例如:"lncRNA", "apoptosis", "WRKY"

β-Cell-specific ablation of sirtuin 4 does not affect nutrient-stimulated insulin secretion in mice.

Am J Physiol Endocrinol Metab. 2020 Oct 01;319(4):E805-E813. doi:10.1152/ajpendo.00170.2020. Epub 2020 Aug 31
Frank K Huynh 1 , Brett S Peterson 2 , Kristin A Anderson 2 , Zhihong Lin 3 , Aeowynn J Coakley 1 , Fiara M S Llaguno 1 , Thi-Tina N Nguyen 1 , Jonathan E Campbell 4 , Samuel B Stephens 5 , Christopher B Newgard 4 , Matthew D Hirschey 4
Frank K Huynh 1 , Brett S Peterson 2 , Kristin A Anderson 2 , Zhihong Lin 3 , Aeowynn J Coakley 1 , Fiara M S Llaguno 1 , Thi-Tina N Nguyen 1 , Jonathan E Campbell 4 , Samuel B Stephens 5 , Christopher B Newgard 4 , Matthew D Hirschey 4
+ et al

[No authors listed]

Author information
  • 1 Department of Biological Sciences, San Jose State University, San Jose, California.
  • 2 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina.
  • 3 Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina.
  • 4 Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, North Carolina.
  • 5 Fraternal Order of Eagles Diabetes Research Center, Iowa City, Iowa.

摘要


Sirtuins are a family of proteins that regulate biological processes such as cellular stress and aging by removing posttranslational modifications (PTMs). We recently identified several novel PTMs that can be removed by sirtuin 4 (SIRT4), which is found in mitochondria. We showed that mice with a global loss of SIRT4 [SIRT4-knockout (KO) mice] developed an increase in glucose- and leucine-stimulated insulin secretion, and this was followed by accelerated age-induced glucose intolerance and insulin resistance. Because whole body SIRT4-KO mice had alterations to nutrient-stimulated insulin secretion, we hypothesized that SIRT4 plays a direct role in regulating pancreatic β-cell function. Thus, we tested whether β-cell-specific ablation of SIRT4 would recapitulate the elevated insulin secretion seen in mice with a global loss of SIRT4. Tamoxifen-inducible β-cell-specific SIRT4-KO mice were generated, and their glucose tolerance and glucose- and leucine-stimulated insulin secretion were measured over time. These mice exhibited normal glucose- and leucine-stimulated insulin secretion and maintained normal glucose tolerance even as they aged. Furthermore, 832/13 β-cells with a CRISPR/Cas9n-mediated loss of SIRT4 did not show any alterations in nutrient-stimulated insulin secretion. Despite the fact that whole body SIRT4-KO mice demonstrated an age-induced increase in glucose- and leucine-stimulated insulin secretion, our current data indicate that the loss of SIRT4 specifically in pancreatic β-cells, both in vivo and in vitro, does not have a significant impact on nutrient-stimulated insulin secretion. These data suggest that SIRT4 controls nutrient-stimulated insulin secretion during aging by acting on tissues external to the β-cell, which warrants further study.

KEYWORDS: SIRT4, diabetes, insulin secretion, sirtuin, β-cell