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October 17, 2019  National Institute on Drug Abuse

Smokers stand a 30-40 percent higher risk of developing type 2 diabetes—a disease in which the body loses the ability to produce or use insulin, leading to excess glucose in the blood and poor use of glucose as cellular fuel. Diabetes can have many serious consequences, including heart and kidney disease, blindness, and poor circulation leading to ulcers and amputation. People with diabetes also have a harder time quitting smoking. Until recently, nicotine’s link to diabetes has been thought to involve inflammation and oxidative stress caused by chemicals in cigarette smoke, but a group of researchers led by Paul J. Kenny at the Icahn School of Medicine at Mount Sinai has discovered an unexpected brain-based mechanism tied specifically to nicotine.

When the researchers deleted a specific diabetes-associated gene in rats, they unexpectedly found that it increased the rats’ nicotine consumption but also had a protective effect against the emergence of diabetes. It revealed that this gene, called transcription factor 7-like 2 (Tcf7l2), plays a dual role: It regulates cellular responsiveness to nicotine in a brain area called the habenula, which is important in aversive responses to stimuli, and it also controls a pathway linking the habenula to the pancreas, where insulin is produced.

When nicotine acetylcholine receptors in the habenula of normal animals (with Tcf7l2) are activated by nicotine, it stimulates an aversive response to the drug that limits nicotine intake but also inhibits the pancreas from releasing glucagon and insulin; this in turn raises blood glucose—and thus, diabetes risk. However, the increased blood sugar also inhibits the neurons in the habenula that express those nicotine acetylcholine receptors—thus the raised blood sugar dials down the brain’s aversive response to nicotine, encouraging more consumption.

Although it has only been found thus far in an animal model, the mechanism identified by Kenny and his colleagues also potentially points to a health consequence of nicotine addiction that would apply to vaping and other non-combustion delivery systems, not just cigarettes. Along with their cigarette-smoking peers, the 21 percent of high school seniors who report vaping nicotine (in the past month), according to last year’s Monitoring the Future survey, could be putting themselves at increased risk for a disease that has traditionally been associated with poor quality diet and poor dietary habits.

The brain and body are intricately interconnected, and science continually brings more, not less, evidence of that fact. The discovery of a gene-mediated connection between the habenula and pancreas invites us to think about ways that brain circuits might be targeted in treating type 2 diabetes. It also invites us to broaden our imagination when considering other disease processes we ordinarily think of as involving peripheral organs or systems. For instance, could other smoking-related diseases like high blood pressure and heart disease also have a brain component mediated by nicotine, or even other addictive substances? These are just some of the many fascinating questions raised by the new finding, which was published this week in Nature.

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