Endothelin-1 Reduces Glucose Uptake in Human Skeletal Muscle In Vivo and In Vitro

Abstract

OBJECTIVEEndothelin (ET)-1 is a vasoconstrictor and proinflammatory peptide that may interfere with glucose uptake. Our objective was to investigate whether exogenous ET-1 affects glucose uptake in the forearm of individuals with insulin resistance and in cultured human skeletal muscle cells.RESEARCH DESIGN AND METHODSNine male subjects (aged 61 ± 3 years) with insulin resistance (M value <5.5 mg/kg/min or a homeostasis model assessment of insulin resistance index >2.5) participated in a protocol using saline infusion followed by ET-1 infusion (20 pmol/min) for 2 h into the brachial artery. Forearm blood flow (FBF), endothelium-dependent vasodilatation, and endothelium-independent vasodilatation were assessed. Molecular signaling and glucose uptake were determined in cultured skeletal muscle cells.RESULTSET-1 decreased forearm glucose uptake (FGU) by 39% (P < 0.05) after the 2-h infusion. ET-1 reduced basal FBF by 36% after the 2-h infusion (P < 0.05) and impaired both endothelium-dependent vasodilatation (P < 0.01) and endothelium-independent vasodilatation (P < 0.05). ETA and ETB receptor expression was detected on cultured skeletal muscle cells. One-hour ET-1 incubation increased glucose uptake in cells from healthy control subjects but not from type 2 diabetic patients. Incubation with ET-1 for 24 h reduced glucose uptake in cells from healthy subjects. ET-1 decreased insulin-stimulated Akt phosphorylation and increased phosphorylation of insulin receptor substrate-1 serine 636.CONCLUSIONSET-1 not only induces vascular dysfunction but also acutely impairs FGU in individuals with insulin resistance and in skeletal muscle cells from type 2 diabetic subjects. These findings suggest that ET-1 may contribute to the development of insulin resistance in skeletal muscle in humans.

Counteracting neuronal nitric oxide synthase proteasomal degradation improves glucose transport in insulin-resistant skeletal muscle from Zucker fa/fa rats

“…*p <0.05; **p <0.01; ***p <0.001 uptake at the 100 nmol/l concentration in insulin-resistant muscle cells (+9±4.6%; p <0.05; n =6) (Fig. 4b), as observed by others in type 2 diabetic patients [22]. We confirmed that nNOS expression remained reduced in cultured myocytes, as in entire muscles (Fig.…”

The transcriptomic signature of myostatin inhibitory influence on the differentiation of mouse C2C12 myoblasts

“…Among the regulated genes there was Edn1 (↑ 1,85) which impairs insulin-stimulated glucose uptake (Shemyakin et al 2010). This confirms our hypothesis that GDF8 action could occur through the Fig.…”

Autocrine role of interleukin-13 on skeletal muscle glucose metabolism in type 2 diabetic patients involves microRNA let-7

“…This overexpression of let-7 was associated with a let-7-mediated repression of components of the insulin/PI3K/mammalian target of rapamycin pathway, including abundance of the insulinlike growth factor receptor, the insulin receptor, and insulin receptor substrate-2 (47). Interestingly, insulin-stimulated Akt phosphorylation was not reduced in myotubes from T2DM patients, indicating that the function of the insulin-PI3K axis is preserved (40). This could be due to the more modest endogenous overexpression of let-7 in muscle from T2DM subjects (ϳ50%) compared with transgenic overexpression (6-to 10-fold) (47).…”

“…However, in myotubes derived from T2DM patients, IL-13-induced metabolic responses were impaired, with only a significant effects on glycogen synthesis and glucose oxidation noted. We have previously noted impaired metabolic responses to endothelin 1 (40) and IL-6 (21) in cells from derived T2DM patients, which may be indicative of a general metabolic impairment that persists in these cells.…”