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.
Highlights
Insulin increases glucose uptake into adipocytes and skeletal muscle cells to control blood glucose levels in the circulation via a cascade of signal transduction activation, which triggers glucose transporter-4 (GLUT4) from the cytosol to the cell membrane [1,2].Skeletal muscle comprises 40% to 45% of adult human body weight and has remarkable plasticity, which can adapt to physiological and environmental influences by changing the characteristics of contraction and metabolism [3,4]
The low-dose acrolein (1 μM) impaired glucose homeostasis by inhibition of protein expressions of glucose metabolism-related signals on skeletal myotubes in vitro. These results suggest that acrolein exposure at doses relevant to human exposure is capable of impairing glucose transport in the skeletal muscle cells and inducing hyperglycemia in mice
The present study found that low-concentration acrolein significantly inhibited the phosphorylation of GSK3α/β in C2C12 myotubes, which could be effectively reversed by transfection of the constitutively active form of Akt
Summary
Insulin increases glucose uptake into adipocytes and skeletal muscle cells to control blood glucose levels in the circulation via a cascade of signal transduction activation, which triggers glucose transporter-4 (GLUT4) from the cytosol to the cell membrane [1,2].Skeletal muscle comprises 40% to 45% of adult human body weight and has remarkable plasticity, which can adapt to physiological and environmental influences by changing the characteristics of contraction and metabolism [3,4]. Insulin increases glucose uptake into adipocytes and skeletal muscle cells to control blood glucose levels in the circulation via a cascade of signal transduction activation, which triggers glucose transporter-4 (GLUT4) from the cytosol to the cell membrane [1,2]. Skeletal muscle undergoes a regenerative process that involves tissue, cellular, and molecular signals when responding to injury [5]. Skeletal muscle is an important tissue that maintains glucose homeostasis through glucose transporter-4 (GLUT4) by translocation to plasma membrane and facilitating glucose uptake [6,7]. GLUT4 is known as the major insulin-mediated glucose transporter in muscle and adipose tissues. The impairment of glucose transport in skeletal muscle is a major factor responsible for reduced glucose uptake in type 2 diabetic patients [9]
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