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

• Published in: American journal of physiology: endocrinology and metabolism Vol. 319; no. 4; pp. E805 - E813
• Main Authors: Huynh, Frank K, Peterson, Brett S, Anderson, Kristin A, Lin, Zhihong, Coakley, Aeowynn J, Llaguno, Fiara M S, Nguyen, Thi-Tina N, Campbell, Jonathan E, Stephens, Samuel B, Newgard, Christopher B, Hirschey, Matthew D
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.10.2020
• Subjects: Animals; Glucose - pharmacology; Glucose Intolerance - metabolism; Insulin Resistance; Insulin Secretion - physiology; Insulin-Secreting Cells - metabolism; Islets of Langerhans - cytology; Islets of Langerhans - metabolism; Leucine - pharmacology; Mice; Mice, Knockout; Mitochondria - metabolism; Mitochondrial Proteins - metabolism; Nutrients; Protein Processing, Post-Translational; Sirtuins - metabolism; SIRT4; insulin secretion; sirtuin; β-cell; diabetes
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00170.2020

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.