β-Cell-specific ablation of sirtuin 4 does not affect nutrient-stimulated insulin secretion in mice
American Journal of Physiology - Endocrinology and Metabolism
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.
National Institutes of Health
Diabetes, Insulin secretion, SIRT4, Sirtuin, β-cell
Frank K. Huynh, Brett S. Peterson, Kristin A. Anderson, Zhihong Lin, Aeowynn J. Coakley, Fiara M.S. Llaguno, Thi Tina N. Nguyen, Jonathan E. Campbell, Samuel B. Stephens, Christopher B. Newgard, and Matthew D. Hirschey. "β-Cell-specific ablation of sirtuin 4 does not affect nutrient-stimulated insulin secretion in mice" American Journal of Physiology - Endocrinology and Metabolism (2020): E805-E813. https://doi.org/10.1152/ajpendo.00170.2020