Over the past decade, there has been increasing scientific and public interest in the so-called antioxidant hypothesis. In general, the reducing environment inside cells helps to prevent oxidative damage. This reducing environment is maintained by oxidative metabolism and by the action of antioxidant enzymes and substances, such as glutathione, vitamins E and C, enzymes such as superoxide dismutase (SOD), catalase etc, which serve to remove the ROS. Current hypothesis favor the idea that lowering oxidative stress can have a clinical benefit. Reports about the status of antioxidants and scavengers as defense mechanisms in diabetic patients are very contradictory. Both increase and decrease antioxidant activity are reported. Studies evaluating the various serum circulating antioxidants in diabetes are still conflicting. It is not known whether oral treatment with antioxidants can reduce oxidative stress in patients with type2 diabetes.

           The present study was undertaken to assess the status of lipid peroxidation and to evaluate various antioxidants (Melatonin, Silymarin and a-Lipoic acid) in experimental diabetes mellitus. It appears from the observations of the UKPDS that monotherapy with any oral agent either fails at the outset or will fail overtime. It is often necessary to use multiple drugs for an optimal outcome. We have studied the effects of various antioxidants alone and in combination with gliclazide. Gliclazide was used as a reference drug because it has both insulin releasing and antioxidant property.

          Melatonin is mainly used in sleep disorders and jet lags. Frequently melatonin is prescribed for NIDDM patients along with oral antidiabetic drugs. However, the possible outcome of this combination therapy is not reported in the literature. Silymarin is a flavonoid extracted from the milk thistle of Silybum marianum. It is a free radical scavenger and a membrane stabilizer, which prevents LPO and its associated cell damage in some experimental model. Similarly, this concept is further examined in an experimental model of diabetes mellitus, using thioctic acid (a-Lipoic acid) for protection. Potential mechanisms for antioxidant intervention are explored in the above studies.

          The ultimate goal of the study was to illustrate the therapeutic potential of antioxidants for treatment of the diabetes mellitus.

          The diabetic state, in both humans and experimental animals, is associated with oxidative stress. Diabetes and its complications present a serious medical and socioeconomic problem. The management of diabetes has changed significantly during the past half century. The current strategy to combat diabetes focuses on increasingly stringent control of hyperglycemia to prevent or modify the onset and progression of the disease and its complications. Because of the therapeutic limitations of hypoglycemic therapy in practice, further interventional strategies must be developed. In addition to elevated blood glucose levels, increased production of reactive oxygen species (free radicals), which are known to exhibit direct tissue damaging properties, may contribute to a number of diabetic complications and to the development of insulin resistance itself. These deleterious species can be neutralized by endogenous and exogenous antioxidant substances such as vitamins A, E, C, flavonoids (Silymarin), polyphenols, carotenoids, alpha lipoic acid and other nutrients present in food and beverages.

          Increased oxidative stress in diabetic patients appears to be related to the underlying metabolic abnormalities, and is also an early stage in the disease pathology that may contribute to the development of complications. Therefore, in addition to control of blood sugar, control of oxidative stress offers another avenue for the treatment of the disease. The present research work summarizes the current knowledge of the pathogenic role of oxidative stress in the onset and progression of diabetes and its complications and presents the results of studies aimed at modulating oxidative stress through the use of anti oxidants in experimental diabetes.

         The main finding of the study on Silymarin was that it prevented a rise in both blood glucose and pancreatic lipid peroxidation (LPO), induced by STZ in rats.

         Furthermore, in extension of this work, silymarin showed a dose dependent protective effect on STZ induced diabetic dyslipidemia. Silymarin improved the lipid profile (by decreasing the levels of serum triglycerides, total cholesterol, LDL and VLDL and increasing HDL cholesterol) and restored the liver glycogen content in STZ diabetic rats.

         The effect of B-20 drops, a homoeopathic formulation, on lipid peroxidation, liver glycogen content and microscopic structure of pancreas and liver in STZ diabetes was studied. The study demonstrates the dose-dependent reduction in blood glucose levels and TBARS levels in the pancreas of STZ diabetic rats.

         The effect of simultaneous treatment with gliclazide and melatonin in n-STZ diabetic rats was evaluated. Gliclazide alone and also in combination with melatonin were administered to NIDDM rats. The influence of the above treatment on LPO and glucose levels was evaluated.

         The modulatory effect a-LA, a naturally occurring compound and a radical scavenger was studied in vivo in STZ induced oxidative stress and hyperglycemia.

         Based on the observations made from these studies, it is concluded that, oxidative stress, antioxidants and the antioxidant network can be relevant to diabetes because diabetes appears to involve oxidative stress. The relevance of oxidative stress mediated mechanism, in this context, may be more appropriate. Antioxidants, vitamins, drugs or diet rich in natural antioxidants would enhance the longevity of life by increasing the threshold, sparing co-enzymes for detoxification pathways during early stages of diabetes, delaying the onset of diabetic complications and may be useful as supportive therapy at later stages of the disease.