AI Article Synopsis
- - TBC1D1 is a protein involved in glucose regulation and GLUT4 trafficking, which is influenced by AMPK through phosphorylation, implicating it in insulin-independent muscle glucose uptake.
- - Research using mice with specific genetic modifications showed that when AMPK was inactivated, glucose uptake was significantly reduced in response to an activating agent (AICAR) and the TBC1D1 mutation also limited this glucose-lowering effect.
- - The study concluded that TBC1D1's phosphorylation and interaction with 14-3-3 proteins are key in regulating glucose homeostasis, but interestingly, the mutation did not impair glucose uptake during exercise or the mice's overall exercise capacity.
Article 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 Ser, 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-Ser 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 -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 -knockin mice.
Results: Skeletal muscle-specific deletion of Ampkα1/a2 in mice prevented AICAR-induced hypoglycaemia and muscle glucose uptake. The Tbc1d1 -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 -knockin mice upon stimulation with a submaximal dose of AICAR. However, this Tbc1d1 -knockin mutation neither impaired exercise-induced muscle glucose uptake nor affected exercise capacity in mice.
Conclusions/interpretation: TBC1D1-Ser 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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| http://dx.doi.org/10.1007/s00125-016-4151-9 | DOI Listing |
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