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.


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.
Bergman
Bryan C
BC
Division of Endocrinology, Diabetes, and Metabolism, University of Colorado Denver School of Medicine, Aurora, Colorado, USA. Bryan.Bergman@ucdenver.edu
Perreault
Leigh
L
Hunerdosse
Devon M
DM
Koehler
Mary C
MC
Samek
Ali M
AM
Eckel
Robert H
RH
D015992:Body Mass Index; D004032:Diet; D004075:Diglycerides / Q000378:metabolism*; D002149:Energy Intake; D015444:Exercise; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008055:Lipids / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D047493:PPAR alpha / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values; D047491:Retinoid X Receptor gamma / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000503:physiopathology*; D013230:Stearoyl-CoA Desaturase / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism*; D055815:Young Adult
D004075:Diglycerides; D008055:Lipids; D047493:PPAR alpha; D012333:RNA, Messenger; D047491:Retinoid X Receptor gamma; D014280:Triglycerides; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase