In the context of high human consumption of fructose diets, there is an imperative need to understand how dietary fructose intake influence cellular and molecular mechanisms and thereby affect β-cell dysfunction and insulin resistance. While evidence exists for a relationship between high-fat-induced insulin resistance and metabolic disorders, there is lack of studies in relation to high-fructose diet. Therefore, we attempted to study the effect of different diets viz., high-fat diet (HFD), high-fructose diet (HFS), and a combination (HFS + HFD) diet on glucose homeostasis and insulin sensitivity in male Wistar rats compared to control animals fed with normal pellet diet. Investigations include oral glucose tolerance test, insulin tolerance test, histopathology by H&E and Masson's trichrome staining, mRNA expression by real-time PCR, protein expression by Western blot, and caspase-3 activity by colorimetry. Rats subjected to high-fat/fructose diets became glucose intolerant, insulin-resistant, and dyslipidemic. Compared to control animals, rats subjected to different combination of fat/fructose diets showed increased mRNA and protein expression of a battery of ER stress markers both in pancreas and liver. Transcription factors of β-cell function (INSIG1, SREBP1c and PDX1) as well as hepatic gluconeogenesis (FOXO1 and PEPCK) were adversely affected in diet-induced insulin-resistant rats. The convergence of chronic ER stress towards apoptosis in pancreas/liver was also indicated by increased levels of CHOP mRNA & increased activity of both JNK and Caspase-3 in rats subjected to high-fat/fructose diets. Our study exposes the experimental support in that high-fructose diet is equally detrimental in causing metabolic disorders.
Gallic acid is claimed to possess antioxidant, antiinflammatory and cytoprotective effects. Since pancreatic islets from Type 2 diabetic patients have functional defects, it was hypothesized that glucolipotoxicity might induce apoptosis in beta-cells and gallic acid could offer protection. To test this, RINm5F beta-cells were exposed to high glucose (25 microM) or palmitate (500 microM) or a combination of both for 24 h in the presence and absence of gallic acid. Cells subjected to glucolipotoxicity in the absence and presence of gallic acid were assessed for DNA damage by comet assay. Apoptosis was inferred by caspase-3 protein expression and caspase-3 activity and changes in Bcl-2 mRNA. RT-PCR was used to analyse PDX-1, insulin and UCP-2 mRNA expression in RINm5F beta-cells and insulin levels were quantified from the cell culture supernatant. NFkappaB signal was studied by EMSA, immunofluorescence and Western blot analysis. While RINm5F beta-cells subjected to glucolipotoxicity exhibited increased DNA damage, apoptotic markers and NFkappaB signals, all these apoptotic perturbations were resisted by gallic acid. Gallic acid dose-dependently increased insulin secretion in RINm5F beta-cells and upregulated mRNA of PDX-1 and insulin. It is suggested that the insulin-secretagogue and transcriptional regulatory action of gallic acid is a newly identified mechanism in our study.
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