Pharmacological Research 52 (2005) 264–270 Protective effect of red grape seeds proanthocyanidins against induction of diabetes by alloxan in rats Abir T. El-Alfy ∗ , Amany A.E. Ahmed, Amal J. Fatani Pharmacology Department, Faculty of Pharmacy, King Saud University, Riyadh 11495, P.O. Box 22452, Saudi Arabia Accepted 6 April 2005 Abstract It has been documented that impaired homeostasis in diabetes mellitus is associated with increased production of reactive oxygen species and depletion of the antioxidant defense systems. Natural grape seed proanthocyanidins (GSP) are potent free radical scavengers and hence provide significant protection against oxidative stress. Accordingly, the present study focused on investigating the possible protective role of GSP against free radical-mediated damage in pancreatic tissues of alloxan-induced diabetes in rats. The results revealed that oral administration of 50 and 100 mg kg -1 (body weight) of GSP for 72 h significantly increased pancreatic glutathione (GSH) levels and inhibited the increase in lipid peroxidation caused by alloxan (p < 0.001). On the other hand, a significant reduction in pancreatic total nitrate/nitrite content (p < 0.001) was observed. Furthermore, GSP caused significant decline in the hyperglycemia induced by alloxan (p < 0.001). Such antihyperglycemic effect of GSP was accompanied by a significant increase in serum insulin levels in diabetic rats following 72 h of administration (p < 0.001). In conclusion, the study suggests that GSP are effective in ameliorating the damage to pancreatic tissue in experimental diabetes mellitus. Such effect may be related to their potent antioxidant properties as evidenced by the increase in pancreatic GSH and reduction of lipid peroxidation as well as total nitrate/nitrite levels. © 2005 Elsevier Ltd. All rights reserved. Keywords: Diabetes; Grape seeds proanthocyanidins (GSP); Glutathione; Lipid peroxidation; Nitric oxide; Oxidative stress 1. Introduction Diabetes is a chronic metabolic disorder that continues to present a major worldwide health problem. It is characterized by absolute or relative deficiencies in insulin secretion and/or insulin action associated with chronic hyperglycemia and dis- turbances of carbohydrate, lipid, and protein metabolism. As a consequence of the metabolic derangements in diabetes, various complications develop including both macro- and mi- crovascular dysfunctions [1]. New biochemical and molecu- lar advances have contributed to a more profound understand- ing of the pathogenesis of diabetes and its complications [2]. Recently, increased oxidative stress has been proven to play a pivotal role in the etiology and pathogenesis of diabetes mellitus and its complications [3]. ∗ Corresponding author. Tel.: +966 1 4771561x1624; fax: +966 1 4771107. E-mail address: aalfy2001@yahoo.com (A.T. El-Alfy). The role of oxidative stress in both type I and type II diabetes mellitus is currently under intensive scientific investigation [4–6]. It is believed that insulin-dependent diabetes mellitus (IDDM) results from the destruction of insulin-producing pancreatic -cells by multiple factors, in- cluding viruses, chemical toxins, and autoimmune responses [7–9]. The exact cellular mechanism of -cell destruction remains unclear. However, it has been established that locally produced reactive oxygen species (ROS) and nitric oxide (NO) induced after cytokine stimulation are involved [10,11]. Recent studies by Kaneto et al. [12] and Matsuoko et al. [13] have proven that ROS lead to damage of -cells through the induction of apoptosis and suppression of insulin biosynthesis. Similarly, the development of type II diabetes has been associated with pancreatic -cell dysfunction, and once hyperglycemia becomes apparent, -cell function progressively deteriorates [14]. Previous studies have shown that sustained hyper- glycemia, a characteristic of diabetes, increases intracellular 1043-6618/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2005.04.003