Intramuscular Lipid Metabolism in the Insulin Resistance of Smoking

OBJECTIVE: Smoking decreases insulin action and increases the risk of type 2 diabetes in humans. Mechanisms responsible for smoking-induced insulin resistance are unclear. We hypothesized smokers would have increased intramuscular triglyceride (IMTG) and diacylglycerol (DAG) concentration and decreased fractional synthesis rate (FSR) compared with nonsmokers. RESEARCH DESIGN AND METHODS: Nonsmokers (n = 18, aged 20 ± 0.5 years, BMI 22 ± 0.4 kg/m(2), body fat 20 ± 2%, 0 cigarettes per day) and smokers (n = 14, aged 21 ± 0.7 years, BMI 23 ± 0.4 kg/m(2), body fat 20 ± 3%, 18 ± 0.7 cigarettes per day) were studied in a fasted condition after a standardized diet. [U-(13)C]palmitate was infused during 4 h of rest followed by a skeletal muscle biopsy and intravenous glucose tolerance test. RESULTS: Smokers were less insulin sensitive (S(i)) compared with nonsmokers (S(i) 5.28 ± 0.5 nonsmokers vs. 3.74 ± 0.3 smokers 10(−4) · μU(−1) · ml(−1), P = 0.03). There were no differences in IMTG or DAG concentration (IMTG 24.2 ± 3.4 nonsmokers vs. 27.2 ± 5.9 smokers μg/mg dry wt, DAG 0.34 ± 0.02 nonsmokers vs. 0.35 ± 0.02 smokers μg/mg dry wt) or IMTG FSR between groups (0.66 ± 0.1 nonsmokers vs. 0.55 ± 0.09 smokers %/hr). Intramuscular lipid composition was different, with increased percent saturation of IMTG (32.1 ± 1.2 nonsmokers vs. 35.2 ± 1.0 smokers %, P = 0.05) and DAG (52.8 ± 1.7 nonsmokers vs. 58.8 ± 2.2 smokers %, P = 0.04) in smokers. Smokers had significantly decreased peroxisome proliferator–activated receptor-γ (1.76 ± 0.1 nonsmokers vs. 1.42 ± 0.11 smokers arbitrary units [AU], P = 0.03) and increased monocyte chemotactic protein-1 (3.11 ± 0.41 nonsmokers vs. 4.83 ± 0.54 smokers AU, P = 0.02) mRNA expression compared with nonsmokers. We also found increased insulin receptor substrate-1 Ser(636) phosphorylation in smokers compared with nonsmokers (0.73 ± 0.08 nonsmokers vs. 1.14 ± 0.09 smokers AU, P = 0.002). CONCLUSIONS: These data suggest: 1) IMTG concentration and turnover are not related to alterations in insulin action in smokers compared to nonsmokers, 2) increased saturation of IMTG and DAG in skeletal muscle may be related to insulin action, and 3) basal inhibition of insulin receptor substrate-1 may decrease insulin action in smokers.