not a physiologist, biochemist or dietician - just a bio major who sometimes stays at a Holiday Inn express.
You probably know this but I'll reveiw.
Insulin doesn't actually directly accomplish the uptake of glucose by the cell.
Uptake is actually done by glucose transport proteins (GLUT) that facilitate the diffusion of glucose into the cell (or they could run in reverse I suppose). These proteins are integral proteins located in the cell membranes. For example, in muscle this is GLUT4. GLUT4 is an insulin responsive transport protein.
The action of insulin (in the GLUT4 context) is to trigger actions within the cell to that result in more GLUT4 proteins in the cell membrane. GLUT4 (this insulin triggered GLUT) is present in skeletal muscle, cardiac muscle and fat cells.
My guess is that there may be some GLUT4 proteins out on the muscle because there is always some level of insulin in the bloodstream - but this would be a small effect on circulating blood glucose. However, the increase in insulin postprandialy brings more to the surface (note: I can't specifically recall that these are always present in some number, the great majority are certainly sequestered in vesicles waiting to be called into action).
Other GLUT proteins present in other cell types are not insulin dependent.
As far as I know, insulin is never 0 in a normal individual, though the fasting level would vary between individuals.
I assume there there is some normal baseline level for glucagon but don't know what it might be. You know that glucagon influences the breakdown of glycogen to release glucose into the blood not glucose uptake from the blood - so I'm not sure what you are asking about glucose getting into cells in the context of glucagon.
ETA: this is not the only action of insulin of course, just the one that you asked about.
the more I think about it the less I think that GLUT4 would be consistantly present in the cell membranes at low insulin levels. I may have to go look for that answer now that I'm thinking about it.
Thanks for the answer Lisa. I should have been more clear on the glucagon. I know that glucagon breaks down glycogen, but does it also do it in a indirect way such as insulin through stimulating GLUT4? I'm assuming that it would need to pass through the cell walls again to get to the blood, right?
you could look at the cartoon here or here for an idea of the action of glucagon in the liver:
it binds its receptor which starts a cascade of actions in the cell which result in the breakdown of glycogen into glucose
Well, you just answered my question by saying that the process is triggered by glucagon. I wasn't clear on whether glucagon could release the storage of glycogen on its own independent of the liver. Thanks for links. That helped a lot.
Only liver glycogen is broken down to glucose that is released to the blood stream - muscle glycogen is used locally and glucose is not released to the blood stream (AFAIK muscle depolymerization of glycogen into glucose is need driven and not facilitated by glucagon - but that's going from memory)
Glucogon: liver and perhaps a few other cell types - but not skeletal muscle.
In muscle, adrenaline plays a triggering role - and adrenaline would be present in the blood in greater amounts with exercise, danger (fight/flight), etc.
Also, locally within the cell, the presence of molecules like AMP (which would indicate lots of activity breaking down ATP) will cause some shape-shifting of the enzymes to favor glycogen breakdown.
Also, in active tissue, the concentration of Ca++ can increase - which also makes glycogen breakdown favorable.
In response to lowered blood glucose the a cells of the pancreas secrete glucagon which binds to cell surface receptors on liver and several other cells. Liver cells are the primary target for the action of this peptide hormone. The response of cells to the binding of glucagon to its cell surface receptor is the activation of the enzyme adenylate cyclase which is associated with the receptor. Activation of adenylate cyclase leads to a large increase in the formation of cAMP. cAMP binds to an enzyme called cAMP-dependent protein kinase, PKA. Binding of cAMP to the regulatory subunits of PKA leads to the release and subsequent activation of the catalytic subunits. The catalytic subunits then phosphorylate a number of proteins on serine and threonine residues. Of significance to this discussion is the PKA-mediated phosphorylation of phosphorylase kinase as shown in the diagram above. Phosphorylation of phosphorylase kinase activates the enzyme which in turn phosphorylates the b form of phosphorylase. Phosphorylation of phosphorylase-b greatly enhances its activity towards glycogen breakdown. The modified enzyme is called phosphorylase-a. The net result is an extremely large induction of glycogen breakdown in response to glucagon binding to cell surface receptors.
This identical cascade of events occurs in skeletal muscle cells as well. However, in these cells the induction of the cascade is the result of epinephrine (adrenalin) binding to receptors on the surface of muscle cells. Epinephrine is released from the adrenal glands in response to neural signals indicating an immediate need for enhanced glucose utilization in muscle, the so called fight or flight response. Muscle cells lack glucagon receptors. The presence of glucagon receptors on muscle cells would be futile anyway since the role of glucagon release is to increase blood glucose concentrations and muscle glycogen stores cannot contribute to blood glucose levels.
Regulation of phosphorylase kinase activity is also affected by two distinct mechanisms involving Ca2+ ions. The ability of Ca2+ ions to regulate phosphorylase kinase is through the function of one of the subunits of this enzyme. One of the subunits of this enzyme is the ubiquitous protein, calmodulin. Calmodulin is a calcium binding protein. Binding induces a conformational change in calmodulin which in turn enhances the catalytic activity of the phosphorylase kinase towards its substrate, phosphorylase-b. This activity is crucial to the enhancement of glycogenolysis in muscle cells where muscle contraction is stimulated by acetylcholine stimulation of neuromuscular junctions. The effect of acetylcholine release from nerve terminals at a neuromuscular junction is to depolarize the muscle cell leading to increased release of sarcoplasmic Ca2+, thereby activating phosphorylase kinase.Thus, not only does the increased intracellular calcium increase the rate of muscle contraction, it increases glycogenolysis which provides the muscle cell with the increased ATP it also needs for contraction.
The second Ca2+ ion-mediated pathway to phosphorylase kinase activation is through activation of a-adrenergic receptors by epinephrine.
Glycogen phosphorylase is the rate-limiting enzyme of glycogen breakdown. In muscle, glycogen serves mainly to provide glucose for energy production during exercise, although it is also consumed in the resting state. During exercise muscle glycogenolysis is triggered by the dual control of contractile activity and epinephrine(1) . These stimuli result in the release of Ca and an increase in cyclic AMP, respectively, which in turn lead to the phosphorylation and activation of glycogen phosphorylase by phosphorylase kinase(2) .
During exercise, glucose uptake and metabolism are greatly increased in muscle despite low physiological concentrations of insulin. Indeed, it has been shown that insulin is not required to mediate glucose uptake during contractions (3, 4) and that contractile activity augments glucose uptake by muscle even in severely insulin-deficient diabetic rats(5) . Furthermore, in exercised muscle, glucose uptake and disposal are enhanced independently of insulin(6) . Insulin sensitivity of glucose uptake and glycogen synthesis are increased in exercised muscle, in normal humans and insulin-deficient type I diabetic patients (7, 8) . The mechanism by which exercise increases basal and insulin-stimulated muscle glucose uptake remains to be elucidated. The system accounting for such effects appears to be located at a post-receptor level, because exercise does not affect the amount of insulin receptors or insulin-stimulated kinase activity(9, 10) . Breakdown of glycogen stores (11, 12, 13) or the activation of glycogen synthase (9) have been suggested as possible mediators of this phenomenon. On the other hand, even though these studies are consistent with the fact that glucose uptake is limited by glucose metabolism, other studies suggest that it is glucose transport that limits glucose uptake(14, 15) .
Glucose passing through cell walls
Linear Mode
