Abstract:
Diabetes Mellitus (DM) is an endocrine disorder characterized by the decreased effectiveness of the body to control blood glucose level due to increased resistance of peripheral cells towards insulin action and pancreatic beta cell failure. Agomelatine is a structural analog of melatonin and prescribed for the therapeutic management of depression and anxiety. Studies have shown streptozotocin-induced mice did not develop hyperglycaemia and hyperinsulinemia when subjected to treatment with agomelatine. The objective was to determine the association of melatonin receptors and insulin signalling pathway/insulin secretion by agomelatine using rat insulinoma cell line (INS-1E). Agomelatine was tested for its cytotoxic effect using MTT assay followed by glucose stimulated insulin secretion (GSIS) assay and Western Blot analysis. Based on the MTT assay, 0.5 μM and 1.0 μM of agomelatine were found to be non-toxic which was further tested in GSIS. The GSIS assay detected agomelatine increased the insulin secretion in glucotoxic conditions and blocking MT2 receptors with a selective antagonist, 4P-PDOT significantly (P<0.01) reduced insulin secretion in cells treated with agomelatine (0.5 μM and 1.0 μM) whereas, non-selective blocker, Luzindole did not completely block the insulin secretion of agomelatine although a minor reduction was observed. PDX-1 protein which is mostly responsible for pancreatic cell development, beta-cell maturation and insulin secretion was analysed in INS-1E cell by Western blot technique. PDX-1 expression was decreased in high glucose condition. Agomelatine treatment showed slight change in PDX-1 expression and a striking difference among the groups were not observed due to few numbers of replicates used. However, the GSIS has demonstrated a significant role of MT2 receptors in insulin secretion that is induced by agomelatine. The insulin secretion stimulated by MT2 receptors could be possibly through PDX-1 or insulin signalling.
In conclusion, agomelatine does confer anti-diabetic effect and it is regulated by the MT2 receptors that provide insulin secretion function
