SIRT6 Deficiency Results in Severe Hypoglycemia by Enhancing Both Basal and Insulin-stimulated Glucose Uptake in Mice

Abstract

Glucose homeostasis in mammals is mainly regulated by insulin signaling. It was previously shown that SIRT6 mutant mice die before 4 weeks of age, displaying profound abnormalities, including low insulin, hypoglycemia, and premature aging. To investigate mechanisms underlying the pleiotropic phenotypes associated with SIRT6 deficiency, we generated mice carrying targeted disruption of SIRT6. We found that 60% of SIRT6 ؊/؊ animals had very low levels of blood glucose and died shortly after weaning. The remaining animals, which have relatively higher concentrations of glucose, survived the early post-weaning lethality, but most died within one year of age. Significantly, feeding the mice with glucose-containing water increased blood glucose and rescued 83% of mutant mice, suggesting that the hypoglycemia is a major cause for the lethality. We showed that SIRT6 deficiency results in more abundant membrane association of glucose transporters 1 and 4, which enhances glucose uptake. We further demonstrated that SIRT6 negatively regulates AKT phosphorylation at Ser-473 and Thr-308 through inhibition of multiple upstream molecules, including insulin receptor, IRS1, and IRS2. The absence of SIRT6, consequently, enhances insulin signaling and activation of AKT, leading to hypoglycemia. These data uncover an essential role of SIRT6 in modulating glucose metabolism through mediating insulin sensitivity. Silent information regulator 2 (Sir2)3 in yeast, Caenorhabditis elegans, and Drosophila serves as a histone deacetylase that regulates DNA recombination, genomic stability, and lifespan (1-4). Mammalian homologs of Sir2 expand to a gene family of seven sirtuin proteins (SIRT1-7), which not only serve as type III histone deacetylases but also deacetylate many proteins that are involved in multiple biological processes, including cell fate determination, DNA damage repair, neuronal protection, adaptation to calorie restriction, organ metabolism and function, age-related diseases, and tumorigenesis (3-12).Using gene targeting, six Sirtuins have been disrupted. Whereas these mutant mice displayed distinct phenotypes, SIRT1 and SIRT6 mutant mice showed the most severe phenotypes (8). SIRT1 mutant mice die during gestation and early postnatal life, displaying genetic instability and some developmental defects (13-15). SIRT1 ϩ/Ϫ mice were normal; however suffered spontaneous tumorigenesis when one wild-type allele of p53 is mutated (13). SIRT6 mutant mice died before 4 weeks of age, displaying profound lymphopenia, loss of subcutaneous fat, lordokyphosis, low insulin and hypoglycemia, and premature aging (16). Because SIRT6 is involved in base excision repair (BER), it was suspected that DNA damage could serve as a trigger for the death (16,17). Recently, a study showed that SIRT6 deficiency activates NF-B signaling through interaction with RelA/p65, which may be partially responsible for the lethality of SIRT6 Ϫ/Ϫ mice (18). Consistent with this, deletion of one allele of RelA/p65 overcame lethality of ϳ40% of SIRT6 mutant mice. H...

Effects of intrinsic aerobic capacity, aging and voluntary running on skeletal muscle sirtuins and heat shock proteins

“…SIRT6-knockout mice have aging-like phenotype, including severe hypoglycemia and loss of subcutaneous fat, leading to death at early age (Mostoslavsky et al, 2006;Xiao et al, 2010). SIRT7-knockout mice display cardiac hypertrophy (Vakhrusheva et al, 2008), whereas SIRT2-knockdown mice develop tumorigenesis, leading to the notion that SIRT2 acts as a tumor suppressor (Park et al, 2012).…”

Sirtuins, aging, and cardiovascular risks

“…Hafner et al (2010) have identified a role for SIRT3 in cell protection and mitochondrial function in heart tissue during aged and induced stress: SIRT3 deacetylates cyclophilin D, inhibiting apoptosis by the opening of the mitochondrial permeability transition pore, while the loss of SIRT3 activity leads to increased cardiac stress and so to a decline in cardiac function. SIRT3 has been shown to block cardiac hypertrophy by reducing ROS synthesis from the mitochondria (Kim et al 2010). A recent study of Porter et al (2014) showed that under ischemic/reperfusion insult, at heart level, SIRT3 +/− adult and wild-type aged mice showed a similar phenotype of injury, resulting in a significant myocardial infarction area with respect to wild-type adult hearts.…”

“…In particular, SIRT6-deficient mice are smaller compared to the wild-type mice and, remarkably, show a premature aging-like phenotype that includes cardiac hypertrophy and heart failure, lymphopenia, reduced subcutaneous fat, lordokyphosis, genomic instability, hypoglycemia, low blood insulin-like growth factor (IGF) level, increased glucose uptake, and fatty liver (Kim et al 2010;Schwer et al 2010;Xiao et al 2010). As result, SIRT6-deficient mice die around 4 weeks after birth Pillai et al 2014).…”

“…Based on the striking phenotype of SIRT6 knockout mice, which are predisposed to accelerated senescence, significant researches have shown in vivo that SIRT6 can also regulate cardiac hypertrophy and age-related cardiovascular alterations (Kim et al 2010;Jia et al 2012). In particular, SIRT6-deficient mice are smaller compared to the wild-type mice and, remarkably, show a premature aging-like phenotype that includes cardiac hypertrophy and heart failure, lymphopenia, reduced subcutaneous fat, lordokyphosis, genomic instability, hypoglycemia, low blood insulin-like growth factor (IGF) level, increased glucose uptake, and fatty liver (Kim et al 2010;Schwer et al 2010;Xiao et al 2010).…”

“…SIRT3 is a protein deacetylase (Lombard et al 2007) and plays a crucial role in cellular energy metabolism or redox regulation by deacetylating key mitochondrial proteins, including acetyl-coenzyme A synthetase 2, glutamate dehydrogenase (GDH), and Mn-SOD2 (Kim et al 2010;Someya et al 2010).…”