Help!! Why is glucagon a stimulator of insulin secretion?

[telomerasa]

Hi everybody! Does anyone know why does glucagon stimulate pancreatic beta-cells to secrete insulin? I have searched many articles, but I haven't found an answer.... I know that beta-cells have glucagon membrane receptors and that they work activating cAMP production, but what is the physiological translation of this? Why is glucagon an insulin secretagogue? Isn't high blood glucose concentration enough stimuli? I hope that someone can help me with this...

[armygas]

Glucagon's actions actually oppose those of insulin.....

 

"Exogenous administration of glucagon produces the same pharmacologic effects as endogenous glucagon. These effects include increases in blood glucose, relaxation of smooth muscle of the GI tract, and a positive inotropic and chronotropic effect on the heart. Increases in blood glucose are secondary to stimulation of glycogenolysis. In liver and adipose tissue, glucagon increases the production of adenylate cyclase, which catalyzes the conversion of ATP to cAMP. Cyclic AMP then initiates a series of enzymatic reactions that include activation of phosphorylase, which promotes the breakdown of glycogen to glucose. As a result, blood glucose levels are increased within minutes of glucagon administration. The degree to which glucagon increases blood glucose is dependent on the liver glycogen reserves and the presence of phosphorylases. The increase in blood glucose is not as great in patients with type I diabetes mellitus as compared to those with type II diabetes mellitus. The exact mechanism by which glucagon exerts its effects on GI smooth muscle and cardiac muscle are unknown."

[Phi for All]

Please give citation or post links when you quote other sources. It's the proper thang t'do.

[telomerasa]

I know that the effects of glucagon are the opposite of those of insulin. My question is if insulin acts as an inhibitor of glucagon secretion, why doesn't it work the other way round? Yes,I know it sounds weird and somewhat illogical but it is true, you can look in any physiology text and you will find that glucagon stimulates insulin secretion. But my question is why???

[Realitycheck]

I don't have enough time to digest all of this, but you can check out these links. These guys are pretty good about doing their homework and backing up everything they say with scientific documentation. Beware though, this has been retrieved from deep inside the lines of the hardcore creationist camp.

 

http://www.abcbodybuilding.com/Nutrientpartitioningpart1.php

 

http://www.abcbodybuilding.com/magazine03/exerciseendocronology1.htm

 

http://www.abcbodybuilding.com/13weekstohardcorefatburningdiet.php

[Realitycheck]

It says here that glucagon gets broken down into glucose which, in turn, will release insulin.

 

Glucagon works with E and NE to stimulate the Cori cycle (Kusaka and Ui, 1977) The Cori cycle begins as glycogen phosphorylase breaks down glycogen into glucose. Glucose is then released into the blood plasma, where it enters skeletal muscle through specialized receptors known as GLUT-4 receptors. As previously stated, the glucose enters the enzymatic pathway glycolysis and can form the gluconeogenic substrates pyruvate and lactate. If they enter the circulation and reach the liver, they may be transformed back into glucose. Glucagon facilitates this process through specific gluconeogenic enzymes. One such enzyme is known as phosphoenolpyruvate carboxykinase (PEPCK) which is important in the formation of glucose. It takes a substrate from the krebs cycle ( Oxaloacetic acid or OAA) and converts it to phosphoenolpyruvate ( this is the substrate in glycolysis that is actually itself converted to pyruvate)(Jiang and Zhang, 2003). Current evidence suggests that glucagon actually increases PEPCK mRNA in the cell (Beale, 1984, Iynedjian, 1985) (mRNA carries the nuclear instructions for building PEPCK in the cell, the higher the concentration of these ‘instructions’ the more PEPCK that can be built) through a protein kinase A mechanism (Jiang and Zhang, 2003).

 

http://www.abcbodybuilding.com/Nutrientpartitioningpart1.php

[armygas]

It says here that glucagon gets broken down into glucose which, in turn, will release insulin.

 

 

 

http://www.abcbodybuilding.com/Nutrientpartitioningpart1.php

 

 

Actually glucagon will agonize a GPCR (Gs type) and eventually activate phosphorylase. Now phosphorylase is a rate limiting step in the whole glycogenolysis process so glycogenolysis is enhanced thus breaking down glycogen into glucose. Glucagon itself is not made into glucose, it only activates a Gs protein coupled receptor.

 

If you want a good pharm book get Goodman and Gilman...it is a great but expensive book

[armygas]

Please give citation or post links when you quote other sources. It's the proper thang t'do.

Understood, but according to factor 1 of the fair use act that small quotation used for and educational, not-for-profit use is "fair use"... Just FYI

[Realitycheck]

Actually glucagon will agonize a GPCR (Gs type) and eventually activate phosphorylase. Now phosphorylase is a rate limiting step in the whole glycogenolysis process so glycogenolysis is enhanced thus breaking down glycogen into glucose. Glucagon itself is not made into glucose, it only activates a Gs protein coupled receptor.

 

If you want a good pharm book get Goodman and Gilman.

 

Somebody finally said something about my oversight.

[Moh]

Glucagon does not stimmulate the production of insulin. it actually stimmulates the liver and paticular muscles to convert glycogen back into glucose. this process is done when glucose levels are low in the body.

[blike]

Hi everybody! Does anyone know why does glucagon stimulate pancreatic beta-cells to secrete insulin? I have searched many articles, but I haven't found an answer.... I know that beta-cells have glucagon membrane receptors and that they work activating cAMP production, but what is the physiological translation of this? Why is glucagon an insulin secretagogue? Isn't high blood glucose concentration enough stimuli? I hope that someone can help me with this...

That's actually a very good question, I had the same question when I was taking endocrine physiology. I always rationalized it simply by the fact that glucagon will raise serum glucose levels, which will them stimulate insulin secretion.

 

However, the answer to the question seems to be that glucagon actually acts directly on the GLP-1 receptors in the pancreatic beta islet cells to cause insulin secretion. Check out this paper: Evidence that glucagon stimulates insulin secretion through its own receptor in rats. So glucagon has both a primary and secondary insulin secreting effect -- the primary being through the GLP-1 receptors on pancreatic islet cells, and the secondary being due to increased serum glucose.

[Revenged]

Hi everybody! Does anyone know why does glucagon stimulate pancreatic beta-cells to secrete insulin?

 

I wouldn't think too much about it... In any case, the delta cells of the islets produce somatostatin that acts to decrease production of both insulin and glucagon...

[marcz90]

That's actually a very good question, I had the same question when I was taking endocrine physiology. I always rationalized it simply by the fact that glucagon will raise serum glucose levels, which will them stimulate insulin secretion.

 

However, the answer to the question seems to be that glucagon actually acts directly on the GLP-1 receptors in the pancreatic beta islet cells to cause insulin secretion. Check out this paper: Evidence that glucagon stimulates insulin secretion through its own receptor in rats. So glucagon has both a primary and secondary insulin secreting effect -- the primary being through the GLP-1 receptors on pancreatic islet cells, and the secondary being due to increased serum glucose.

According to the last sentence of the abstract of the paper that you linked to (Evidence that glucagon stimulates insulin secretion through its own receptor in rats), "glucagon stimulates insulin release mainly through glucagon receptors but not GLP-1 receptors on islet beta cells."

 

So glucagon has both a primary and secondary insulin secreting effect -- the primary being through the glucagon receptors on pancreatic islet cells, and the secondary being due to increased serum glucose.

 

Having clarified the ways that glucagon stimulates insulin secretion, the initial question still remains: "Why is glucagon a stimulator of insulin secretion?"

 

In my own case, I really only ask this question with regard to the primary insulin secreting effect of glucagon, which I think is probably also true for OP (what we have been calling glucagon's "secondary insulin stimulating effect" is really the primary way that insulin secretion is stimulated—no confusion there. High blood-glucose = insulin release).

 

So the question, "why is glucagon a stimulator of insulin secretion," could be directed more bluntly at the point of confusion by asking, "why does glucagon directly stimulate the secretion of insulin?"

 

While doing research into this question I found the following relevant excerpt from p. 1410 of Williams Textbook of Endocrinology 13th edition:

 

The hormones produced by pancreatic alpha and beta cells also modulate insulin release. Whereas glucagon has a stimulatory effect on the beta cell,⁵⁴¹ somatostatin suppresses insulin release.⁵⁴² It is currently unclear whether these hormones reach the beta cell by traveling through the islet cell interstitium (thus exerting a paracrine effect) or through islet cell capillaries. Indeed, the importance of these two hormones in regulating basal and postprandial insulin levels under normal physiologic circumstances is in doubt. Paradoxically, the low insulin levels observed during prolonged periods of starvation have been attributed to the elevated glucagon concentrations seen in this setting.^500,543-546

541. Samols E, Marri G, Marks V. Promotion of insulin secretion by glucagon. Lancet. 1965;2:15-16.

542. Alberti K, Christensen NJ, Christensen SE, et al. Inhibition of insulin secretion by somatostatin. Lancet. 1973;2:1299-1301.

543. Aguilar-Parada E, Eisentraut A, Unger R. Effects of starvation on plasma pancreatic glucagon in normal man. Diabetes. 1969;18:717-723.

544. Marliss E, Aoki TT, Unger RH, et al. Glucagon levels and metabolic effects in fasting man. J Clin Invest. 1970;49:2256-2270.

545. Malaisse W, Malaisse L, Wright P. Effect of fasting upon insulin secretion in the rat. Am J Physiol. 1967;213:843-848.

546. Zawalich W, Dye ES, Pagliara AS, et al. Starvation diabetes in the rat: onset, recovery and specificity of reduced responsiveness of pancreatic β-cells. Endocrinology. 1979;104:1344-1351.

Edited February 16, 2017 by marcz90