenty of NO is present and leading to muscle relaxation.
"If insulin relieves gastroparesis, you might ask why patients would need a drug like Viagra," says Crystal C. Watkins, an M.D./Ph.D. candidate and first author on the study. "We know patients with the problem do better on insulin. Their gastroparesis is much worse without it or worse if their insulin control goes awry due to illness or injury.
"But just getting a shot of insulin won't reverse the gastroparesis right away," says Ferris. "That can sometimes take days," he adds, "and even then some of the more uncomfortable symptoms may remain because insulin therapy isn't a precise mimic of normal insulin release from the pancreas." That's where the Viagra may come in, he says. "It works very well and very quickly in the mice."
Ferris' team is now considering controlled trials of Viagra for gastroparesis in diabetic patients. The need is great, Ferris says, because the most widely used therapy, a drug called cisapride (trade name Propulsid), has just been taken off the market. Cisapride works differently from Viagra, by increasing muscle contractions in the digestive system rather than by relaxing the sphincter muscle. The research was funded by U.S. Public Health Service grants and Research Scientist awards, as well as by Ferris's Howard Hughes Fellowship for Physicians.
Others in the study are Akira Sawa, M.D., Samie Jaffrey, M.D., Ph.D., Seth Blackshaw, Ph.D., Roxanne Barrow, B.S., and Solomon Snyder, M.D.
For research study information visit http://hopkins.med.jhu.edu/news/diabetes/