The role of antioxidants in the prevention of diabetic complications

Posted on April 14, 2010

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The role of antioxidants in the prevention of diabetic complications

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK),

the National Eye Institute (NEI), the National Heart, Lung and Blood

Institute (NHLBI), the National Institute on Aging (NIA), the National

Institute of Neurological Disorders and Stroke (NINDS) and the Office of

Dietary Supplements (ODS) seek basic and clinical research applications to

study the use of vitamin E and other antioxidants in the prevention or

amelioration of diabetic complications.

Prevention and treatment of long-term micro- and macrovascular complications

remain critical problems in the management of type 1 or type 2 diabetes

mellitus. A growing body of in vitro and in vivo research indicates that

hyperglycemia leads to increased oxidative stress and endothelial

dysfunction. In addition, numerous studies have suggested that patients with

diabetes appear to have decreased antioxidant defense capability, measured as

lower levels of specific antioxidants, such as ascorbic acid (vitamin C) or

vitamin E, or reduced activities of antioxidant enzymes, such as catalase,

superoxide dismutase or glutathione peroxidase.

This Program Announcement solicits applications to 1) determine the efficacy

of vitamin E or other antioxidants in preventing, delaying or ameliorating

the micro- or macrovascular complications of diabetes, and 2) provide insight

into the mechanism(s) by which antioxidants might prevent or influence the

development of diabetic vascular disease.

Prevention and treatment of long-term micro- and macrovascular complications

remain a critical problem in the management of type 1 or type 2 diabetes

mellitus. In the United States, diabetes is the leading cause of new

blindness in working-age adults, of new cases of end stage renal disease and

of non-traumatic lower leg amputations. In addition, cardiovascular

complications are now the leading cause of diabetes-related morbidity and

mortality, particularly among women and the elderly.  In adult patients with

diabetes, the risk of cardiovascular disease (CVD) is three to five fold

greater than in the general population.

A growing body of in vitro and in vivo research indicates that hyperglycemia

leads to increased oxidative stress and endothelial dysfunction. Evidence of

oxidative damage has been demonstrated in arterial samples obtained from

animal models of experimental diabetes and from human diabetic subjects.  It

has been recognized that oxidation of glucose can generate oxygen free

radicals and excess reactive oxygen species such as superoxides. These

molecules can promote lipid peroxidation, leading to excessive oxidative

burden in patients with diabetes.  Oxidative stress can also influence the

expression of multiple genes in vascular cells, including signaling molecules

such as PKC, NFkB and ERK; overexpression of these genes may lead to

endothelial dysfunction and, ultimately, to micro- and macrovascular disease.

Molecules in the arterial wall can also be modified by glycation, which

usually is associated with oxidation. The formation of advanced glycation

end-products (AGEs) can occur on proteins, lipids and nucleic acids.  AGEs

can lead to increased production of oxygen free radicals and may, therefore,

play a role in the development of microvascular disease and atheroscerosis

Numerous studies have also suggested that patients with diabetes appear to

have decreased antioxidant defense capability, measured as lower levels of

specific antioxidants, such as ascorbic acid (vitamin C) or vitamin E, or

reduced activities of antioxidant enzymes, such as catalase, superoxide

dismutase or glutathione peroxidase.

In diabetic animals, many, but not all, studies support the use of

antioxidant supplementation in reducing various parameters of oxidative

stress and in slowing or preventing the development of microvascular

complications. Studies in humans have also been promising. Recently,

particular interest has focused on the use of vitamin E for the prevention of

microvascular complications. Several studies of vitamin E supplementation in

diabetic individuals have demonstrated a decrease in biochemical markers of

oxidative stress. One small, short-term study of vitamin E supplementation in

patients with diabetes showed improvement in some surrogate markers for

retinopathy and nephropathy.

A limiting feature of the published studies is that the preparation and dose

of vitamin E used has been widely variable. In addition, little data is

available regarding potential toxicity of high doses of vitamin E, nor is

there data on potential interactions of vitamin E with other nutrients or

other antioxidants. Furthermore, interest in mounting a large clinical trial

to study the efficacy of vitamin E in preventing diabetic vascular disease

has been tempered by the recent negative results of several large,

randomized, prospective trials of vitamin E in the prevention of

cardiovascular disease and cancer. These large trials were undertaken based

on the results of animal studies and a wealth of epidemiologic data

suggesting that increased antioxidant consumption is associated with

protection from cancer and atherosclerosis. The reason for the discrepancy

between the epidemiologic and intervention data is not clear.

http://grants.nih.gov/

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