Abstract Introduction Nicotine-replacement products and e-cigarettes are increasingly used, yet the independent metabolic effects of nicotine on glucose and lipid homeostasis remain uncertain. We examined how dose and dosing frequency shape these effects in mice. Methods Male C57BL/6J mice received subcutaneous nicotine at 0.5, 1.0, or 2.0 mg/kg once (qd), twice (bid), or four times daily (qid) for 4 weeks; controls received saline. Blood glucose, glucose-tolerance tests (GTT), insulin-tolerance tests (ITT), plasma insulin, total cholesterol (TC), triglycerides (TG), non-esterified fatty acids (NEFA), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), and the HDL-C/LDL-C ratio were measured. Results High-frequency nicotine (qid) elevated blood glucose and impaired glucose tolerance at every dose, whereas qd and bid schedules were neutral except for a 1.0 mg/kg bid group. Insulin sensitivity and plasma insulin were unchanged. Nicotine significantly reduced TC levels, especially at 0.5 mg/kg across all frequencies. It had a minor impact on TG and NEFA, except for a decrease in TG at 2 mg/kg and an NEFA increase at 0.5 mg/kg qd. Nicotine lowered HDL-C and raised LDL-C across schedules, reducing the HDL-C/LDL-C ratio in almost all groups. Conclusions Four-week nicotine treatment disrupted glucose control only with four-times-daily dosing, indicating that exposure frequency—not dose—drives nicotine-induced hyperglycaemia. In contrast, an atherogenic lipid shift (HDL-C↓, LDL-C↑, HDL-C/LDL-C↓) occurred across doses and frequencies, with minimal change in TG or NEFA. These findings suggest that dose-frequency interplay must be considered when assessing the cardiometabolic safety of nicotine-based cessation products. Implications Nicotine’s metabolic safety profile is governed more by how often it is used than by the nominal dose. High-frequency exposure drives hyperglycaemia, whereas dyslipidaemia—lower HDL-C, higher LDL-C, and a reduced HDL-C/LDL-C ratio—emerges across all doses and schedules. These findings indicate that regulatory guidance, clinical counselling, and product-design standards for nicotine-replacement therapies and e-cigarettes must account for dosing pattern, not merely total nicotine intake. Routine metabolic monitoring may be warranted in individuals who use nicotine products frequently, even at low doses, to mitigate potential cardiometabolic risk.
Qin et al. (Tue,) studied this question.