October 29, 2019
Written by: Nitsan Goldstein
The dangers of smoking have been widely recognized for years. Smoking increases the chances of developing many dangerous diseases, including lung cancer and cardiovascular disease. A perhaps lesser known relationship, however, is that between smoking and type 2 diabetes. Consistent tobacco smoking increases one’s risk of developing type 2 diabetes, which is a condition where the body is no longer able to regulate blood glucose levels1. The reasons behind this relationship, however, were not well understood. A new study published in the journal Nature found a small brain region that seems to connect nicotine, the addictive substance in tobacco, with the regulation of blood sugar2. Here we will break down their findings and what they might mean for the treatment and prevention of both nicotine addiction and type 2 diabetes.
Nicotine, like other drugs, hijacks the brain’s natural reward system to produce pleasure. Also like other drugs, nicotine can become addictive when used consistently as the brain becomes dependent on the drug. However, nicotine is unique in its effect on a type of neuron in the brain that responds to a chemical called acetylcholine. Acetylcholine is important in muscle activation, but functions in the central nervous system as well by influencing memory formation, sleep, and motivation. One class of acetylcholine receptors is also activated by nicotine. Thus, tobacco smoking, through the action of nicotine on these receptors, has wide ranging effects on the brain. It has been previously shown that taking high levels of nicotine activates a group of neurons in a tiny brain region called the medial habenula (mHb) that contain the acetylcholine receptors3. Importantly, these neurons are thought to respond to negative, unpleasant stimuli and, when active, cause negative affect or feelings. This site of action in the brain, therefore, counteracts the pleasurable effects of nicotine, making it an important factor in whether or not nicotine use becomes a nicotine addiction.
The findings linking smoking with diabetes focus on this “unpleasant” pathway – the activation of mHb neurons with acetylcholine receptors by nicotine. The scientists had previously found a link between nicotine’s effects on this pathway and a hormone that acts in the brain and other organs in the body4. In non-brain organs, this hormone strongly affects blood glucose levels through a pathway involving a protein called TCF7L2. Interestingly, the gene encoding this protein is one of the genes most strongly associated with type 2 diabetes5. The role of this protein in the brain, however, was not well understood. The researchers used mice and rats to study the function of TCF7L2 in the brain, which turned out to provide a potential link between smoking and diabetes.
The first major finding from this study is that TCF7L2 seems to be specifically involved in the motivation to seek out nicotine through its actions on the mHb “unpleasant” pathway. Just like in humans, nicotine is addictive to rodents, so they are often used as a model for studying nicotine addiction. When investigators inactivated the protein in rats or mice, they found that the neurons in the mHb that contain the acetylcholine receptors (those that normally respond to nicotine) are no longer activated by the drug. Since the activity of the “unpleasant” pathway is decreased, the rats self-administered (chose to take) significantly more nicotine than the control animals, where TCF7L2 was functioning properly.
When they looked at the effect of nicotine on the acetylcholine receptors, they found that TCF7L2 seems to be important in the ability of the acetylcholine receptors to properly recover normal activity following exposure to nicotine. This is why they were not able to respond to nicotine when the TCF7L2 was mutated. The conclusion here is that TCF7L2 does play a role in the brain, and that role is to increase the responsiveness of mHb neurons to nicotine (Figure 1). Without it, the unpleasant pathway is less active. The authors hypothesize this may increase the risk of developing a nicotine addiction. The question still remains, though, how does this relate to blood sugar regulation and diabetes?
The second major finding in this study is that TCF7L2 in mHb neurons also plays a direct role in blood glucose regulation, linking smoking with risk of developing diabetes, a disease whose hallmark symptom is dysregulation of blood glucose. The authors found that nicotine increases blood glucose levels. Interestingly, stimulation of the mHb pathway also increases blood glucose levels, and this depends on the neurons having the functional TCF7L2. The scientists found that there is a neural pathway between these neurons and the pancreas, which releases glucagon when glucose in the blood is low, like when you’re hungry. Glucagon then binds to liver cells and causes them to release glucose, raising blood glucose levels until food is consumed. When mice were exposed to nicotine for several days, the glucagon, and therefore glucose in the blood was elevated even though the rats were not hungry. Ultimately, the activity of the mHb circuit was causing excess release of glucagon from the pancreas (Figure 2).
Finally, prior research has shown that people with type 2 diabetes have a harder time quitting smoking than people without diabetes6. Could this relationship also involve the mHb circuit? The researchers exposed rats to a sugar solution for several weeks, which increases their blood glucose levels. The high blood glucose levels actually decreased the response of mHb neurons to nicotine (Figure 2). Remember that these neurons are part of the “unpleasant” pathway, so this could explain why people with diabetes, who generally have high blood glucose levels, have a harder time quitting.
This research highlights a potential mechanistic link between cigarette smoking and type 2 diabetes, though several questions remain. For example, it is puzzling that TCF7L2 dysfunction was found to increase nicotine seeking yet protect against the increase in blood glucose caused by nicotine. Additionally, acetylcholine receptors are found throughout the brain, so it’s possible that the mHb is one of several regions where nicotine could exert its effects over peripheral hormone release7. Finally, while studies in rodents such as this one are critical to understanding the underlying biological causes of disease, scientists will have to examine whether these systems play a similar role in humans. If so, TCF7L2 may be a novel target for drugs to protect against addiction, help people quit smoking, or even mitigate type 2 diabetes symptoms.
- Willi, C., Bodenmann, P., Ghali, W. A., Faris, P. D. & Cornuz, J. Active smoking and the risk of type 2 diabetes: a systematic review and meta-analysis. Am. Med. Assoc. 298, 2654–2664 (2007).
- Duncan, A. et al. Habenular TCF7L2 links nicotine addiction to diabetes. Nature 574, 372-377 (2019).
- Fowler, C. D., Lu, Q., Johnson, P. M., Marks, M. J. & Kenny, P. J. Habenular α5 nicotinic receptor subunit signalling controls nicotine intake. Nature471, 597–601 (2011).
- Tuesta, L. M. et al. GLP-1 acts on habenular avoidance circuits to control nicotine intake. Neurosci. 20, 708–716 (2017).
- Sladek, R. et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature445, 881–885 (2007).
- Solberg, L. I., Desai, J. R., O’Connor, P. J., Bishop, D. B. & Devlin, H. M. Fam. Med.2, 26–32 (2004).
- Bruschetta, G., Diano, S. Brain-to-pancreas signaling axis links nicotine and diabetes. Nature 574, 336-337 (2019).
Cover Photo by Assef Elweter and Wikimedia Commons (CC BY-SA 3.0) https://commons.wikimedia.org/wiki/File:Assef_ganja.jpg
Figures 1 and 2 created using BioRender
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