Beta2 Effect on Insulin and Glucagon

[justadream]

Current (2016) edition of FA indicates that Beta2-binding causes increased insulin release.

Previous editions of FA (although not the current one I think) and Wikipedia (see quote below) indicate that Beta2-binding causes increased glucagon release.

"Hypoglycemia can occur with beta blockade because β2-adrenoceptors normally stimulate hepatic glycogen breakdown (glycogenolysis) and pancreatic release of glucagon, which work together to increase plasma glucose. Therefore, blocking β2-adrenoceptors lowers plasma glucose. "

https://en.wikipedia.org/wiki/Beta_blocker#Adverse_effects

So is it both?

Assuming it is both, then why would Beta2-blockage cause the hypoglycemia effect illustrated in the Wikipedia quote? Blocking Beta2 ==> blocking insulin AND glucagon ==> ??? ==> hypoglycemia?

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[Kendragon]

Beta 2 binding can cause both insulin release and glucagon release. I've tried looking through this article to figure out the mechanisms, but it seems like the exact mechanisms still aren't quite clear yet. So I wouldn't get too caught up on the wikipedia quote.

I think the important higher yield things to focus on are:
-The first aid "Glycogen regulation by insulin and glucagon/epinephrine" chart, showing how Beta receptor stimulation by epinephrine triggers glycogenolysis via cAMP.
-That beta blockers can increase the risk of severe hypoglycemia because it masks the epinephrine induced warning signs of neuroglycopenia (sweating, anxiety).

 

[Taco Time]

Beta 2 binding can cause both insulin release and glucagon release. I've tried looking through this article to figure out the mechanisms, but it seems like the exact mechanisms still aren't quite clear yet. So I wouldn't get too caught up on the wikipedia quote.

I think the important higher yield things to focus on are:
-The first aid "Glycogen regulation by insulin and glucagon/epinephrine" chart, showing how Beta receptor stimulation by epinephrine triggers glycogenolysis via cAMP.
-That beta blockers can increase the risk of severe hypoglycemia because it masks the epinephrine induced warning signs of neuroglycopenia (sweating, anxiety).

Also, the biggest beta-adrenergic effect to keep in mind that'll be masked is tachycardia. This is especially important because the patient that isn't adherent with their meds comes into the hospital with a blood glucose of nearly 1,000 with their serum osmolarity off the charts, but they're urine is loaded with glucose and they're peeing out a ton of fluids. A patient not on B-blockers will get tachycardia to counter the volume depleted state, CO = HR x SV. Whereas a patient on a B-blocker will have their tachycardia masked. It's important to keep this in mind on exams (I remember Rx had a question on it) and in real life with T2DM patients that are on a B-blocker for CHF and diabetes meds.

 

[justadream]

Beta 2 binding can cause both insulin release and glucagon release. I've tried looking through this article to figure out the mechanisms, but it seems like the exact mechanisms still aren't quite clear yet. So I wouldn't get too caught up on the wikipedia quote.

I think the important higher yield things to focus on are:
-The first aid "Glycogen regulation by insulin and glucagon/epinephrine" chart, showing how Beta receptor stimulation by epinephrine triggers glycogenolysis via cAMP.
-That beta blockers can increase the risk of severe hypoglycemia because it masks the epinephrine induced warning signs of neuroglycopenia (sweating, anxiety).

Thanks for the answer.

I have a question about the bolded that is semi-off-topic.

I know sweating is sympathetic (but uses muscarinic receptors) but if you look in FA 2016 page 242 (basically listing all the receptor types and their functions), it lists increased sweat secretion as under the "M3" receptor and under the "parasympathetic" category.

Lots of other things are listed under M3 such as increased gut peristalsis, increased bladder contraction, etc (these are all things clearly parasympathetic) so I'm wondering if the M3 receptors on sweat glands are different from the M3 receptors on, say, the gut or bladder?

 

[FindMeOnTheLinks]

Thanks for the answer.

I have a question about the bolded that is semi-off-topic.

I know sweating is sympathetic (but uses muscarinic receptors) but if you look in FA 2016 page 242 (basically listing all the receptor types and their functions), it lists increased sweat secretion as under the "M3" receptor and under the "parasympathetic" category.

Lots of other things are listed under M3 such as increased gut peristalsis, increased bladder contraction, etc (these are all things clearly parasympathetic) so I'm wondering if the M3 receptors on sweat glands are different from the M3 receptors on, say, the gut or bladder?

Remember that M3 receptors are coupled to Gq and thus increase intracellular calcium to stimulate smooth muscle contraction and glandular secretion. In sweat glands, contraction of myoepithelial cells causes secretion of sweat. So it would make sense for sweat glands to be innervated by those M3 receptors. Hope that helps.


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[justadream]

Remember that M3 receptors are coupled to Gq and thus increase intracellular calcium to stimulate smooth muscle contraction and glandular secretion. In sweat glands, contraction of myoepithelial cells causes secretion of sweat. So it would make sense for sweat glands to be innervated by those M3 receptors. Hope that helps.


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I guess what I'm confused by is how to reconcile these facts:

1) Epinephrine causes sweat secretion
2) Sweat secretion is mediated by M3 receptors (as you explained quite well) and muscarinic receptors are acted on by ACh (not Epi)

So how does epinephrine have it's effect on M3 to cause sweating?

Also, since M3 mediates sweat secretion, wouldn't parasympathetic activation cause sweating?

 

[FindMeOnTheLinks]

I guess what I'm confused by is how to reconcile these facts:

1) Epinephrine causes sweat secretion
2) Sweat secretion is mediated by M3 receptors (as you explained quite well) and muscarinic receptors are acted on by ACh (not Epi)

So how does epinephrine have it's effect on M3 to cause sweating?

Also, since M3 mediates sweat secretion, wouldn't parasympathetic activation cause sweating?

I found a source that says eccrine sweat glands (in all skin but mostly palms and soles) have both beta-1 and M3 receptors. With increased SNS activity, circulating epi will act on those Beta-1 receptors which will have additive effects with the M3 receptors (according to the source I found). Sweat glands are innervated mostly by sympathetic cholinergic neurons but also by fewer adrenergic neurons (which presumably would secrete norepi onto the beta-1 receptors and wouldn't have as much of an effect as circulating Epi).

The same source says that apocrine sweat glands (in the armpit and groin) are NOT innervated at all but have beta-1 receptors that are activated by circulating epinephrine.

This follows back to the discussion about beta blockers masking the sweating caused by hypoglycemia. If there's no beta-1 activity, you ain't gonna get a ton of sweating.

I can't find anything that explains the exact role of the beta-1 receptor in sweat secretion but we can surmise that the increase in cAMP-->PKA must act on something to stimulate secretion (calcium channel perhaps?).

For your last question, you are correct that usually parasympathetic neurons act on muscarinic receptors but remember that the target cell must actually be innervated by PSNS to have an effect. In the case of sweat glands, they are innervated by those special muscarinic sympathetic neurons which release ACh and stimulate M3. We can also tie this back to the anatomy of the autonomic nervous system: we know the vagus and pelvic splanchnic nerves ain't gonna be widespread enough to innervate sweat glands throughout the skin, so that's why we get the sympathetic to do it. Since there is no parasympathetic innervation going on there, parasympathetic activity won't have an effect. Now if you somehow had some circulating acetylecholine, that would definitely light up those sweat glands. Does that all make sense?

Anyhow, I hope this helps your understanding of the physiology of sweating.


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