title: Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model.
abstract: Sirtuin 6 (SIRT6) is a sirtuin family member involved in a wide range of physiologic and disease processes, including cancer and glucose homeostasis. Based on the roles played by SIRT6 in different organs, including its ability to repress the expression of glucose transporters and glycolytic enzymes, inhibiting SIRT6 has been proposed as an approach for treating type 2 diabetes mellitus (T2DM). However, so far, the lack of small-molecule Sirt6 inhibitors has hampered the conduct ofin vivostudies to assess the viability of this strategy. We took advantage of a recently identified SIRT6 inhibitor, compound 1, to study the effect of pharmacological Sirt6 inhibition in a mouse model of T2DM (i.e.,in high-fat-diet-fed animals). The administration of the Sirt6 inhibitor for 10 d was well tolerated and improved oral glucose tolerance, it increased the expression of the glucose transporters GLUT1 and -4 in the muscle and enhanced the activity of the glycolytic pathway. Sirt6 inhibition also resulted in reduced insulin, triglycerides, and cholesterol levels in plasma. This study represents the firstin vivostudy of a SIRT6 inhibitor and provides the proof-of-concept that targeting SIRT6 may be a viable strategy for improving glycemic control in T2DM.-Sociali, G., Magnone, M., Ravera, S., Damonte, P., Vigliarolo, T., Von Holtey, M., Vellone, V. G., Millo, E., Caffa, I., Cea, M., Parenti, M. D., Del Rio, A., Murone, M., Mostoslavsky, R., Grozio, A., Nencioni, A., Bruzzone S. Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model.
authors.affiliation: Section of Biochemistry, Department of Experimental Medicine, Center of Excellence for Biomedical Research (CEBR), University of Genova, Genoa, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Sociali
authors.affiliation: Section of Biochemistry, Department of Experimental Medicine, Center of Excellence for Biomedical Research (CEBR), University of Genova, Genoa, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: Magnone
authors.affiliation: Biochemistry Laboratory, Department of Pharmacy, University of Genova, Genoa, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ravera
authors.affiliation: Department of Internal Medicine, University of Genova, Genoa, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Damonte
authors.affiliation: Section of Biochemistry, Department of Experimental Medicine, Center of Excellence for Biomedical Research (CEBR), University of Genova, Genoa, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Vigliarolo
authors.affiliation: Debiopharm International S.A., Lausanne, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Von Holtey
authors.affiliation: Department of Surgical Sciences and Integrated Diagnostics, University of Genova, Genoa, Italy.
authors.forename: Valerio G
authors.initials: VG
authors.lastname: Vellone
authors.affiliation: Section of Biochemistry, Department of Experimental Medicine, Center of Excellence for Biomedical Research (CEBR), University of Genova, Genoa, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Millo
authors.affiliation: Department of Internal Medicine, University of Genova, Genoa, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Caffa
authors.affiliation: Department of Internal Medicine, University of Genova, Genoa, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Cea
authors.affiliation: Institute of Organic Synthesis and Photoreactivity (ISOF), National Research Council (CNR), Bologna, Italy.
authors.forename: Marco Daniele
authors.initials: MD
authors.lastname: Parenti
authors.affiliation: Institute of Organic Synthesis and Photoreactivity (ISOF), National Research Council (CNR), Bologna, Italy.|Innovamol Srls, Modena, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Del Rio
authors.affiliation: Debiopharm International S.A., Lausanne, Switzerland.|Cellestia Biotech AG, Basel, Switzerland.
authors.forename: Maximilien
authors.initials: M
authors.lastname: Murone
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
authors.affiliation: Section of Biochemistry, Department of Experimental Medicine, Center of Excellence for Biomedical Research (CEBR), University of Genova, Genoa, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Grozio
authors.affiliation: Department of Internal Medicine, University of Genova, Genoa, Italy; alessio.nencioni@unige.it.|Istituto di Ricovero e Cura a Carattere Scientifico, Azienda Ospedaliera Universitaria San Martino Istituto Nazionale per la Ricerca sul Cancro (IST), Genoa, Italy; and.
authors.forename: Alessio
authors.initials: A
authors.lastname: Nencioni
authors.affiliation: Section of Biochemistry, Department of Experimental Medicine, Center of Excellence for Biomedical Research (CEBR), University of Genova, Genoa, Italy; santina.bruzzone@unige.it.|Institute of Protein Biochemistry, National Research Council, Naples, Italy.
authors.forename: Santina
authors.initials: S
authors.lastname: Bruzzone
mesh_terms: D000818:Animals; D001786:Blood Glucose; D002470:Cell Survival / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2; D059305:Diet, High-Fat; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology*; D037761:Sirtuins / Q000037:antagonists & inhibitors*; D013449:Sulfonamides
chemical_list: C000622538:2,4-dioxo-N-(4-(pyridin-3-yloxy)phenyl)-1,2,3,4-tetrahydroquinazoline-6-sulfonamide; D001786:Blood Glucose; D007328:Insulin; D052999:Quinazolinones; D013449:Sulfonamides; C501860:Sirt6 protein, mouse; D037761:Sirtuins
keywords: glucose metabolism; glucose transporters; sirtuin inhibitors