British Journal of Nutrition

Metabolism and Metabolic Studies

Up-regulation of PPARγ, heat shock protein-27 and -72 by naringin attenuates insulin resistance, β-cell dysfunction, hepatic steatosis and kidney damage in a rat model of type 2 diabetes

Ashok Kumar Sharmaa1, Saurabh Bhartia1, Shreesh Ojhaa1, Jagriti Bhatiaa1, Narender Kumara2, Ruma Raya2, Santosh Kumaria3 and Dharamvir Singh Aryaa1 c1

a1 Department of Pharmacology, Cardiovascular and Diabetes Research Laboratory, All India Institute of Medical Sciences, New Delhi 110029, India

a2 Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India

a3 Department of Plant Physiology, Indian Agricultural Research Institute, Pusa, New Delhi 110012, India

Abstract

Naringin, a bioflavonoid isolated from grapefruit, is well known to possess lipid-lowering and insulin-like properties. Therefore, we assessed whether naringin treatment ameliorates insulin resistance (IR), β-cell dysfunction, hepatic steatosis and kidney damage in high-fat diet (HFD)–streptozotocin (STZ)-induced type 2 diabetic rats. Wistar albino male rats were fed a HFD (55 % energy from fat and 2 % cholesterol) to develop IR and on the 10th day injected with a low dose of streptozotocin (40 mg/kg, intraperitoneal (ip)) to induce type 2 diabetes. After confirmation of hyperglycaemia (>13·89 mmol/l) on the 14th day, different doses of naringin (25, 50 and 100 mg/kg per d) and rosiglitazone (5 mg/kg per d) were administered orally for the next 28 d while being maintained on the HFD. Naringin significantly decreased IR, hyperinsulinaemia, hyperglycaemia, dyslipidaemia, TNF-α, IL-6, C-reactive protein and concomitantly increased adiponectin and β-cell function in a dose-dependent manner. Increased thiobarbituric acid-reactive substances and decreased antioxidant enzyme activities in the serum and tissues of diabetic rats were also normalised. Moreover, naringin robustly increased PPARγ expression in liver and kidney; phosphorylated tyrosine insulin receptor substrate 1 in liver; and stress proteins heat shock protein (HSP)-27 and HSP-72 in pancreas, liver and kidney. In contrast, NF-κB expression in these tissues along with sterol regulatory element binding protein-1c and liver X receptor- expressions in liver were significantly diminished. In addition, microscopic observations validated that naringin effectively rescues β-cells, hepatocytes and kidney from HFD-STZ-mediated oxidative damage and pathological alterations. Thus, this seminal study provides cogent evidence that naringin ameliorates IR, dyslipidaemia, β-cell dysfunction, hepatic steatosis and kidney damage in type 2 diabetic rats by partly regulating oxidative stress, inflammation and dysregulated adipocytokines production through up-regulation of PPARγ, HSP-27 and HSP-72.

(Received February 02 2011)

(Revised March 15 2011)

(Accepted March 15 2011)

(Online publication June 21 2011)

Correspondence:

c1 Corresponding author: D. S. Arya, fax +91 11 26584121, email dsarya16@hotmail.com

Footnotes

Abbreviations: CRP, C-reactive protein; ER, endoplasmic reticulum; GSH+Px, glutathione peroxidase; HFD, high-fat diet; HOMA, homoeostasis model assessment; HSP, heat shock protein; ip, intraperitoneal; IR, insulin resistance; IRS1, insulin receptor substrate 1; LXRα, liver X receptor-α; P-IRS1, phosphorylated tyrosine 612 IRS1; SOD, superoxide dismutase; SREBP-1c, sterol regulatory element binding protein-1c; STZ, streptozotocin; T2DM, type 2 diabetes mellitus; TBARS, thiobarbituric acid-reactive substances; TC, total cholesterol

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