High fructose and streptozotocin induced diabetic impairments are mitigated by Indirubin-3-hydrazone via downregulation of PKR pathway in Wistar rats

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.

The Aqueous Extract of Sclerocarya birrea, Nauclea latifolia, and Piper longum Mixture Protects Striatal Neurons and Movement‐Associated Functionalities in a Rat Model of Diabetes‐Induced Locomotion Dysfunction

“…Fructose (10%) ingestion for 6 weeks followed by streptozotocin administration (35 mg/kg) resulted in high blood glucose levels which altered locomotor function and increased oxidative and nitrative stress and inflammation in the striatum. A combination of fructose (10%) and low-dose STZ (35 mg/kg) is a well-known alternative model to induce major pathogeneses of T2D, insulin resistance, and partial pancreatic β -cell dysfunction in rats [ 34 , 35 ]. This model more closely resembles the later stages of T2D and has demonstrated a stable diabetic condition over an 11-week experimental period useful for chronic research studies as well as for routine pharmacological screening [ 35 , 36 ].…”

Development of Syringaldehyde as an Agonist of the GLP-1 Receptor to Alleviate Diabetic Disorders in Animal Models

“…Moreover, intraperitoneal injections of STZ, at low doses (35 mg/kg), were repeated every Monday for 6 weeks. Fructose (20%) in drinking water [ 61 ], combined with an HFD containing 34.9% (wt/wt) of fat (58Y1; Test Diet, Richmond, IN, USA), was applied to replace the rats’ regular diet (Rodent Laboratory Chow 5001, Purina, St. Louis, MO, USA). Tolbutamide (10 mg/kg, i.p.…”

Interplay between Senescence and Macrophages in Diabetic Cardiomyopathy: A Review of the Potential Role of GDF-15 and Klotho

“…Elevated glucose levels lead to the release of pro-inflammatory cytokines (interleukin (IL)-6, IL-18, pro-IL-1ß, and tumor necrosis factoralpha (TNF-α) [25,33,34]. Recent studies have shown that the STZ-induced T2DM animal model exhibits fibrosis and tissue damage, features of chronic inflammation [32,35]. Moreover, both in vitro and animal research have revealed that elevated blood glucose levels are a substantial factor in diabetes-induced myocardial fibrosis.…”