Nicotine Exposure Connected to Insulin Response

While exposure to nicotine promoted insulin resistance in non-obese, non-diabetic mice, chronic nicotine exposure was found to increase insulin sensitivity in a new study.

A team led by researchers from the University of California San Diego determined that acute nicotine treatment raised plasma norepinephrine (NE) and epinephrine (Epi) levels, while chronic nicotine exposure raised only Epi. Additionally, acute nicotine treatment raised both basal and glucose-stimulated insulin secretion (GSIS). As such, the authors concluded that nicotine causes both insulin resistance as well as sensitivity to insulin, depending on the duration of the treatment.
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According to the investigators, they undertook the study in an effort to better understand the metabolic effects of nicotine exposure in smokers who are neither obese or insulin-resistant, subjecting normal mice to acute nicotine treatment (30 minutes at 0.2 mcg/g body weight) and chronic nicotine treatment (administering the same treatment on a daily basis over 10 weeks).

The nicotine dose used in the studies was selected to mirror the average cigarette smoker’s peak blood level of cotinine, a stable nicotine metabolite with a half-life of 24 hours, versus 30 minutes for nicotine. The authors found that acute nicotine exposure increased fasting hyperglycemia and lower insulin sensitivity, with this action depending on the activation of nicotinic acetylcholine receptors (nAChRs), and correlated with increased catecholamine secretion, nitric oxide (NO) production, and glycogenolysis. The researchers report that the nAChR inhibitor chlorisondamine (CSM) reduced acute nicotine-induced hyperglycemia.

The researchers’ analysis of mRNA expression for nAChR subunits “revealed an unusual feature: the presence of alpha-10 mRNA, along with beta-4 mRNA in the adrenal gland, liver, and muscle,” the authors wrote. “Currently, the functions of alpha-10 in peripheral tissue are unknown. The presence of beta-4 subunit in bovine chromaffin cells has been previously demonstrated.”

According to study co-author Sushil Mahata, PhD, a professor of medicine and research physiologist at the University of California San Diego, a non-peptide chemical targeting alpha-2 beta-4 could represent a novel therapy for insulin resistance and other metabolic disorders.

“We propose that the hyperglycemia induced by acute nicotine treatment was predominantly the result of glycogen breakdown mediated by increased plasma catecholamine levels and hepatic NO concentrations,” the authors wrote. “In vivo, NE and Epi activate both alpha- and beta-ADR and the alpha-ADR antagonist phentolamine blocked catecholamine effects on hyperglycemia and glycogenolysis.”

—Mark McGraw

Reference

Vu C, Siddiqui J, et al. Nicotinic cholinergic receptors in glucose homeostasis: the acute hyperglycemic and chronic insulin-sensitive effects of nicotine suggest dual opposing roles of the receptors in male mice. Endocrinology. 2014.