Oxidative Stress in Diabetes Mellitus Associated ED

Diabetes mellitus is one of the major risk factors for ED. It has been estimated that 50-75% of diabetic men have ED [41].

Compelling data from molecular, cellular, and in vivo animal studies implicate a crucial role for oxidative stress in the development and progression of ED associated with diabetes. Both hyperglycemia and free fatty acids augment ROS

production. Penile tissue and blood from diabetic men with ED [42-45] and type 1 diabetic animals [46-53] contain high levels of superoxide. Oxidative stress impairs neuronal and endothelial production of NO in the penis, increases cavernosal tissue apoptosis and fibrosis, and induces nerve damage via membrane lipid peroxidation [34, 54-59], DNA damage and consequent activation of downstream signaling molecules leads to increased synthesis of proinflammatory molecules and inhibition of eNOS activity [52, 53, 60, 61] , All of these derangements contribute to diabetic ED.

The mechanisms for ROS production and the source of ROS in the diabetic penis are, however, only starting to be evaluated. In type 1 diabetic animals, increased protein expression of NADPH oxidase subunit p47phox implies the role of NADPH oxidase as a ROS-producing source [50, 62]. While the role of eNOS uncoupling in diabetic ED is not known, several studies in the diabetic penis [54, 63], and our unpublished studies (Musicki and Burnett, unpublished) indicate the role of eNOS uncoupling as another ROS source. Future studies are needed to establish the mechanism of NADPH upregulation and eNOS uncoupling in diabetes-associated ED.

Although the majority of diabetes related ED develops in men with type 2 diabetes [64], studies examining oxidative stress in animal models of type 2 diabetes are scant. One study demonstrated that type 2 diabetic rats and mice exhibit decreased antioxidant levels in the penis, indicating increased oxidative stress [65] .

Diabetes is associated with progressive deterioration of nitrergic neurons in the penis. In type 1 diabetic rats, an early reversible decrease in nNOS content of nitrer-gic penile nerves is followed in more advanced diabetes by apoptosis of nitrergic nerve cell bodies in the MPG. The latter has been attributed to increased oxidative stress [34, 35] .

These studies demonstrate that oxidative stress-mediated neural and vascular alterations play an integral role in diabetes-associated ED.

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