Elsevier

Metabolism

Volume 54, Issue 2, February 2005, Pages 247-254
Metabolism

Evidence for functional nicotinic receptors on pancreatic β cells

https://doi.org/10.1016/j.metabol.2004.08.020Get rights and content

Abstract

Epidemiological studies associate smoking with reduced insulin secretion. We hypothesized that nicotine could negatively affect pancreatic β-cell function. Acute or 48-hour exposures to nicotine (10−4 to 10−6 mol/L) moderately inhibited insulin release at basal (3.3 mmol/L) and/or elevated (27 mmol/L) glucose in rat and human islets. Acute exposure to nicotine (10−6 mol/L) inhibited tolbutamide (200 μmol/L)-induced insulin release by 41% (P < .05), but did not affect secretion induced by KCl (20 mmol/L) or 3-isobutyl-1-methylxanthine (1 mmol/L) (tested in rat islets). Specific binding of [3H]nicotine was demonstrated in rat islets and in a β-cell line of rat origin, INS-1. Such binding was enhanced by 48 hours of coculture with nicotine (10−7 mol/L). Expression of mRNA for the nicotinic receptor subunits α2, α3, α4, α5, α7, and β2 was detected in INS-1 cells by reverse transcriptase polymerase chain reaction. Acute exposure to cytisine (10−6 mol/L), an agonist of α4, β2 subunits, partially inhibited tolbutamide-induced insulin release. Specific binding of α bungarotoxin (10−10 mol/L), an antagonist of the α7 subunit, could be demonstrated in INS-1 cells, and culture with α bungarotoxin modestly increased insulin release in postculture incubations at basal and elevated glucose, P < .05. Our data indicate that functional nicotinic receptors are present in pancreatic islets and β cells.

Introduction

Cigarette smoking is a risk factor for type 2 diabetes [1], [2]. An epidemiological study in Stockholm, Sweden, in addition, showed that snuffing was associated with a risk for type 2 diabetes [3]. Nicotine is an obvious common constituent of smoking and snuffing. Nicotine would therefore be a prime “suspect” for the diabetogenic effect of tobacco use.

Previous evidence links a diabetogenic effect of smoking to insulin resistance [4], [5], [6], and in vivo studies provide evidence that nicotine can induce insulin resistance [7], [8]. Such effects may be secondary to increased sympathetic tone and/or to release of insulin-antagonistic hormones such as cortisol [9]. However, recent evidence suggests that the risk associated with nicotine exposure may also involve insulin secretion. Smoking and snuffing were thus associated with a low insulin response in the Stockholm study [3]. Similar results were obtained for smoking in another population-based study [10].

Long-term administration of nicotine in rats results in reduction in plasma insulin levels [11], [12]. However, because nicotine administration reduces body weight and plasma glucose [11], [12], one cannot deduce from these studies a direct effect of nicotine on β cells. A previous study of in vitro effects of nicotine on β-cell function in rat pancreatic islets tested for acute effects in rat pancreatic islets of nicotine as well as of the nicotinic antagonist α bungarotoxin [13]. There was no effect of nicotine but a stimulatory one by α bungarotoxin, and the latter effect was antagonized by nicotine. Although suggestive of functional nicotinic receptors, the previous study did not directly test for presence of nicotinic receptors or for longer term effects of nicotine. Furthermore, effects of nicotine in vitro on human β cells have, to our knowledge, not been tested. Against this background, we here tested for functional effects by acute and longer term exposure to nicotine in rat and human pancreatic islets of Langerhans as well as for the presence of nicotinic receptors in rat islets and in a clonal β-cell line of rat origin (INS-1).

Section snippets

Materials

Nicotine (free base), tolbutamide, potassium chloride (KCl), and 3-isobutyl-1-methylxanthine (IBMX) were from Sigma Co (St Louis, Mo). Cytisine was from Tocris Cookson Inc (Missouri). Collagenase was from Boehringer Mannheim (Mannheim, Germany). [3H]nicotine (specific activity, 85 or 50 Ci/mmol) (3-[125I]iodotyrosyl) α bungarotoxin (specific activity, 2000 Ci/mmol) were from American Radiolabeled Chemicals, Inc (St Louis).

Rat islets

Male Sprague-Dawley rats were obtained from Scanbur Co (Stockholm,

Acute exposure to nicotine exerts inhibitory effects on insulin secretion

In rat islets, a 60-minute exposure to nicotine exerted moderate inhibitory effects, which were, during some conditions, significant. Thus, 10−7 to 10−4 mol/L concentration of nicotine in the presence of 3.3 mmol/L concentration of glucose either tended to inhibit (P < .1) or significantly (P < .05) inhibited insulin release (Fig. 1). In human islets, 10−6 and 10−4 mol/L concentrations of nicotine significantly inhibited the insulin response to 27 mmol/L concentration of glucose (Fig. 1).

In

Discussion

This study demonstrates that nicotine can exert negative effects on insulin secretion both acutely and as a result of longer time exposure to the alkaloid. The effects observed were generally modest or moderate. However, they could still be of clinical significance.

Thus, the concentrations of nicotine used appear relevant in relation to tobacco use. It has been reported that the mean plasma nicotine level in average smokers varies from 7.4 × 10−9 to 1.7 × 10−7 mol/L and that the peak plasma

Acknowledgments

This work was supported by the Norwegian Medical Research Council (grant 161188/V40), the Juvenile Diabetes Foundation, the Norwegian Diabetes Research Association, and the Norwegian Endocrine Society.

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