Diabetes is accompanied by changes in the levels of proteins involved in endosomal GLUT4 trafficking in obese human skeletal muscle
Abstract Introduction The regulated delivery of the glucose transporter GLUT4 from intracellular stores to the plasma membrane underpins insulin‐stimulated glucose transport. Insulin‐stimulated glucose transport is impaired in skeletal muscle of patients with type‐2 diabetes, and this may arise beca...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-09-01
|
| Series: | Endocrinology, Diabetes & Metabolism |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/edm2.361 |
| _version_ | 1818050467829121024 |
|---|---|
| author | Rachel Livingstone Nia J. Bryant James G. Boyle John R. Petrie Gwyn W. Gould |
| author_facet | Rachel Livingstone Nia J. Bryant James G. Boyle John R. Petrie Gwyn W. Gould |
| author_sort | Rachel Livingstone |
| collection | DOAJ |
| description | Abstract Introduction The regulated delivery of the glucose transporter GLUT4 from intracellular stores to the plasma membrane underpins insulin‐stimulated glucose transport. Insulin‐stimulated glucose transport is impaired in skeletal muscle of patients with type‐2 diabetes, and this may arise because of impaired intracellular trafficking of GLUT4. However, molecular details of any such impairment have not been described. We hypothesized that GLUT4 and/or levels of proteins involved in intracellular GLUT4 trafficking may be impaired in skeletal muscle in type‐2 diabetes and tested this in obese individuals without and without type‐2 diabetes. Methods We recruited 12 participants with type‐2 diabetes and 12 control participants. All were overweight or obese with BMI of 25–45 kg/m2. Insulin sensitivity was measured using an insulin suppression test (IST), and vastus lateralis biopsies were taken in the fasted state. Cell extracts were immunoblotted to quantify levels of a range of proteins known to be involved in intracellular GLUT4 trafficking. Results Obese participants with type‐2 diabetes exhibited elevated fasting blood glucose and increased steady state glucose infusion rates in the IST compared with controls. Consistent with this, skeletal muscle from those with type‐2 diabetes expressed lower levels of GLUT4 (30%, p = .014). Levels of Syntaxin4, a key protein involved in GLUT4 vesicle fusion with the plasma membrane, were similar between groups. By contrast, we observed reductions in levels of Syntaxin16 (33.7%, p = 0.05), Sortilin (44%, p = .006) and Sorting Nexin‐1 (21.5%, p = .039) and −27 (60%, p = .001), key proteins involved in the intracellular sorting of GLUT4, in participants with type‐2 diabetes. Conclusions We report significant reductions of proteins involved in the endosomal trafficking of GLUT4 in skeletal muscle in obese people with type 2 diabetes compared with age‐ and weight‐matched controls. These abnormalities of intracellular GLUT4 trafficking may contribute to reduced whole body insulin sensitivity. |
| first_indexed | 2024-12-10T10:53:57Z |
| format | Article |
| id | doaj.art-a6887227242943f8bbaed46984d0ab8e |
| institution | Directory Open Access Journal |
| issn | 2398-9238 |
| language | English |
| last_indexed | 2024-12-10T10:53:57Z |
| publishDate | 2022-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Endocrinology, Diabetes & Metabolism |
| spelling | doaj.art-a6887227242943f8bbaed46984d0ab8e2022-12-22T01:51:56ZengWileyEndocrinology, Diabetes & Metabolism2398-92382022-09-0155n/an/a10.1002/edm2.361Diabetes is accompanied by changes in the levels of proteins involved in endosomal GLUT4 trafficking in obese human skeletal muscleRachel Livingstone0Nia J. Bryant1James G. Boyle2John R. Petrie3Gwyn W. Gould4Institute of Cardiovascular and Medical Sciences University of Glasgow Glasgow UKDepartment of Biology University of York York UKSchool of Medicine University of Glasgow Glasgow UKInstitute of Cardiovascular and Medical Sciences University of Glasgow Glasgow UKInstitute of Molecular Cell and Systems Biology University of Glasgow Glasgow UKAbstract Introduction The regulated delivery of the glucose transporter GLUT4 from intracellular stores to the plasma membrane underpins insulin‐stimulated glucose transport. Insulin‐stimulated glucose transport is impaired in skeletal muscle of patients with type‐2 diabetes, and this may arise because of impaired intracellular trafficking of GLUT4. However, molecular details of any such impairment have not been described. We hypothesized that GLUT4 and/or levels of proteins involved in intracellular GLUT4 trafficking may be impaired in skeletal muscle in type‐2 diabetes and tested this in obese individuals without and without type‐2 diabetes. Methods We recruited 12 participants with type‐2 diabetes and 12 control participants. All were overweight or obese with BMI of 25–45 kg/m2. Insulin sensitivity was measured using an insulin suppression test (IST), and vastus lateralis biopsies were taken in the fasted state. Cell extracts were immunoblotted to quantify levels of a range of proteins known to be involved in intracellular GLUT4 trafficking. Results Obese participants with type‐2 diabetes exhibited elevated fasting blood glucose and increased steady state glucose infusion rates in the IST compared with controls. Consistent with this, skeletal muscle from those with type‐2 diabetes expressed lower levels of GLUT4 (30%, p = .014). Levels of Syntaxin4, a key protein involved in GLUT4 vesicle fusion with the plasma membrane, were similar between groups. By contrast, we observed reductions in levels of Syntaxin16 (33.7%, p = 0.05), Sortilin (44%, p = .006) and Sorting Nexin‐1 (21.5%, p = .039) and −27 (60%, p = .001), key proteins involved in the intracellular sorting of GLUT4, in participants with type‐2 diabetes. Conclusions We report significant reductions of proteins involved in the endosomal trafficking of GLUT4 in skeletal muscle in obese people with type 2 diabetes compared with age‐ and weight‐matched controls. These abnormalities of intracellular GLUT4 trafficking may contribute to reduced whole body insulin sensitivity.https://doi.org/10.1002/edm2.361clinical medicinediabetesmetabolic disease |
| spellingShingle | Rachel Livingstone Nia J. Bryant James G. Boyle John R. Petrie Gwyn W. Gould Diabetes is accompanied by changes in the levels of proteins involved in endosomal GLUT4 trafficking in obese human skeletal muscle Endocrinology, Diabetes & Metabolism clinical medicine diabetes metabolic disease |
| title | Diabetes is accompanied by changes in the levels of proteins involved in endosomal GLUT4 trafficking in obese human skeletal muscle |
| title_full | Diabetes is accompanied by changes in the levels of proteins involved in endosomal GLUT4 trafficking in obese human skeletal muscle |
| title_fullStr | Diabetes is accompanied by changes in the levels of proteins involved in endosomal GLUT4 trafficking in obese human skeletal muscle |
| title_full_unstemmed | Diabetes is accompanied by changes in the levels of proteins involved in endosomal GLUT4 trafficking in obese human skeletal muscle |
| title_short | Diabetes is accompanied by changes in the levels of proteins involved in endosomal GLUT4 trafficking in obese human skeletal muscle |
| title_sort | diabetes is accompanied by changes in the levels of proteins involved in endosomal glut4 trafficking in obese human skeletal muscle |
| topic | clinical medicine diabetes metabolic disease |
| url | https://doi.org/10.1002/edm2.361 |
| work_keys_str_mv | AT rachellivingstone diabetesisaccompaniedbychangesinthelevelsofproteinsinvolvedinendosomalglut4traffickinginobesehumanskeletalmuscle AT niajbryant diabetesisaccompaniedbychangesinthelevelsofproteinsinvolvedinendosomalglut4traffickinginobesehumanskeletalmuscle AT jamesgboyle diabetesisaccompaniedbychangesinthelevelsofproteinsinvolvedinendosomalglut4traffickinginobesehumanskeletalmuscle AT johnrpetrie diabetesisaccompaniedbychangesinthelevelsofproteinsinvolvedinendosomalglut4traffickinginobesehumanskeletalmuscle AT gwynwgould diabetesisaccompaniedbychangesinthelevelsofproteinsinvolvedinendosomalglut4traffickinginobesehumanskeletalmuscle |