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- Dollet, L, et al.
(författare)
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Glutamine Regulates Skeletal Muscle Immunometabolism in Type 2 Diabetes
- 2022
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 71:4, s. 624-636
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Tidskriftsartikel (refereegranskat)abstract
- Dysregulation of skeletal muscle metabolism influences whole-body insulin sensitivity and glucose homeostasis. We hypothesized that type 2 diabetes–associated alterations in the plasma metabolome directly contribute to skeletal muscle immunometabolism and the subsequent development of insulin resistance. To this end, we analyzed the plasma and skeletal muscle metabolite profile and identified glutamine as a key amino acid that correlates inversely with BMI and insulin resistance index (HOMA-IR) in men with normal glucose tolerance or type 2 diabetes. Using an in vitro model of human myotubes and an in vivo model of diet-induced obesity and insulin resistance in male mice, we provide evidence that glutamine levels directly influence the inflammatory response of skeletal muscle and regulate the expression of the adaptor protein GRB10, an inhibitor of insulin signaling. Moreover, we demonstrate that a systemic increase in glutamine levels in a mouse model of obesity improves insulin sensitivity and restores glucose homeostasis. We conclude that glutamine supplementation may represent a potential therapeutic strategy to prevent or delay the onset of insulin resistance in obesity by reducing inflammatory markers and promoting skeletal muscle insulin sensitivity.
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- Benziane, B, et al.
(författare)
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AMP-activated protein kinase activator A-769662 is an inhibitor of the Na(+)-K(+)-ATPase
- 2009
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Ingår i: American journal of physiology. Cell physiology. - : American Physiological Society. - 1522-1563 .- 0363-6143. ; 297:6, s. C1554-C1566
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Tidskriftsartikel (refereegranskat)abstract
- Muscle contraction and metabolic stress are potent activators of AMP-activated protein kinase (AMPK). AMPK restores energy balance by activating processes that produce energy while inhibiting those that consume energy. The role of AMPK in the regulation of active ion transport is unclear. Our aim was to determine the effect of the AMPK activator A-769662 on Na+-K+-ATPase function in skeletal muscle cells. Short-term incubation of differentiated rat L6 myotubes with 100 μM A-769662 increased AMPK and acetyl-CoA carboxylase (ACC) phosphorylation in parallel with decreased Na+-K+-ATPase α1-subunit abundance at the plasma membrane and ouabain-sensitive86Rb+uptake. Notably, the effect of A-769662 on Na+-K+-ATPase was similar in muscle cells that do not express AMPK α1- and α2-catalytic subunits. A-769662 directly inhibits the α1-isoform of the Na+-K+-ATPase, purified from rat and human kidney cells in vitro with IC5057 μM and 220 μM, respectively. Inhibition of the Na+-K+-ATPase by 100 μM ouabain decreases sodium pump activity and cell surface abundance, similar to the effect of A-769662, without affecting AMPK and ACC phosphorylation. In conclusion, the AMPK activator A-769662 inhibits Na+-K+-ATPase activity and decreases the sodium pump cell surface abundance in L6 skeletal muscle cells. The effect of A-769662 on sodium pump is due to direct inhibition of the Na+-K+-ATPase activity, rather than AMPK activation. This AMPK-independent effect on Na+-K+-ATPase calls into question the use of A-769662 as a specific AMPK activator for metabolic studies.
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| 5. |
- Kjobsted, R, et al.
(författare)
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Prior AICAR stimulation increases insulin sensitivity in mouse skeletal muscle in an AMPK-dependent manner
- 2015
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 64:6, s. 2042-2055
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Tidskriftsartikel (refereegranskat)abstract
- An acute bout of exercise increases glucose uptake in skeletal muscle by an insulin-independent mechanism. In the period after exercise, insulin sensitivity to increased glucose uptake is enhanced. The molecular mechanisms underpinning this phenomenon are poorly understood but appear to involve an increased cell surface abundance of GLUT4. While increased proximal insulin signaling does not seem to mediate this effect, elevated phosphorylation of TBC1D4, a downstream target of both insulin (Akt) and exercise (AMPK) signaling, appears to play a role. The main purpose of this study was to determine whether AMPK activation increases skeletal muscle insulin sensitivity. We found that prior AICAR stimulation of wild-type mouse muscle increases insulin sensitivity to stimulate glucose uptake. However, this was not observed in mice with reduced or ablated AMPK activity in skeletal muscle. Furthermore, prior AICAR stimulation enhanced insulin-stimulated phosphorylation of TBC1D4 at Thr649 and Ser711 in wild-type muscle only. These phosphorylation events were positively correlated with glucose uptake. Our results provide evidence to support that AMPK activation is sufficient to increase skeletal muscle insulin sensitivity. Moreover, TBC1D4 phosphorylation may facilitate the effect of prior AMPK activation to enhance glucose uptake in response to insulin.
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