SIRT6 Overexpression Protects Against Diet-Induced Diabetes in Mice

Numerous studies in a variety of species indicate that caloric restriction (CR) elicits beneficial metabolic effects including reduced adiposity and improved glucose homeostasis, as well as enhanced insulin and leptin sensitivity. Conversely, chronic feeding on high caloric diets brings about opposite outcomes and can progress to type-II-diabetes and obesity. An intense effort by many researchers has begun to elucidate the homeostatic mechanisms accounting for these beneficial metabolic effects of CR in order to facilitate development of CR-mimetic drugs to combat the alarming increase of these diseases. Mounting experimental evidence suggests that Sirtuins may be principal mediators of the metabolic effects of CR (1). Sirtuins are believed to sense and respond to cellular energy deficit via their (NAD+)-dependent enzymatic activities including lysine deacetylation of a variety of cytosolic, mitochondrial and nuclear proteins (2). Initial studies involving SIRT6, one of three nuclear sirtuins, suggest that it may be an attractive drug target for obesity and type-II-diabetes therapy. Knockout studies indicate that SIRT6 is required for normal growth, adiposity, and glucose homeostasis (3). Yet, contrasting these Sirt6-null phenotypes with those from opposing SIRT6 gain-of-function animal models lead to incongruous and seemingly contradictory conclusions regarding the stress-responsive homeostatic functions of SIRT6, casting doubt as to whether SIRT6 agonist or antagonist drugs should be sought after. To address these issues, I generated genetically engineered mice (Sirt6BAC mice) designed to eutopically overexpress SIRT6 and mimic its moderate eutopic upregulation observed during CR. This was achieved via BAC- mediated genomic insertion of an isogenic 187kb DNA region from chromosome 10 of mus musculus encompassing Sirt6. These Sirt6BAC mutants fed a high caloric diet exhibit improved glucose homeostasis as indicated via intraperitoneal glucose tolerance tests and intraperitoneal pyruvate tolerance tests. Hyperinsulinemic/euglycemic clamp indicate that these mutants exhibit enhanced insulin-sensitive inhibition of endogenous glucose production as well as enhanced blood glucose disposal and uptake into gastrocnemius and soleus muscle. Importantly, these data suggest that SIRT6 agonist drugs may be worthy of translational research for the treatment of type-II diabetes in humans.