A New Road for Treating the Vascular Complications of Diabetes: So Let's Step on the Gas.

The authors van den Born et al. (1) have written a timely Perspective in this issue of Diabetes. Both type 1 and type 2 diabetes have reached epidemic proportions throughout the world, afflicting over 400 million people. Moreover, the number of individuals that will develop diabetes is predicted to rise (2). Both individuals with type 1 and type 2 diabetes are at a significantly greater risk for developing microvascular and macrovascular diseases. People with diabetes who cannot maintain adequate glycemic control (such as the failure to reach the recommended target level of HbA1c ,7%) are predisposed to develop neuropathy, retinopathy, nephropathy, cardiovascular disease, cerebrovascular disease, and premature death. In response to the enormity of this medical problem, there have been major initiatives on the part of global health organizations, national diabetes associations, and primary caregivers to educate patients about the benefits of appropriate nutrition and physical activity. For individuals with diabetes who have insufficient appropriate nutrition and physical activity, an increasing number of oral and injectable interventions are available to improve glycemic control (3,4). For many patients, however, the current forms of therapy now used for treating both types of diabetes are inadequate. Thus, there clearly remains a large area of unmet therapeutic need for novel pharmacological interventions that target the major complications of diabetes. Such therapies need to be identified and developed with greater efficiency by exploiting innovative molecular targets. In the current Perspective, van den Born et al. (1) present interesting data suggesting that the modulation of one or more of the three major gasotransmitters (nitric oxide [NO], carbon monoxide [CO], and hydrogen sulfide [H2S]) could eventually offer a novel therapeutic option(s) targeting the vascular complications of diabetes, as there is evidence to suggest that there is a reduced bioavailability of these gasotransmitters in people with diabetes. In addition to other risk factors (hypertension, tobacco use, and obesity), chronic hyperglycemia can be regarded as a root cause of the vascular complications of diabetes (5,6). The basis for this assertion is that diabetes complications occur with a significantly greater frequency in hyperglycemic individuals with diabetes when compared with those with controlled diabetes. Elevated blood glucose levels cause oxidative stress due to increased production of mitochondrial reactive oxygen species (ROS), nonenzymatic glycation of proteins, and glucose autoxidation (6,7). Oxidative stress resulting from either the increased production or inadequate removal of ROS plays a key role in the pathogenesis of vascular diabetes complications (5,7). The pathogenesis of vascular damage is multifactorial but is clearly mediated by increased concentration of ROS (8). In addition, increased concentrations of reactive nitrogen species and other inflammatory molecules (whose expression is increased by hyperglycemia and ROS) cause vascular damage (1,9). Vascular function is also dependent on NO, CO, and H2S. Included in their myriad physiological functions (1) is vasodilatory activity. Furthermore, each gasotransmitter can reduce oxidative stress through direct interaction with ROS (1). In addition, these gasotransmitters are able to upregulate the endogenous antioxidant system via activation of nuclear factor (erythroid-derived 2)–like 2 (Nrf2) (10–12). Nrf2 is a basic leucine zipper transcription factor that controls the expression of a large number of genes including heme oxygenase-1 (HO-1), an enzyme that produces CO; antioxidant enzymes; and glutathione-related enzymes (13). Overall, Nrf2 activation is linked to reductions in both oxidative stress and inflammation (local and systemic) and has been proposed as a therapeutic approach for diabetic nephropathy (14). Depleted or even reduced levels of NO, CO, or H2S are associated with impaired vascular function. NO is reduced in conditions of endothelial dysfunction,