Cigarette smoking is a well-recognized risk factor for type 2 diabetes (T2DM), and may result in islet β cell damage and impaired insulin secretion. However, the underlying mechanisms remain largely elusive. In the present study, we demonstrated that nicotine induced premature senescence of pancreatic β cells in vitro and in vivo. The senescence-associated β-galactosidase (SA-β-Gal) assay showed that nicotine exposure induced apparent senescence phenotype of β-TC-6 cells at an initiating dose of 100 μM and starting from 12 h. In addition, 100 and 500 μM of nicotine exposure altered the expression of senescence marker proteins, such as p16, p19 and p21. Furthermore, we uncovered that the levels of intracellular Ca2+ and reactive oxygen species (ROS) were significantly elevated in β-TC-6 cells following exposure to 100 and 500 μM nicotine, while calcium channel blocker can reverse this effect. Furthermore, the senescence-inducing phenotype was confirmed in rat insulinoma INS-1 cells at a similar dose range, whereas blockade of nAChRs, calcium and ROS led to apparent impairment of senescence. Finally, we found that administration with 100 and 200 μg/mL nicotine in drinking water for 28 days significantly exacerbated aberrant glucose homeostasis in a mouse model of fat-induced T2DM. Of great intrigue, pancreatic β cells exhibited significantly enhanced senescence following nicotine administration. Taken together, this study suggests that premature senescence plays a pivotal role in nicotine-triggered β cell destruction and glucose intolerance, providing a theoretical basis for targeted prevention and treatment of smoking-induced T2DM.
Keywords: ROS; islet β cells; nicotine; senescence; type 2 diabetes.
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