Antidiabetic effects of quercetin and liraglutide combination through modulation of TXNIP/IRS-1/PI3K pathway

The study was designed to assess the possible augmented antidiabetic effects of combining quercetin and liraglutide in a type 1 diabetes model, with emphasis on the contribution of hepatic thioredoxin interacting protein (TXNIP)/insulin receptor substrate 1 (IRS-1)/phosphatidyl inositol-3 kinase (PI3K) pathway. The wound-healing effects were also examined. Diabetes was induced by a single i.p STZ injection (55 mg/kg). Diabetic rats were treated with either quercetin (100 mg/kg/day, orally) or liraglutide (0.3 mg/kg/twice daily, S.C.) or their combination. Drugs were also applied topically on the wound. Blood glucose levels, serum albumin, total protein, total cholesterol and triglycerides were measured. Histopathological examination of the liver, pancreas and skin tissues was performed using haematoxylin and eosin staining. The hepatic malondialdehyde level was measured spectrophotometrically. Hepatic TXNIP and PI3K levels were measured by enzyme-linked immunsorbent assay (ELISA). Tissue expression of IRS-1 and phospho-IRS-1 (Ser 616) was assessed by immunohistochemistry. Quercetin, liraglutide and their combination effectively decreased blood glucose levels, improved lipid profile, upregulated albumin and total protein serum levels and reduced hepatic oxidative stress with the combination being most effective. Moreover, the combination group showed enhanced wound-healing effects and almost normalized hepatic and pancreatic histopathology. Quercetin and/or liraglutide significantly decreased TXNIP levels and serine phosphorylation of IRS-1 and increased PI3K levels compared to the diabetic untreated group. Interestingly, only the combination therapy normalized hepatic IRS-1 expression. The combination of quercetin and liraglutide showed enhanced antidiabetic effects, possibly through lowering hepatic TXNIP levels, with the resultant up-regulation of the IRS-1/PI3K pathway.