Abstract Background 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. Methods 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. Results 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. Conclusions 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. General significance Our study suggests that Morin is a useful lead for development of new low Mr compounds potentially active as antidiabetic drugs.

The insulin-mimetic effect of Morin: A promising molecule in diabetes treatment / Paolo Paoli; Paolo Cirri; Anna Caselli; Francesco Ranaldi; Giulia Bruschi; Alice Santi; Guido Camici. - In: BIOCHIMICA ET BIOPHYSICA ACTA. - ISSN 0006-3002. - ELETTRONICO. - 1830:(2013), pp. 3102-3111. [10.1016/j.bbagen.2013.01.017]

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

PAOLI, PAOLO;CIRRI, PAOLO;CASELLI, ANNA;RANALDI, FRANCESCO;BRUSCHI, GIULIA;SANTI, ALICE;CAMICI, GUIDO
2013

Abstract

Abstract Background 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. Methods 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. Results 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. Conclusions 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. General significance Our study suggests that Morin is a useful lead for development of new low Mr compounds potentially active as antidiabetic drugs.
2013
1830
3102
3111
Paolo Paoli; Paolo Cirri; Anna Caselli; Francesco Ranaldi; Giulia Bruschi; Alice Santi; Guido Camici
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/804294
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