title: Enhanced insulin sensitivity in skeletal muscle and liver by physiological overexpression of SIRT6.
abstract: OBJECTIVE
  Available treatment for obesity and type 2 diabetes mellitus (T2DM) is suboptimal. Thus, identifying novel molecular target(s) exerting protective effects against these metabolic imbalances is of enormous medical significance. Sirt6 loss- and gain-of-function studies have generated confounding data regarding the role of this sirtuin on energy and glucose homeostasis, leaving unclear whether activation or inhibition of SIRT6 may be beneficial for the treatment of obesity and/or T2DM.
  
  
  METHODS
  To address these issues, we developed and studied a novel mouse model designed to produce eutopic and physiological overexpression of SIRT6 (Sirt6BAC mice). These mutants and their controls underwent several metabolic analyses. These include whole-blood reverse phase high-performance liquid chromatography assay, glucose and pyruvate tolerance tests, hyperinsulinemic-euglycemic clamp assays, and assessment of basal and insulin-induced level of phosphorylated AKT (p-AKT)/AKT in gastrocnemius muscle.
  
  
  RESULTS
  Sirt6BAC mice physiologically overexpress functionally competent SIRT6 protein. While Sirt6BAC mice have normal body weight and adiposity, they are protected from developing high-caloric-diet (HCD)-induced hyperglycemia and glucose intolerance. Also, Sirt6BAC mice display increased circulating level of the polyamine spermidine. The ability of insulin to suppress endogenous glucose production was significantly enhanced in Sirt6BAC mice compared to wild-type controls. Insulin-stimulated glucose uptake was increased in Sirt6BAC mice in both gastrocnemius and soleus muscle, but not in brain, interscapular brown adipose, or epididymal adipose tissue. Insulin-induced p-AKT/AKT ratio was increased in gastrocnemius muscle of Sirt6BAC mice compared to wild-type controls.
  
  
  CONCLUSIONS
  Our data indicate that moderate, physiological overexpression of SIRT6 enhances insulin sensitivity in skeletal muscle and liver, engendering protective actions against diet-induced T2DM. Hence, the present study provides support for the anti-T2DM effect of SIRT6 and suggests SIRT6 as a putative molecular target for anti-T2DM treatment.
authors.affiliation: Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Anderson
authors.affiliation: Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA ; Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland ; Diabetes Center of Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ramadori
authors.affiliation: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland ; Diabetes Center of Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Rafael M
authors.initials: RM
authors.lastname: Ioris
authors.affiliation: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Mirco
authors.initials: M
authors.lastname: Galiè
authors.affiliation: Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA ; Department of Pharmacology, Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Berglund
authors.affiliation: Department of Pharmacology, Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Katie C
authors.initials: KC
authors.lastname: Coate
authors.affiliation: Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Teppei
authors.initials: T
authors.lastname: Fujikawa
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pucciarelli
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Moreschini
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy.
authors.forename: Augusto
authors.initials: A
authors.lastname: Amici
authors.affiliation: School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Andreani
authors.affiliation: Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA ; Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland ; Diabetes Center of Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Roberto
authors.initials: R
authors.lastname: Coppari
keywords: BAC, bacterial artificial chromosome; Diabetes; EndoRa, endogenous glucose appearance rate; GIR, glucose infusion rate; Glucose homeostasis; HCD, high-caloric diet; IPGTT, intraperitoneal glucose tolerance test; IPPTT, intraperitoneal pyruvate tolerance test; Insulin sensitivity; Rd, glucose disposal rate; Rg, tissue-specific glucose uptake rate; SIRT6 overexpression; Sirtuin; T2DM, type 2 diabetes mellitus