Novel and reversible mechanisms of smoking-induced insulin resistance in humans

Bryan C Bergman, Leigh Perreault, Devon Hunerdosse, Anna Kerege, Mary Playdon, Ali M Samek, Robert H Eckel, Bryan C Bergman, Leigh Perreault, Devon Hunerdosse, Anna Kerege, Mary Playdon, Ali M Samek, Robert H Eckel

Abstract

Smoking is the most common cause of preventable morbidity and mortality in the United States, in part because it is an independent risk factor for the development of insulin resistance and type 2 diabetes. However, mechanisms responsible for smoking-induced insulin resistance are unclear. In this study, we found smokers were less insulin sensitive compared with controls, which increased after either 1 or 2 weeks of smoking cessation. Improvements in insulin sensitivity after smoking cessation occurred with normalization of IRS-1(ser636) phosphorylation. In muscle cell culture, nicotine exposure significantly increased IRS-1(ser636) phosphorylation and decreased insulin sensitivity, recapitulating the phenotype of smoking-induced insulin resistance in humans. The two pathways known to stimulate IRS-1(ser636) phosphorylation (p44/42 mitogen-activated protein kinase [MAPK] and mammalian target of rapamycin [mTOR]) were both stimulated by nicotine in culture. Inhibition of mTOR, but not p44/42 MAPK, during nicotine exposure prevented IRS-1(ser636) phosphorylation and normalized insulin sensitivity. These data indicate nicotine induces insulin resistance in skeletal muscle by activating mTOR. Therapeutic agents designed to oppose skeletal muscle mTOR activation may prevent insulin resistance in humans who are unable to stop smoking or are chronically exposed to secondhand smoke.

Figures

FIG. 1.
FIG. 1.
Time-course breath CO (A) and urinary cotinine (B) concentration at baseline and during smoking cessation. Values are means ± SEM.
FIG. 2.
FIG. 2.
Insulin sensitivity measured using the Bergman minimal model in nonsmokers and smokers. Data for the change in each individual are shown. Values are means ± SEM. §Significantly different than nonsmokers, P < 0.05; *significantly different after smoking cessation, P < 0.05. Si, insulin sensitivity index.
FIG. 3.
FIG. 3.
Palmitate Ra (A), oxidation (B), and glucose Ra (C) before and after smoking cessation intervention in control subjects and cigarette smokers. Values are means ± SEM. §Significantly different than control subjects, P < 0.05.
FIG. 4.
FIG. 4.
IMTG concentration (A), FSR (B), and saturation (C) and intramuscular DAG concentration (D) and saturation (E) in nonsmokers and smokers. Values are means ± SEM. §Significantly different than nonsmokers, P < 0.05.
FIG. 5.
FIG. 5.
IRS-1 serine636 phosphorylation before and after smoking cessation in control subjects and cigarette smokers. Values are means ± SEM. §Significantly different than control subjects, P < 0.05; *significantly different after smoking cessation, P < 0.05.
FIG. 6.
FIG. 6.
Effects of nicotine on cell signaling and insulin sensitivity in L6 skeletal muscle myotubes. A: Serine phosphorylation of IRS-1 in response to nicotine exposure at 200 μmol. B: Stimulation of p44/p42 MAPK over time with continuous nicotine exposure at 200 μmol with and without MEK inhibitor UO126, the upstream kinase of p44/p42 activation. C: Stimulation of p70s6k over time with continuous nicotine exposure at 200 μmol with and without the mTOR inhibitor rapamycin. D: Effects of nicotine at 200 μmol on IRS-1ser636 phosphorylation in L6 muscle cell culture with and without inhibitors against p44/p42 MAPK and mTOR. Values are mean ± SEM. §Significantly different than control, P < 0.05; ¥significantly different than time 0, P < 0.05; #significantly different than nicotine, P < 0.05.
FIG. 6.
FIG. 6.
Effects of nicotine on cell signaling and insulin sensitivity in L6 skeletal muscle myotubes. A: Serine phosphorylation of IRS-1 in response to nicotine exposure at 200 μmol. B: Stimulation of p44/p42 MAPK over time with continuous nicotine exposure at 200 μmol with and without MEK inhibitor UO126, the upstream kinase of p44/p42 activation. C: Stimulation of p70s6k over time with continuous nicotine exposure at 200 μmol with and without the mTOR inhibitor rapamycin. D: Effects of nicotine at 200 μmol on IRS-1ser636 phosphorylation in L6 muscle cell culture with and without inhibitors against p44/p42 MAPK and mTOR. Values are mean ± SEM. §Significantly different than control, P < 0.05; ¥significantly different than time 0, P < 0.05; #significantly different than nicotine, P < 0.05.
FIG. 7.
FIG. 7.
Effects of nicotine, with and without inhibitors against p44/p42 MAPK and mTOR, on insulin-stimulated glucose uptake in L6 muscle cell culture. Values are mean ± SEM. §Significantly different than control, P < 0.05; #significantly different than nicotine, P < 0.05.

References

    1. Centers for Disease Control and Prevention (CDC) Cigarette smoking among adults—United States, 2007. MMWR Morb Mortal Wkly Rep 2008;57:1221–1226
    1. Schroeder SA, Warner KE. Don’t forget tobacco. N Engl J Med 2010;363:201–204
    1. Kannel WB, D’Agostino RB, Belanger AJ. Fibrinogen, cigarette smoking, and risk of cardiovascular disease: insights from the Framingham Study. Am Heart J 1987;113:1006–1010
    1. Feskens EJ, Kromhout D. Cardiovascular risk factors and the 25-year incidence of diabetes mellitus in middle-aged men. The Zutphen Study. Am J Epidemiol 1989;130:1101–1108
    1. Perry IJ, Wannamethee SG, Walker MK, Thomson AG, Whincup PH, Shaper AG. Prospective study of risk factors for development of non-insulin dependent diabetes in middle aged British men. BMJ 1995;310:560–564
    1. Barnoya J, Glantz SA. Cardiovascular effects of secondhand smoke: nearly as large as smoking. Circulation 2005;111:2684–2698
    1. Pirkle JL, Flegal KM, Bernert JT, Brody DJ, Etzel RA, Maurer KR. Exposure of the US population to environmental tobacco smoke: the Third National Health and Nutrition Examination Survey, 1988 to 1991. JAMA 1996;275:1233–1240
    1. Pirkle JL, Bernert JT, Caudill SP, Sosnoff CS, Pechacek TF. Trends in the exposure of nonsmokers in the U.S. population to secondhand smoke: 1988-2002. Environ Health Perspect 2006;114:853–858
    1. Eliasson B, Taskinen MR, Smith U. Long-term use of nicotine gum is associated with hyperinsulinemia and insulin resistance. Circulation 1996;94:878–881
    1. Epifano L, Di Vincenzo A, Fanelli C, et al. Effect of cigarette smoking and of a transdermal nicotine delivery system on glucoregulation in type 2 diabetes mellitus. Eur J Clin Pharmacol 1992;43:257–263
    1. Albuquerque EX, Pereira EF, Alkondon M, Rogers SW. Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev 2009;89:73–120
    1. Kelić S, Olsson T, Kristensson K. Interferon-gamma promotes proliferation of rat skeletal muscle cells in vitro and alters their AChR distribution. J Neurol Sci 1993;114:62–67
    1. Attvall S, Fowelin J, Lager I, Von Schenck H, Smith U. Smoking induces insulin resistance—a potential link with the insulin resistance syndrome. J Intern Med 1993;233:327–332
    1. Eliasson B, Attvall S, Taskinen MR, Smith U. The insulin resistance syndrome in smokers is related to smoking habits. Arterioscler Thromb 1994;14:1946–1950
    1. Hellerstein MK, Benowitz NL, Neese RA, et al. Effects of cigarette smoking and its cessation on lipid metabolism and energy expenditure in heavy smokers. J Clin Invest 1994;93:265–272
    1. Eliasson B, Attvall S, Taskinen MR, Smith U. Smoking cessation improves insulin sensitivity in healthy middle-aged men. Eur J Clin Invest 1997;27:450–456
    1. Bergman BC, Perreault L, Hunerdosse DM, Koehler MC, Samek AM, Eckel RH. Intramuscular lipid metabolism in the insulin resistance of smoking. Diabetes 2009;58:2220–2227
    1. Bergström J, Hermansen L, Hultman E, Saltin B. Diet, muscle glycogen and physical performance. Acta Physiol Scand 1967;71:140–150
    1. Lexell J, Henriksson-Larsén K, Winblad B, Sjöström M. Distribution of different fiber types in human skeletal muscles: effects of aging studied in whole muscle cross sections. Muscle Nerve 1983;6:588–595
    1. Boston RC, Stefanovski D, Moate PJ, Sumner AE, Watanabe RM, Bergman RN. MINMOD Millennium: a computer program to calculate glucose effectiveness and insulin sensitivity from the frequently sampled intravenous glucose tolerance test. Diabetes Technol Ther 2003;5:1003–1015
    1. Bergman BC, Cornier MA, Horton TJ, Bessesen DH. Effects of fasting on insulin action and glucose kinetics in lean and obese men and women. Am J Physiol Endocrinol Metab 2007;293:E1103–E1111
    1. Patterson BW, Zhao G, Elias N, Hachey DL, Klein S. Validation of a new procedure to determine plasma fatty acid concentration and isotopic enrichment. J Lipid Res 1999;40:2118–2124
    1. Patterson BW, Zhao G, Klein S. Improved accuracy and precision of gas chromatography/mass spectrometry measurements for metabolic tracers. Metabolism 1998;47:706–712
    1. Kilaru S, Frangos SG, Chen AH, et al. Nicotine: a review of its role in atherosclerosis. J Am Coll Surg 2001;193:538–546
    1. Schievelbein H, Eberhardt R, Löschenkohl K, Rahlfs V, Bedall FK. Absorption of nicotine through the oral mucosa. I. Measurement of nicotine concentration in the blood after application of nicotine and total particulate matter. Agents Actions 1973;3:254–258
    1. Klip A, Gumà A, Ramlal T, Bilan PJ, Lam L, Leiter LA. Stimulation of hexose transport by metformin in L6 muscle cells in culture. Endocrinology 1992;130:2535–2544
    1. Wolfe R. Radioactive and Stable Isotope Tracers in Biomedicine: Principles and Practice of Kinetic Analysis. New York, Wiley-Liss, 1992
    1. Manson JE, Ajani UA, Liu S, Nathan DM, Hennekens CH. A prospective study of cigarette smoking and the incidence of diabetes mellitus among US male physicians. Am J Med 2000;109:538–542
    1. Nilsson P, Lundgren H, Söderström M, Fagerström KO, Nilsson-Ehle P. Effects of smoking cessation on insulin and cardiovascular risk factors—a controlled study of 4 months’ duration. J Intern Med 1996;240:189–194
    1. Yeh HC, Duncan BB, Schmidt MI, Wang NY, Brancati FL. Smoking, smoking cessation, and risk for type 2 diabetes mellitus: a cohort study. Ann Intern Med 2010;152:10–17
    1. Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest 2000;106:171–176
    1. Bergman BC, Perreault L, Hunerdosse DM, Koehler MC, Samek AM, Eckel RH. Increased intramuscular lipid synthesis and low saturation relate to insulin sensitivity in endurance-trained athletes. J Appl Physiol 2010;108:1134–1141
    1. van Hees AM, Jans A, Hul GB, Roche HM, Saris WH, Blaak EE. Skeletal muscle fatty acid handling in insulin resistant men. Obesity (Silver Spring) 2011;19:1350–1359
    1. Bergman BC, Hunerdosse DM, Kerege A, Playdon MC, Perreault L. Localisation and composition of skeletal muscle diacylglycerol predicts insulin resistance in humans. Diabetologia 2012;55:1140–1150
    1. Hinderliter AK, Dibble AR, Biltonen RL, Sando JJ. Activation of protein kinase C by coexisting diacylglycerol-enriched and diacylglycerol-poor lipid domains. Biochemistry 1997;36:6141–6148
    1. Montell E, Turini M, Marotta M, et al. DAG accumulation from saturated fatty acids desensitizes insulin stimulation of glucose uptake in muscle cells. Am J Physiol Endocrinol Metab 2001;280:E229–E237
    1. Holland WL, Brozinick JT, Wang LP, et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 2007;5:167–179
    1. Houmard JA, Tanner CJ, Yu C, et al. Effect of weight loss on insulin sensitivity and intramuscular long-chain fatty acyl-CoAs in morbidly obese subjects. Diabetes 2002;51:2959–2963
    1. Gual P, Le Marchand-Brustel Y, Tanti JF. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie 2005;87:99–109
    1. Bouzakri K, Roques M, Gual P, et al. Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. Diabetes 2003;52:1319–1325
    1. Morino K, Petersen KF, Dufour S, et al. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest 2005;115:3587–3593
    1. Ozes ON, Akca H, Mayo LD, et al. A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1. Proc Natl Acad Sci USA 2001;98:4640–4645
    1. Axelsson T, Jansson PA, Smith U, Eliasson B. Nicotine infusion acutely impairs insulin sensitivity in type 2 diabetic patients but not in healthy subjects. J Intern Med 2001;249:539–544
    1. Mora-Martínez JM, González-Ortiz M, Balcázar-Muñoz BR, Martínez-Abundis E. Acute effect of the transdermal administration of nicotine on insulin sensitivity in healthy individuals with and without a family history of type 2 diabetes mellitus in the first branch. Metab Syndr Relat Disord 2004;2:227–233
    1. Memmott RM, Dennis PA. The role of the Akt/mTOR pathway in tobacco carcinogen-induced lung tumorigenesis. Clin Cancer Res 2010;16:4–10
    1. Newgard CB, An J, Bain JR, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 2009;9:311–326
    1. Krebs M, Brunmair B, Brehm A, et al. The Mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man. Diabetes 2007;56:1600–1607
    1. Tatebe J, Morita T. Enhancement of TNF-α expression and inhibition of glucose uptake by nicotine in the presence of a free fatty acid in C2C12 skeletal myocytes. Horm Metab Res 2011;43:11–16
    1. Ijzerman RG, Serne EH, van Weissenbruch MM, de Jongh RT, Stehouwer CD. Cigarette smoking is associated with an acute impairment of microvascular function in humans. Clin Sci (Lond) 2003;104:247–252
    1. Rönnemaa EM, Rönnemaa T, Utriainen T, et al. Decreased blood flow but unaltered insulin sensitivity of glucose uptake in skeletal muscle of chronic smokers. Metabolism 1999;48:239–244
    1. Narkiewicz K, van de Borne PJ, Hausberg M, et al. Cigarette smoking increases sympathetic outflow in humans. Circulation 1998;98:528–534
    1. Jamerson KA, Julius S, Gudbrandsson T, Andersson O, Brant DO. Reflex sympathetic activation induces acute insulin resistance in the human forearm. Hypertension 1993;21:618–623
    1. Benowitz NL, Jacob P, 3rd, Jones RT, Rosenberg J. Interindividual variability in the metabolism and cardiovascular effects of nicotine in man. J Pharmacol Exp Ther 1982;221:368–372

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