Low-Dose Acrolein, an Endogenous and Exogenous Toxic Molecule, Inhibits Glucose Transport via an Inhibition of Akt-Regulated GLUT4 Signaling in Skeletal Muscle Cells

Abstract

Urinary acrolein adduct levels have been reported to be increased in both habitual smokers and type-2 diabetic patients. The impairment of glucose transport in skeletal muscles is a major factor responsible for glucose uptake reduction in type-2 diabetic patients. The effect of acrolein on glucose metabolism in skeletal muscle remains unclear. Here, we investigated whether acrolein affects muscular glucose metabolism in vitro and glucose tolerance in vivo. Exposure of mice to acrolein (2.5 and 5 mg/kg/day) for 4 weeks substantially increased fasting blood glucose and impaired glucose tolerance. The glucose transporter-4 (GLUT4) protein expression was significantly decreased in soleus muscles of acrolein-treated mice. The glucose uptake was significantly decreased in differentiated C2C12 myotubes treated with a non-cytotoxic dose of acrolein (1 μM) for 24 and 72 h. Acrolein (0.5–2 μM) also significantly decreased the GLUT4 expression in myotubes. Acrolein suppressed the phosphorylation of glucose metabolic signals IRS1, Akt, mTOR, p70S6K, and GSK3α/β. Over-expression of constitutive activation of Akt reversed the inhibitory effects of acrolein on GLUT4 protein expression and glucose uptake in myotubes. These results suggest that acrolein at doses relevant to human exposure dysregulates glucose metabolism in skeletal muscle cells and impairs glucose tolerance in mice.

Diet as a Source of Acrolein: Molecular Basis of Aldehyde Biological Activity in Diabetes and Digestive System Diseases

“…The high affinity between acrolein and various proteins is likely also responsible for aldehyde’s ability to modulate the expression of glucose transporter type 4 (GLUT4) [ 102 ]. The impairment of glucose transport in skeletal muscle is one of the main factors responsible for reducing glucose uptake in type 2 diabetic patients [ 103 ].…”

“…The exposure of mice to acrolein significantly increased fasting blood glucose levels and impaired glucose tolerance, which was caused by decreased GLUT4 expression in rodent muscles. The molecular basis of these events was the acrolein-dependent phosphorylation suppression of key signaling proteins for GLUT4 expression and carbohydrate metabolism, including insulin receptor (IR) substrate 1 (IRS1), protein kinase B (Akt), mammalian target of rapamycin kinase (mTOR), ribosomal protein S6 kinase beta-1 (p70S6K), and glycogen synthase kinase 3 α/β (GSK3 α/β) [ 102 ].…”

The Therapeutic Effects of Magnesium in Insulin Secretion and Insulin Resistance

“…Akt has an essential role in the regulation of glucose transport, lipid synthesis, gluconeogenesis, and glycogen synthesis. [ 1 49 ]…”