Beneficial effects of antioxidants in diabetes: possible protection of pancreatic beta-cells against glucose toxicity.

Abstract

Oxidative stress is produced under diabetic conditions and possibly causes various forms of tissue damage in patients with diabetes. The aim of this study was to examine the involvement of oxidative stress in the progression of pancreatic beta-cell dysfunction in type 2 diabetes and to evaluate the potential usefulness of antioxidants in the treatment of type 2 diabetes. We used diabetic C57BL/KsJ-db/db mice, in whom antioxidant treatment (N-acetyl-L-cysteine [NAC], vitamins C plus E, or both) was started at 6 weeks of age; its effects were evaluated at 10 and 16 weeks of age. According to an intraperitoneal glucose tolerance test, the treatment with NAC retained glucose-stimulated insulin secretion and moderately decreased blood glucose levels. Vitamins C and E were not effective when used alone but slightly effective when used in combination with NAC. No effect on insulin secretion was observed when the same set of antioxidants was given to nondiabetic control mice. Histologic analyses of the pancreases revealed that the beta-cell mass was significantly larger in the diabetic mice treated with the antioxidants than in the untreated mice. As a possible cause, the antioxidant treatment suppressed apoptosis in beta-cells without changing the rate of beta-cell proliferation, supporting the hypothesis that in chronic hyperglycemia, apoptosis induced by oxidative stress causes reduction of beta-cell mass. The antioxidant treatment also preserved the amounts of insulin content and insulin mRNA, making the extent of insulin degranulation less evident. Furthermore, expression of pancreatic and duodenal homeobox factor-1 (PDX-1), a beta-cell-specific transcription factor, was more clearly visible in the nuclei of islet cells after the antioxidant treatment. In conclusion, our observations indicate that antioxidant treatment can exert beneficial effects in diabetes, with preservation of in vivo beta-cell function. This finding suggests a potential usefulness of antioxidants for treating diabetes and provides further support for the implication of oxidative stress in beta-cell dysfunction in diabetes.

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

“…Because in previous research only post-transcriptional regulation of Pdx1 expression and function by ROS or antioxidant has been suggested [6,20,23,25], our finding on the hyperacetylation of H3 and H4 histone at the proximal promoter of Pdx1 in the OE mice reveals not only a novel, in vivo epigenetic, but also a potential transcriptional regulation for this key factor by antioxidant enzymes. Preceding transcriptional activation [43], hyperacetylation of H3 and H4 helps remodel the chromatin at Pdx1 promoter to form a more accessible structure for transcription [44].…”

“…Along with a modest decrease (24%) in pancreatic PDX1 phosphorylation (degradation) [25], the upregulation of Pdx1 gene expression enabled the OE mice to maintain a higher level of functional PDX1 protein than the WT mice to promote beta cell differentiation and insulin synthesis. While similar positive effects on PDX1 protein were produced by three dietary antioxidant supplements in C57BL/KsJ-db/db mice [23], overproduction of catalase in beta cells accelerated cytokine-induced PDX1 protein disappearance [9]. It is intriguing to see such different impacts on PDX1 protein by GPX1 and catalase, given the so similar catalytic functions.…”

“…Uncoupling protein 2 (UCP2) serves as a negative regulator of mitochondrial membrane potential (Δ= m ) [18], which positively correlates with glucosestimulated insulin secretion (GSIS) [19]. Levels and function of PDX1 and UCP2 are affected by intracellular ROS status [20,21], glucotoxicity [22] and antioxidants [6,23,24]. However, it is not known whether in vivo global overexpression of Gpx1 could overly diminish intracellular production of hydroperoxides and subsequently dysregulate production of PDX1 and UCP2 and their role in insulin synthesis and secretion.…”

“…Although post-transcriptional regulation of PDX1 by ROS or antioxidants has been postulated [20,[23][24][25], new mechanisms such as epigenetic modification [26] of Pdx1 have not been studied. The proximal region of Pdx1 promoter consists of an islet-specific expression consensus E-box motif, which predominantly binds the upstream transcription factor [27].…”

Exendin-4 protects mice from D-galactose-induced hepatic and pancreatic dysfunction

“…The fact that exendin-4 treatment was able to attenuate D-galactose-induced reduction of insulin secretion suggests that exendin-4 can alter oxidant signaling. The observations by Kaneto et al [25] showed that catalase and SOD can protect ß-cells against ROS-induced damage. Also, antioxidant treatment can suppress apoptosis of ß-cells and preserve ß-cell function in diabetic mice.…”