SIRT6 deficiency results in severe hypoglycemia by enhancing both basal and insulin-stimulated glucose uptake in mice.
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.
Xiao
Cuiying
C
Genetics of Development and Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA.
Kim
Hyun-Seok
HS
Lahusen
Tyler
T
Wang
Rui-Hong
RH
Xu
Xiaoling
X
Gavrilova
Oksana
O
Jou
William
W
Gius
David
D
Deng
Chu-Xia
CX
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D005455:Fluorescent Antibody Technique; D005804:Genes, Lethal; D005947:Glucose / Q000493:pharmacokinetics*; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism; D007003:Hypoglycemia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007124:Immunoenzyme Techniques; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D037761:Sirtuins / Q000502:physiology*; D014018:Tissue Distribution
D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; D007328:Insulin; D012333:RNA, Messenger; C495678:Slc2a1 protein, mouse; C495682:Slc2a2 protein, mouse; C501860:Sirt6 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D037761:Sirtuins; D005947:Glucose