Habenular Tcf7l2 links nicotine addiction to diabetes

Diabetes is far more prevalent in smokers than non-smokers, but little is known about underlying mechanisms of vulnerability. Here, we show that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula (mHb), where it regulates the function of nicotinic acetylcholine receptors. Inhibition of Tcf7l2 signaling in the mHb increases nicotine intake in mice and rats. Nicotine elevates blood glucose levels through a Tcf7l2-dependent stimulatory action on the mHb. Virus tracing identifies a polysynaptic connection from the mHb to the pancreas, and wild-type rats with a history of nicotine consumption show elevated circulating levels of glucagon and insulin and diabetes-like dysregulation of blood glucose homeostasis. In contrast, Tcf7l2(mut) rats are resistant to these actions of nicotine. Our findings suggest that Tcf7l2 regulates the stimulatory actions of nicotine on a habenula-pancreas axis that links the addictive properties of nicotine to its diabetes-promoting actions.