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-1ser636 phosphorylation. In muscle cell culture, nicotine exposure significantly increased IRS-1ser636 phosphorylation and decreased insulin sensitivity, recapitulating the phenotype of smoking-induced insulin resistance in humans. The two pathways known to stimulate IRS-1ser636 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-1ser636 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.

Clinical Correlates of Insulin Sensitivity and Its Association with Mortality among Men with CKD Stages 3 and 4

“…Assuming that these associations are causal, the clinical applicability of our study is the identification of modifiable risk factors that can be targeted to improve IS and thereby, potentially attenuate the outcome implications of impaired IS in the CKD population. Supporting this concept, a recent community study showed that chronic cigarette smokers had a lower IS than nonsmokers and that IS improves, although it does not normalize, after 1-2 weeks of smoking cessation (31). Nevertheless, when interpreting these findings, it should be noted that, despite the overall relatively large sample size of the current study, it may not be powered enough to draw firm conclusions in substrata analysis, and additional studies are warranted to confirm this hypothesis.…”

Effects of smoking cessation on β-cell function, insulin sensitivity, body weight, and appetite

“…after 3 months) further deterioration in fasting insulin sensitivity (QUICKI) and fasting hyperinsulinemia, but no change in dynamic insulin sensitivity in the OGTT (OGIS). Two other studies have shown improvements in whole-body insulin sensitivity 1-2 and 8 weeks after stopping smoking respectively (34,35). It is possible that an initial positive effect of smoking cessation on insulin sensitivity (maybe missed in our study on account of the protocol timing) is followed by the deterioration we observed at 3 months -by which time body weight gain was already significant.…”

Metabolic effects of smoking cessation

“…Insulin sensitivity has been shown to improve with smoking cessation that occurs in conjunction with normalization of phosphorylation of insulin receptor substrate 1 (IRS-1) at Ser636 106 . In cell culture studies, nicotine stimulates the two pathways known to stimulate IRS-1 (Ser636) phosphorylation (p44/42 mitogen-activated protein kinase (MAPK)) and mammalian target of rapamycin (mTOR).…”