Exposure Pattern Dictates Nicotine's Metabolic Impact in Mice: Frequency-Driven Hyperglycemia Versus Dose-Independent Dyslipidemia.

INTRODUCTION

Nicotine-replacement products and e-cigarettes are increasingly used, yet the independent metabolic effects of nicotine on glucose and lipid homeostasis remain uncertain.

METHODS

We examined how dose and dosing frequency shape these effects in mice. 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, insulin tolerance tests, plasma insulin, total cholesterol, triglycerides (TGs), non-esterified fatty acids (NEFAs), high-density lipoprotein cholesterol-cholesterol (HDL-C), low-density lipoprotein cholesterol-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 total cholesterol 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 hyperglycemia. 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 hyperglycemia, whereas dyslipidemia-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 counseling, 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.