title: Novel and reversible mechanisms of smoking-induced insulin resistance in humans.
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.
authors.affiliation: Department of Endocrinology, Diabetes, and Metabolism, University of Colorado Denver, Denver, Colorado, USA. bryan.bergman@ucdenver.edu
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Bergman
authors.forename: Leigh
authors.initials: L
authors.lastname: Perreault
authors.forename: Devon
authors.initials: D
authors.lastname: Hunerdosse
authors.forename: Anna
authors.initials: A
authors.lastname: Kerege
authors.forename: Mary
authors.initials: M
authors.lastname: Playdon
authors.forename: Ali M
authors.initials: AM
authors.lastname: Samek
authors.forename: Robert H
authors.initials: RH
authors.lastname: Eckel
mesh_terms: D000328:Adult; D015153:Blotting, Western; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D012907:Smoking / Q000009:adverse effects*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D009538:Nicotine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases