What are the effects of proteins on our body in terms of smoking and diatabase

A protein in the

brain

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may link smoking and diabetes

Nicotine

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overrides the communication pathway between the

brain

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and pancreas, causing high

glucose

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levels in rats

by

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By

Megha Satyanarayana OCTOBER 16, 2019 | APPEARED IN VOLUME 97, ISSUE 41 Smokers develop type 2 diabetes 30–40% more often than nonsmokers, and new research suggests that

nicotine

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’s actions in the

brain

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may be to blame. Experiments in rats suggest that

nicotine

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may needlessly turn on part of the body’s fight-or-flight mechanism, flooding it with useless

glucose

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that would

otherwise

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get used to run, punch, or kick.

Over

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After

years of cigarette or

vape

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Vape

cape

-pen use, those useless

glucose

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bumps wear out the insulin-

signaling

any nonverbal action or gesture that encodes a message

signalling

pathways in cells and eventually lead to diabetes, says Paul J. Kenny, the

neuroscientist

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at the Icahn School of Medicine at Mount Sinai who led the study (Nature 2019, DOI: 10.1038/s41586-019-1653-x). Kenny’s

team

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found that the main player in

this

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signaling

any nonverbal action or gesture that encodes a message

signalling

short circuit is a protein called TCF7L2, which influences two things: the motivation to take

nicotine

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and a conversation between the

brain

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and pancreas. “It all converges on

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one

factor

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,” Kenny says. “Ultimately, a disease like diabetes may be originating in the

brain

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or may reflect

dysregulated

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brain

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-body interactions, and I think that’s absolutely fascinating and absolutely terrifying.” He wonders if other diseases have

brain

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-body connections that can get

similarly

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disrupted. His

team

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studies a part of the

brain

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called the

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habenula

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, which is involved in our stress response and is chock full of

nicotinic

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acetylcholine

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receptors, which

nicotine

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binds to and activates, giving people a buzz when they smoke. Kenny’s group had previously reported that mutations that seem to lead to

nicotine

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addiction in humans were often found in

nicotinic

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acetylcholine

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receptors in the

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habenula

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. Credit: Wikipedia/Emw TCF7L2 is a

transcription

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factor

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active

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activity

in the

brain

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and pancreas. The

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habenula

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is

also

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full of TCF7L2, which is a

transcription

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factor

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that acts as an on-off switch for several genes. Rats missing

this

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transcription

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factor

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“consume absolutely horrendous amounts of

nicotine

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,” Kenny says. But TCF7L2 is

also

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expressed elsewhere in the body and is associated with type 2 diabetes. People with certain gene sequences for TCF7L2 tend to get diabetes more often than people with other sequences. Kenny says his

team

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thought TCF7L2 might be doing something in both the

brain

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and pancreas to influence the role of

nicotine

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in diabetes. The researchers found that after

nicotine

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exposure, the

nicotinic

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acetylcholine

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receptors in rats without TCF7L2 were less sensitive than those of normal rats. Under normal conditions, when

nicotine

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or other molecules turn on the receptors, the proteins eventually enter a

sleepy

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sleep

state in which the receptors can’t turn back on for some time. In rats without TCF7L2, the receptors couldn’t bounce back from

this

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state as quickly as ones in rats with TCF7L2. Basically, their brains weren’t responding in quite the same way, Kenny says. And in an experiment that traced the path of neurons, the

team

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found that neurons in the pancreas led to the

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habenula

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. ADVERTISEMENT SCROLL TO CONTINUE WITH CONTENT Looking at different genes in the

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habenula

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that TCF7L2 is predicted to control, the

team

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found that many were involved in the regulation of

glucose

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metabolism. Given that

nicotine

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is known to cause increases

inblood

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in blood

-

glucose

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levels, the

team

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wondered if TCF7L2 might influence

this

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action of

nicotine

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. Lowering levels of TCF7L2 reduced

nicotine

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’s ability to boost blood sugar. And after treating rats for 21 days with

nicotine

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, the

team

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found that the rats missing TCF7L2 had lower blood-sugar levels, suggesting that the

transcription

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factor

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mediates some diabetes-like symptoms. Kenny doesn’t think that high blood-

glucose

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levels lead to

nicotine

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addiction.

Instead

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, it’s more likely that all the extra

glucose

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is tamping down the activity of

nicotinic

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acetylcholine

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receptors, making each puff less effective and leading people to take more puffs. He says one of the

next

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big questions is whether the

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habenula

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is playing a role in normal

glucose

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metabolism. Kenny thinks the link between the stress-response function of the

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habenula

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and the

nicotine

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override

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overrides

might lead to diabetes. In an actual fight-or-flight situation, “you’re stressed or you’re frightened, and you need to respond to that,” he says. “You need to access energy reserves, and

this

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stress affects the pancreas.” Over time,

this

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regular stress to the pancreas leads to diabetes. TCF7L2 helps regulate all that. The

team

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is now looking at drugs that modulate TCF7L2 activity directly or indirectly. One is

sitagliptin

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, sold as Januvia. It’s a diabetes drug that prevents the breakdown of a protein called GLP-1, which is associated with TCF7L2. Mice given the drug tend to consume less

nicotine

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, and Kenny says there are some anecdotal data that people taking Januvia stop smoking (Nat. Neurosci. 2017, DOI: 10.1038/nn.4540). There are several other drugs in

this

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class, and Kenny thinks these drugs might make an excellent one-two punch in people who have diabetes and may want to stop smoking. Marina Picciotto, a neuroscientist at Yale School of Medicine who was not involved in the research, says these experiments not only define a new way that the

brain

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communicates with the body and vice

versa but

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versa, but also

also

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help pinpoint how

nicotine

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and smoking affect metabolism by overtaking

this

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conversation. SPONSORED CONTENT New, Safer Automated Analysis of Ethylene Oxide

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By

Metrohm Rats are a fairly reliable model for

nicotine

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use and overuse, she says, but it remains to be seen if the same things are happening in humans. Kenny’s

team

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is looking at large databases of human genetics, searching for people who might have mutations in TCF7L2 and seeing whether they smoke and if they ever developed diabetes. There are “all sorts of interactions between [TCF7L2], smoking, and diabetes from human

genetics

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genetic

data,” he says. “

Nicotine

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is a major driver of both

brain

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and body diseases. It’s a very problematic drug.”