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08.11.2016 | Article

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

verfasst von: 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

Erschienen in: Diabetologia | Ausgabe 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.

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Titel: A Tbc1d1 Ser231Ala-knockin mutation partially impairs AICAR- but not exercise-induced muscle glucose uptake in mice
verfasst von: 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
Publikationsdatum: 08.11.2016
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 2/2017
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-016-4151-9

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