RA abrogates hepatic gluconeogenesis and insulin resistance by enhancing IRS-1 and AMPK signalling in experimental type 2 diabetes

Abstract

Hyperglycemia and insulin resistance are the primary features of type 2 diabetes (T2DM). Rosmarinic acid (RA), a dietary polyphenol that is found in culinary herbs like rosemary, mint, and basil, is reported to have a beneficial effect against diabetes. However, the mechanism of its action remains obscure. Oral administration of RA (100 mg kg⁻¹ b.w.) for a period of 30 days restored the levels of blood glucose and regulated the levels of circulating adipokines in the diabetic rats, portraying its insulin sensitising potency. The efficacy of RA in attenuating diabetic pathology is evident from the normal hepatic parenchymal structures in the livers of diabetic rats, which was demonstrated by histological and ultrastructural observations. Treatment with RA also decreased the expression of key gluconeogenic and lipogenic enzymes in the liver of diabetic rats and in insulin resistant HepG2 cells, which was found to be mediated via an AMPK cascade. RA treatment stimulates glucose uptake by enhancing GLUT-2 translocation and by inhibiting the serine phosphorylation of IRS-1 in the liver and insulin resistant HepG2 cells. These findings suggest that RA improves insulin sensitising effects in diabetic livers and in insulin resistant HepG2 cells, thereby preventing potential hepatic dysfunction by attenuating gluconeogenesis, blockading insulin signalling, and modulating glucose uptake via the AMPK pathway.