Cause of diabetes-related erectile dysfunction is clarified by Johns Hopkins researchers

August 09, 2005

A new study from the Brady Urological Institute at Johns Hopkins suggests an over-supply of a simple blood sugar could be a major cause of erectile dysfunction in diabetic men.

Researchers have found that one particular simple sugar, present in increased levels in diabetics, interferes with the chain of events needed to achieve and maintain erection and can lead to permanent penile impairment over time. The results, which have implications for new types of erectile dysfunction treatments targeting this mechanism of erection, are described in the August 16 issue of the Proceedings of the National Academy of Sciences.

Previous research had shown that diabetic erectile dysfunction was partially due to an interruption in an enzyme that starts the chain of vascular events leading to an erection. The Hopkins team suspected O-GlcNAc, a blood sugar present in hyperglycemic (high blood sugar) circumstances, to be that interrupting factor.

"We were interested to determine whether high glucose in diabetes mellitus modifies the endothelial nitric oxide synthase (eNOS) enzyme, which is responsible for the achievement and maintenance of erection," says Biljana Musicki, Ph.D., lead investigator of the study and a research associate in the Brady Urological Institute.

Erectile dysfunction is a common problem for more than half of men with diabetes. Musicki says that an estimated "50 percent to 75 percent of diabetic men have erectile dysfunction to some degree, [a rate] about threefold higher than in non-diabetic men." This is not the same type of erectile dysfunction seen in non-diabetics, and it is less effectively treated with conventional drugs like Viagra.

The study examined rats with type 1 diabetes mellitus as well as the overall mechanism of erection. "Erection begins when a sexual stimulus activates the enzyme neuronal nitric oxide synthase (nNOS) that causes short-term release of nitric oxide (NO) at the nerve endings in the penis," Musicki explains.

This initial release of NO causes rapid and short-term increases in penile blood flow and short-term relaxation of the penile smooth muscle, initiating an erection. The resulting expansion of penile blood vessels and smooth-muscle relaxation allows more blood to flow into the penis. This increased blood flow (shear stress) activates the eNOS in penile blood vessels causing sustained NO release, continued relaxation and full erection.

O-GlcNAc hinders this normal chain of events by inhibiting the activation of eNOS, and consequently reducing the release of NO and preventing the smooth muscle in the penis from relaxing. Without this relaxation, there is no shear stress to stoke the production of more NO and therefore, no normal, sustained erection.

The team also found that in comparison with the controls, the diabetic rats' erectile response was 30 percent lower, full erections were 40 percent smaller and these erections took 70 percent longer to achieve.

The study emphasizes the reduced blood vessel function present in patients with diabetes. "The mechanism we describe here stresses the critical importance of vascular function in the erectile response. It may suggest new ways of treating erectile dysfunction by targeting specifically this mechanism in penile erection," notes Musicki.

Additionally, speaking to more than just the sexual issues related to erectile dysfunction, the research addresses implications related to the overall understanding of penile health. According to Arthur Burnett, M.D., a professor of urology and head of the research team, "eNOS plays roles in both immediate erectile response and the overall health and function of the penile tissue."

Burnett, whose lab has studied penile erection since the early 1990s, continues, "the insight here is tremendous because it speaks to fundamental biological and vascular" mechanisms of diabetes. "This paper gets back to the physiological relevance of hyperglycemia and how it affects erection. We show here -- using erection as a model -- the vascular damage caused by diabetes and provide insights into vascular disease beyond this dysfunction," he adds.

The article, "Inactivation of phosphorylated endothelial nitric oxide synthase (Ser-1177) by O-GlcNAc in diabetes-associated erectile dysfunction," appears in the Aug. 16 issue of the Proceedings of the National Academy of Sciences and was published online Aug. 5. Melissa F. Kramer and Robyn E. Becker, also of the Brady Urological Institute, collaborated on this study.
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This research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Kidney Foundation of Maryland Professional Development Award.

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[This article was written by Stacy Brooks.]

Johns Hopkins Medicine

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