Journal article
β-Cell-specific ablation of sirtuin 4 does not affect nutrient-stimulated insulin secretion in mice
American journal of physiology: endocrinology and metabolism, Vol.319(4), pp.E805-E813
10/01/2020
DOI: 10.1152/ajpendo.00170.2020
PMCID: PMC7750516
PMID: 32865009
Abstract
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.
Details
- Title: Subtitle
- β-Cell-specific ablation of sirtuin 4 does not affect nutrient-stimulated insulin secretion in mice
- Creators
- Frank K Huynh - San Jose State UniversityBrett S Peterson - Duke UniversityKristin A Anderson - Duke UniversityZhihong Lin - Duke UniversityAeowynn J Coakley - San Jose State UniversityFiara M S Llaguno - San Jose State UniversityThi-Tina N Nguyen - San Jose State UniversityJonathan E Campbell - Duke UniversitySamuel B Stephens - University of IowaChristopher B Newgard - Duke UniversityMatthew D Hirschey - Duke University
- Resource Type
- Journal article
- Publication Details
- American journal of physiology: endocrinology and metabolism, Vol.319(4), pp.E805-E813
- DOI
- 10.1152/ajpendo.00170.2020
- PMID
- 32865009
- PMCID
- PMC7750516
- ISSN
- 0193-1849
- eISSN
- 1522-1555
- Grant note
- R01AG045351 / HHS | National Institutes of Health National Institute of Aging R01DK115568 / HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) P30 AG028716 / NIA NIH HHS
- Language
- English
- Date published
- 10/01/2020
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984359681502771
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