Abstract
Diabetic vascular complications are the most common cause of mortality and morbidity worldwide, with numbers of affected individuals steadily increasing. Diabetic vascular complications can be divided into two categories: macrovascular andmicrovascular complications. Macrovascular complications include coronary artery diseaseand cerebrovascular disease, while microvascular complications include retinopathy and chronic kidney disease. These complications result from metabolic abnormalities, including hyperglycemia, elevated levels of free fatty acids, and insulin resistance. Multiple mechanisms have been proposed to mediate the adverse effects of these metabolic disorders on vascular tissues, including stimulation of protein kinase C signaling and activation of the polyol pathway by oxidative stress and inflammation. Additionally, the loss of tissue-specific insulin signaling induced by hyperglycemia and toxic metabolites can induce cellular dysfunction and both macro- and microvascular complications characteristic of diabetes. Despite these insights, few therapeutic methods are available for the management of diabetic complications. Recently, incretin-based therapeutic agents, such as glucagon-like peptide-1 and dipeptidyl peptidase-4 inhibitors, have been reported to elicit vasotropic actions, suggesting a potential for effecting an actual reduction in diabetic vascular complications. The present review will summarize the relationship between multiple adverse biological mechanisms in diabetes and putative incretin-based therapeutic interventions intended to prevent diabetic vascular complications.
Highlights
The number of patients suffering from diabetes worldwide is rapidly increasing
The Diabetes Control and Complications Trial (DCCT) performed in type 1 diabetic patients and United Kingdom Prospective Diabetes Study (UKPDS) in type 2 diabetic patients clearly showed that intensive glycemic control could delay the onset of diabetes and retard the occurrence of diabetic complications [1, 2]
Despite the favorable results observed in animal studies, in the Heart Outcomes Prevention Evaluation (HOPE) study evaluating a large cohort of patients with diabetes, administration of vitamin E did not reduce the risk of cardiovascular complications [30]
Summary
The number of patients suffering from diabetes worldwide is rapidly increasing. A recent report prepared by the international diabetes foundation (IDF) estimates the global number of patients with diabetes to have risen to 380 million, with the total number of patients predicted to reach 590 million by 2035. Other studies have demonstrated the effectiveness of vitamin E administration in normalizing oxidative stress markers and decreasing PKC-induced diabetic vascular complications. Despite the favorable results observed in animal studies, in the Heart Outcomes Prevention Evaluation (HOPE) study evaluating a large cohort of patients with diabetes, administration of vitamin E did not reduce the risk of cardiovascular complications [30]. Bardoxolone methyl, a new antioxidant drug, interacts with the cysteine residues on Keap to cause the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus, increasing its anti-inflammatory effects [33,34,35] This drug was expected to ameliorate diabetic nephropathy on the basis of beneficial effects observed in recent placebo-controlled clinical trials [36, 37]. The effectiveness of antioxidant therapies in management of diabetes remains unknown
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