+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Enhanced insulin sensitivity in skeletal muscle and liver by physiological overexpression of SIRT6



Enhanced insulin sensitivity in skeletal muscle and liver by physiological overexpression of SIRT6



Molecular Metabolism 4(11): 846-856



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. 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. 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. 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.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 057771764

Download citation: RISBibTeXText

PMID: 26629408

DOI: 10.1016/j.molmet.2015.09.003


Related references

SIRT1 overexpression in skeletal muscle in vivo induces increased insulin sensitivity and enhanced complex I but not complex II-V functions in individual subsarcolemmal and intermyofibrillar mitochondria. Journal of Physiology and Biochemistry 71(2): 177-190, 2015

Transgenic mice with overexpression of syntaxin 4 have increased insulin sensitivity but mice with overexpression of Munc18c are insulin resistant in skeletal muscle. Diabetes 52(Suppl. 1): A282, 2003

Overexpression of the adiponectin receptor AdipoR1 in rat skeletal muscle amplifies local insulin sensitivity. Endocrinology 153(11): 5231-5246, 2012

High-fat diet-induced impairment of skeletal muscle insulin sensitivity is not prevented by SIRT1 overexpression. American Journal of Physiology. Endocrinology and Metabolism 307(9): E764-E772, 2014

Increased insulin receptor substrate-1 and enhanced skeletal muscle insulin sensitivity in mice lacking CCAAT/enhancer-binding protein beta. Journal of Biological Chemistry 275(19): 14173-14181, 2000

Enhanced insulin sensitivity in a novel glycogen storage disorder of skeletal muscle. Diabetes 50(Suppl. 2): A329-A330, 2001

Glucose uptake by skeletal muscle enhanced sensitivity to insulin during starvation. Diabetes 27(Suppl. 2): 462, 1978

Skeletal muscle AMP-activated protein kinase γ1(H151R) overexpression enhances whole body energy homeostasis and insulin sensitivity. American Journal of Physiology. Endocrinology and Metabolism 309(7): E679-E690, 2015

Skeletal muscle-specific overexpression of SIRT1 does not enhance whole-body energy expenditure or insulin sensitivity in young mice. Diabetologia 56(7): 1629-1637, 2013

Enhanced skeletal muscle insulin sensitivity in year-old rats adapted to hypergravity. American Journal of Physiology 240(5): E482-E488, 1981

Overexpression of PLIN5 in skeletal muscle promotes oxidative gene expression and intramyocellular lipid content without compromising insulin sensitivity. Biochimica et Biophysica Acta 1831(4): 844-852, 2013

Placental restriction reduces insulin sensitivity and expression of insulin signaling and glucose transporter genes in skeletal muscle, but not liver, in young sheep. Endocrinology 153(5): 2142-2151, 2012

Homozygous staggerer (sg/sg) mice display improved insulin sensitivity and enhanced glucose uptake in skeletal muscle. Diabetologia 54(5): 1169-1180, 2011

Cellular depletion of atypical PKC{lambda} is associated with enhanced insulin sensitivity and glucose uptake in L6 rat skeletal muscle cells. American Journal of Physiology. Endocrinology and Metabolism 299(3): E402-E412, 2010