Intramuscular lipid metabolism in the insulin resistance of smoking

Abstract

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) x microU(-1) x 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 microg/mg dry wt, DAG 0.34 +/- 0.02 nonsmokers vs. 0.35 +/- 0.02 smokers microg/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-gamma (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.

FIG. 1.

Insulin sensitivity measured using the Bergman minimal model in nonsmokers (□) and smokers (■). Values are means ± SE. § = significantly different than nonsmokers, P < 0.05.

FIG. 2.

Intramuscular triglyceride concentration (A), fractional synthesis rate (B), saturation (C) in nonsmokers (□) and smokers (■). Values are means ± SE. § = significantly different than nonsmokers, P < 0.05. The significant relationship between IMTG concentration and turnover in all subjects is shown in panel (D).

FIG. 3.

Intramuscular DAG concentration (A), fractional synthesis rate (B), and saturation (C) in nonsmokers (□) and smokers (■). D: Skeletal muscle DAG composition in nonsmokers and smokers. Values are means ± SE. § = significantly different than nonsmokers, P < 0.05.

FIG. 4.

RT-PCR summary of skeletal muscle biopsy data comparing nonsmokers (□) with smokers (■). Values are means ± SE. § = significantly different than nonsmokers, P < 0.05; † = different than nonsmokers, P < 0.10.

FIG. 5.

Ser⁶³⁶ phosphorylation of IRS-1 in nonsmokers (□) and smokers (■). There was not a significant difference in total IRS-1 content between groups. Values are means ± SE. Nonsmokers = 0.73 ± 0.08, smokers = 1.14 ± 0.9, AU. § = significantly different than nonsmokers, P < 0.05.

FIG. 6.

Whole-body palmitate rate of appearance (A), oxidation (B), and incorporation (C) into IMTG in nonsmokers (□) and smokers (■). Values are means ± SE. § = significantly different than nonsmokers, P < 0.05.