Editors' ChoicePhysiology

A smoky path to diabetes

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Science Signaling  22 Oct 2019:
Vol. 12, Issue 604, eaaz9013
DOI: 10.1126/scisignal.aaz9013

A nicotine-activated brain-pancreas circuit could explain why smokers are more likely to develop type 2 diabetes.

Nicotine, the addictive component of tobacco, increases blood glucose levels, and longtime smokers have an increased risk of developing type 2 diabetes (T2D) compared with nonsmokers. Duncan et al. (see also Bruschetta and Diano) uncovered a circuit that could potentiate nicotine addiction involving the transcription factor TCF7L2 in the brain and pancreas. Variants in TCF7L2 are strongly associated with increased susceptibility to T2D in multiple ethnic groups. TCF7L2 binds to β-catenin and also functions in the GLP-1 and insulin signaling pathways, in addition to its role in the Wnt/β-catenin pathway. The authors showed that Tcf7l2 mRNA was enriched in cholinergic neurons in the medial habenula, a region of the brain involved in nicotine withdrawal symptoms. Rats that globally expressed a form of TCF7L2 that could not bind to β-catenin or mice that were deficient in Tcf7l2 in the medial habenula had an increased response to nicotine and increased self-administered intake of nicotine. These effects required signaling in the medial habenula mediated by GLP-1, but not by Wnt or insulin. Electrophysiological, RNA-sequencing, and pharmacological analyses of neurons from the medial habenula of control and Tcf7l2 mutant rats showed that TCF7L2 promoted the recovery of nicotinic acetylcholine receptors (nAChRs) from nicotine-induced desensitization in a cAMP-dependent manner. The increase in blood glucose levels induced by nicotine injection was mimicked by chemogenetic stimulation of nAChRs in the medial habenula and reversed by knockdown of the GLP-1 receptor or TCF7L2 in the medial habenula. Trans-synaptic tracing revealed a neuronal circuit from the medial habenula to the pancreas. Control rats that self-administered nicotine showed increases in fasting glucose levels and circulating insulin and glucagon levels—effects not seen in Tcf7l2 mutant rats—suggesting that nicotine administration leads to impaired glucose homeostasis. In turn, increased glucose levels suppressed the magnitude of nAChR currents in response to nicotine in the medial habenula, an effect that could promote nicotine addiction. Thus, nicotine stimulation of nAChRs in the medial habenula leads to alterations in glucose homeostasis that feed back onto nAChRs to potentially reinforce addiction to nicotine.

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