期刊
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
卷 319, 期 4, 页码 E805-E813出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00170.2020
关键词
beta-cell; diabetes; insulin secretion; SIRT4; sirtuin
资金
- Ellison Medical Foundation
- National Institutes of Health [R01-AG-045351, R01-DK-115568]
- Duke Pepper Older Americans Independence Center (OAIC) Program in Aging Research - National Institute of Aging [P30-AG-028716-01]
- Canadian Diabetes Association/American Diabetes Association Joint Postdoctoral Fellowship [PF-3-13-4342-FH]
- San Jose State University Undergraduate Research Grant
- joint Doris A. Howell Foundation-California State University Program for Education and Research in Biotechnology (CSUPERB) Award
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-K0 mice had alterations to nutrient-stimulated insulin secretion, we hypothesized that SIRT4 plays a direct role in regulating pancreatic beta-cell function. Thus, we tested whether beta-cell-specific ablation of SIRT4 would recapitulate the elevated insulin secretion seen in mice with a global loss of SIRT4. Tamoxifen-inducible beta-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 beta-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 beta-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 beta-cell, which warrants further study.
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