The insulin-mimetic effect of Morin: A promising molecule in diabetes treatment

• Published in: Biochimica et biophysica acta Vol. 1830; no. 4; pp. 3102 - 3111
• Main Authors: Paoli, Paolo, Cirri, Paolo, Caselli, Anna, Ranaldi, Francesco, Bruschi, Giulia, Santi, Alice, Camici, Guido
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2013
• Subjects: Animals; Antidiabetic drugs; Apigenin - pharmacology; biochemical pathways; cell growth; Cell Proliferation - drug effects; Flavonoid; Flavonoids - pharmacology; gluconeogenesis; glucose; Glucose - biosynthesis; glycogen; Glycogen - biosynthesis; Hep G2 Cells; human cell lines; Humans; hypoglycemic agents; Hypoglycemic Agents - pharmacology; insulin; Insulin - metabolism; Insulin - pharmacology; insulin receptors; insulin resistance; lead; Mice; Morin; NIH 3T3 Cells; noninsulin-dependent diabetes mellitus; phosphorylation; polyphenols; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; PTP; PTP1B inhibitor; screening; signal transduction; Western blotting; Antidiabetic drugs; PTP1B inhibitor; Morin; Flavonoid; PTP
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2013.01.017

Type-2 diabetes is a worldwidely diffuse disease characterized by insulin resistance that arises from alterations of receptor and/or post-receptor events of insulin signalling. Studies performed with PTP1B-deficent mice demonstrated that PTP1B is the main negative regulator of insulin signalling. Inhibition or down regulation of this enzyme causes enhanced insulin sensitivity. Hence this enzyme represents the most attractive target for development of innovative anti-diabetic drugs. Selection of new PTP1B inhibitors among an in house library of polyphenolic compounds was carried out screening their activity. The inhibition mechanism of Morin was determined by kinetic analyses. The cellular action of Morin was assayed on HepG2 cells. Analyses of the insulin signalling pathways was carried out by Western blot methods, glycogen synthesis was estimated by measuring the incorporation of [3H]-glucose, gluconeogenesis rate was assayed by measuring the glucose release in the cell medium. Cell growth was estimated by cell count. Docking analysis was conducted with SwissDock program. We demonstrated that Morin: i) is a non-competitive inhibitor of PTP1B displaying a Ki in the μM range; ii) increases the phosphorylation of the insulin receptor and Akt; iii) inhibits gluconeogenesis and enhances glycogen synthesis. Morin does not enhance cell growth. We have identified Morin as a new small molecular non-competitive inhibitor of PTP1B, which behaves as an activator and sensitizer of the insulin receptor stimulating the metabolic pathways only. Our study suggests that Morin is a useful lead for development of new low Mr compounds potentially active as antidiabetic drugs. ► Morin acts as a competitive inhibitor of PTP1B, displaying Ki in the low micromolar range. ► Morin activates the insulin receptor in HepG2 cells. ► Morin enhances glycogen synthesis and inhibits gluconeogenesis. ► Morin increases insulin sensitivity. ► Morin possesses potential antidiabetic activity.