Researchers have discovered a mechanism in rats that links cigarette smoking and the risk of developing type 2 diabetes. Scientists found a crucial role for a diabetes-associated gene, called transcription factor 7-like 2 (Tcf7l2), in regulating the response to nicotine in the brain. Tcf7l2, which regulates the expression of genes in the pancreas and liver that determine blood glucose levels, also regulates the response of cells in the habenula, an area of the brain that controls reward and aversion behaviors, to nicotine. Variation in Tcf7l2 increases the risk of developing type 2 diabetes, but little has been known about its function in the brain. The study discovered that Tcf7l2 controls a pathway linking the habenula, which controls nicotine intake, to the pancreas, with this circuit responsible for nicotine-induced increases in blood glucose.
To investigate the association between Tcf7l2, nicotine addiction and blood glucose regulation, researchers genetically deleted Tcf7l2, in rats. The mutant rats consumed much greater quantities of nicotine at each dose. Unexpectedly, while the loss of Tcf7l2 function in the habenula increased nicotine consumption in rats, this change also reduced nicotine-driven blood glucose increases and protected against the emergence of diabetes-associated abnormalities in blood glucose levels.
"This unanticipated finding suggests a link between nicotine use and the onset of type 2 diabetes, with implications for future prevention and treatment strategies for both diseases," said NIDA Director Dr. Nora D. Volkow. "Although addiction is a brain disease, this discovery underscores how the body’s complex functions are exquisitely interconnected, revealing the need for integrated and innovative research."
If these findings in rats extend to human cigarette smokers, they suggest a complex dynamic in which variations in the Tcf7l2 gene might influence both the risk of tobacco addiction and the development of tobacco-associated type 2 diabetes. More broadly, these findings suggest that type 2 diabetes – and perhaps other cigarette smoking-related diseases in which abnormalities in the autonomic nervous system play a role, such as hypertension and cardiovascular disease – originate in the brain and implicate nicotine-induced disrupted interactions between the habenula and the peripheral nervous system.
For a copy of the paper, “Habenular Tcf7l2 links nicotine addiction to diabetes,” published in Nature, visit https://www.nature.com/articles/s41586-019-1653-x.
For more information about nicotine and smoking, visit Tobacco/Nicotine and Vaping.
NIDA Press Office
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