Disrupted glucose homeostasis and skeletal-muscle-specific glucose uptake in an exocyst knockout mouse model

J Biol Chem. 2021 Jan-Jun;296:100482. doi: 10.1016/j.jbc.2021.100482. Epub 2021 Feb 27.

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 with 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbohydrate Metabolism
  • Cell Membrane / metabolism
  • Cytoplasm / metabolism
  • Exocytosis
  • Female
  • Glucose / metabolism*
  • Glucose Intolerance / genetics
  • Glucose Transport Proteins, Facilitative / metabolism
  • Glucose Transporter Type 4 / metabolism
  • Homeostasis
  • Insulin / analysis
  • Insulin / blood
  • Insulin / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiprotein Complexes
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / physiology
  • Myoblasts, Skeletal / metabolism
  • Protein Transport
  • Vesicular Transport Proteins / metabolism*
  • Vesicular Transport Proteins / physiology

Substances

  • EXOC5 protein, mouse
  • Glucose Transport Proteins, Facilitative
  • Glucose Transporter Type 4
  • Insulin
  • Multiprotein Complexes
  • Vesicular Transport Proteins
  • Glucose