Abstract
Metabolic disorders are becoming more common in young population due to increased consumption of carbohydrate rich diet, lack of physical activity and stress. Fructose is used as a sweetener in many carbonated beverages and is a known inducer of oxidative stress and hypertension. Up-regulation of the double-stranded RNA-dependent protein kinase (PKR) causes impairment in insulin signaling pathway and metabolic dysfunctions in type 2 diabetes mellitus. In the present study we investigated the role of PKR and associated pathways in high fructose (HF) and streptozotocin (STZ) induced diabetes and whether indirubin-3-hydrazone (IHZ), a novel PKR inhibitor can reverse the HF and STZ induced diabetic impairments in Wistar rats. Diabetes was induced by feeding rats 20% high fructose in drinking water for 6 weeks and by giving a single dose of STZ (35 mg/kg., i.p) at the end of week 5. Glucose and lipid levels were measured by using assay kits. Expression of PKR and its downstream genes were determined by immunohistochemistry, qRT-PCR and western blotting techniques. Histo-pathological studies were performed using H&E staining. Fibrosis was detected in insulin sensitive tissues and organs using Sirius red and Masson’s trichrome staining and apoptosis by TUNEL assay. HF and STZ induced hyperglycemia, fibrosis, oxidative stress, and inflammation in liver, pancreas, skeletal muscle and adipose tissue are mediated via PKR pathway and its downstream effectors, and these effects were attenuated by PKR inhibitor IHZ. Thus, inhibition of PKR can protect insulin sensitive organs and tissues from HF induced diabetic impairments via the inhibition of c-Jun N-terminal kinase (JNK) pathway.
Highlights
Due to the specific metabolic fate and lipogenic property, fructose causes impairment in glucose metabolism, leading to insulin resistance, dyslipidemia and hepatic fibrosis, together with cardiac and renal dysfunctions[1,2,3]
Initially up to 35th day of the study showed no significant change in all the study groups, a significant decrease in body weight was observed in the high fructose (HF) + STZ group on the 42nd day when compared with the control group (p < 0.001) and a significant gain in the HF + STZ + IHZ group when compared with the HF + STZ group (p < 0.05) (Fig. 1a)
Fasting glucose levels (Fig. 1b) increased significantly on 35th (p < 0.001) and 42nd day (p < 0.001) in the HF + STZ treated group when compared with the control group, and were attenuated significantly in the HF + STZ + IHZ treated group when compared with the HF group (p < 0.001)
Summary
Due to the specific metabolic fate and lipogenic property, fructose causes impairment in glucose metabolism, leading to insulin resistance, dyslipidemia and hepatic fibrosis, together with cardiac and renal dysfunctions[1,2,3]. During the course of excess sugar intake, wide range of stress and inflammatory responses are activated in metabolic tissues, such as pancreas, adipose tissue, skeletal muscle, and liver causing activation of c-Jun N-terminal kinase (JNK) and inhibitory κB kinase (IKK) pathways[4,5,6]. These pathways are important contributors in the progression and development of insulin resistance and type 2 diabetes (T2D) via activation of inflammatory cascade, impairment in insulin signaling, and disturbance in systemic glucose homeostasis and lipid profile. Our results demonstrate the protective role of IHZ through restoration of functional alterations in pancreas, liver, skeletal muscle and adipose tissue in T2D rat model
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