UMMS Affiliation

Program in Molecular Medicine; Division of Endocrinology, Metabolism and Diabetes, Department of Medicine

Publication Date

2021-02-26

Document Type

Article

Disciplines

Biochemistry | Endocrine System Diseases | Endocrinology | Endocrinology, Diabetes, and Metabolism | Molecular Biology | Musculoskeletal, Neural, and Ocular Physiology | Nutritional and Metabolic Diseases

Abstract

Skeletal muscle is responsible for the majority of glucose disposal following meals, and this is achieved by insulin-mediated trafficking of glucose transporter type 4 (GLUT4) to the cell membrane. The eight-protein exocyst trafficking complex facilitates targeted docking of membrane-bound vesicles, a process underlying the regulated delivery of fuel transporters. We previously demonstrated the role of exocyst subunit EXOC5 in insulin-stimulated GLUT4 exocytosis and glucose uptake in cultured rat skeletal myoblasts. However, the in vivo role of EXOC5 in skeletal muscle remains unclear. Using mice with inducible, skeletal muscle-specific knockout of exocyst subunit EXOC5 (Exoc5-SMKO), we examined how muscle-specific disruption of the exocyst would affect glucose homeostasis in vivo. We found that both male and female Exoc5-SMKO mice displayed elevated fasting glucose levels. Additionally, male Exoc5-SMKO mice had impaired glucose tolerance and lower serum insulin levels. Using indirect calorimetry, we observed that male Exoc5-SMKO mice have a reduced respiratory exchange ratio during the light period and lower energy expenditure. Using the hyperinsulinemic-euglycemic clamp method, we further showed that insulin-stimulated skeletal muscle glucose uptake is reduced in Exoc5-SMKO males compared to wild-type controls. Overall, our findings indicate that EXOC5 and the exocyst are necessary for insulin-stimulated glucose uptake in skeletal muscle and regulate glucose homeostasis in vivo.

Keywords

diabetes, exocyst complex, glucose transporter, insulin resistance, skeletal muscle

Rights and Permissions

© 2021 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

DOI of Published Version

10.1016/j.jbc.2021.100482

Source

Fujimoto BA, Young M, Nakamura N, Ha H, Carter L, Pitts MW, Torres D, Noh HL, Suk S, Kim JK, Polgar N. Disrupted glucose homeostasis and skeletal muscle-specific glucose uptake in an exocyst knockout mouse model. J Biol Chem. 2021 Feb 26;296:100482. doi: 10.1016/j.jbc.2021.100482. Epub ahead of print. PMID: 33647317; PMCID: PMC8027262. Link to article on publisher's site

Journal/Book/Conference Title

The Journal of biological chemistry

Related Resources

Link to Article in PubMed

PubMed ID

33647317

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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