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Diabetologia
Published in: Diabetologia 2/2017

01-02-2017 | Article

A Tbc1d1 Ser231Ala-knockin mutation partially impairs AICAR- but not exercise-induced muscle glucose uptake in mice

Authors: Qiaoli Chen, Bingxian Xie, Sangsang Zhu, Ping Rong, Yang Sheng, Serge Ducommun, Liang Chen, Chao Quan, Min Li, Kei Sakamoto, Carol MacKintosh, Shuai Chen, Hong Yu Wang

Published in: Diabetologia | Issue 2/2017

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Abstract

Aims/hypothesis

TBC1D1 (tre-2/USP6, BUB2, cdc16 domain family member 1) is a Rab GTPase-activating protein (RabGAP) that has been implicated in regulating GLUT4 trafficking. TBC1D1 can be phosphorylated by the AMP-activated protein kinase (AMPK) on Ser231, which consequently interacts with 14-3-3 proteins. Given the key role for AMPK in regulating insulin-independent muscle glucose uptake, we hypothesised that TBC1D1-Ser231 phosphorylation and/or 14-3-3 binding may mediate AMPK-governed glucose homeostasis.

Methods

Whole-body glucose homeostasis and muscle glucose uptake were assayed in mice bearing a Tbc1d1 Ser231Ala-knockin mutation or harbouring skeletal muscle-specific Ampkα1/α2 (also known as Prkaa1/2) double-knockout mutations in response to an AMPK-activating agent, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR). Exercise-induced muscle glucose uptake and exercise capacity were also determined in the Tbc1d1 Ser231Ala-knockin mice.

Results

Skeletal muscle-specific deletion of Ampkα1/a2 in mice prevented AICAR-induced hypoglycaemia and muscle glucose uptake. The Tbc1d1 Ser231Ala-knockin mutation also attenuated the glucose-lowering effect of AICAR in mice. Glucose uptake and cell surface GLUT4 content were significantly lower in muscle isolated from the Tbc1d1 Ser231Ala-knockin mice upon stimulation with a submaximal dose of AICAR. However, this Tbc1d1 Ser231Ala-knockin mutation neither impaired exercise-induced muscle glucose uptake nor affected exercise capacity in mice.

Conclusions/interpretation

TBC1D1-Ser231 phosphorylation and/or 14-3-3 binding partially mediates AMPK-governed glucose homeostasis and muscle glucose uptake in a context-dependent manner.
Appendix
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Metadata
Title
A Tbc1d1 Ser231Ala-knockin mutation partially impairs AICAR- but not exercise-induced muscle glucose uptake in mice
Authors
Qiaoli Chen
Bingxian Xie
Sangsang Zhu
Ping Rong
Yang Sheng
Serge Ducommun
Liang Chen
Chao Quan
Min Li
Kei Sakamoto
Carol MacKintosh
Shuai Chen
Hong Yu Wang
Publication date
01-02-2017
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 2/2017
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-016-4151-9

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