45: glucose regulation

8/12/2019 45: Glucose Regulation

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Transcribed by Albert Cheng 5/1/14

Organ Systems Lecture 45: Physiology of Glucose Regulation

IntroductionGood morning, we’ve been through a couple of endocrine systems (thyroid, adrenalcortex), that are tightly linked to the hypothalamic pituitary access and have feedback

regulation involving the pituitary and hypothalamus. What I’m gonna be talking about

today are two endocrine regulatory systems that are both involved in homeostasis. One iscalcium and one is glucose, in which the hypothalamus is sort of involved…the pituitary

not so much. And most of it is direct sensory feedback loops and we’ll start off with

regulation of glucose.

Why regulate glucose levels?Glucose concentration in plasma…and I mentioned this before when I was discussing the

kidney…is typically something like 70-110 mg/dl. That corresponds to 5mM, that’s what90 is. And this is what your various homeostatic systems that we’re going to be

discussing today try to maintain. 70-110 is what Americans/Canadians glucose meters

that do the automatic glucose testing show. Some European meters show millimolar(mM), but we’re here. And you wanna keep it that way…why is it so important to keep it

in that range? By the way, tomorrow morning you’re going to get CCP on Diabetes by

Dr. Hammer who among other things, manager of the several major diabetes clinical programs and also she’s on the faculty of nursing school. She tends to make this 80-

100mg/dl, a much narrower range. I’m a little more liberal. The idea is to keep it around

the middle of that range. WHY? What do we need glucose for? It’s fuel. It’s the major

fuel for your brain. If your brain doesn’t get glucose, it tends to go to sleep sometimes permanently. There is dizziness, vertigo, all sorts of autonomic reactions followed by

mental confusion followed by loss of consciousness which can progress into coma

followed by death. So low blood glucose has immediate negative effects. If you get

significantly below 70, they start to become apparent. On the other hand, the effects ofgetting the blood glucose levels too high are not as immediate although it can lead to

some mental confusion and even blurring of vision (and the mechanism of that is not



clearly understood) but the long-term effects of excessively high blood glucose levels are

very serious. The way your liver gets rid of things it doesn’t like is to glycosylate them,

that is bind glucose to the various compounds it wants to get rid of making them water-soluble so you can get rid of them through urine. But the point is that even without a

liver…well you cant live without a liver…even without the liver doing that glucose binds

to certain amino acid residues on proteins. And remember the structure of glucose, it’s asugar (6 membered rings) with all of these hydroxyl groups bound to glucose moleculeare able to bind certain amino acid residues on the protein. So at a fairly steady rate, just

having high glucose levels in your plasma will lead to glucose bind to your protein.

What’s even more dangerous is that because glucose has multiple hydroxyl group, it can bind to 2 proteins at the same time and that tends to lose the flexibility of whatever

structure or membrane that is made up of those proteins because now they just can’t slide

past each other , they’re sort of tied together by a glucose cross bridge. And so what

happens is tissues tend to lose their elasticity and flexibility and there are certain tissuesespecially blood vessels which have to be flexible. Specially capillary, remember

capillaries are like a snake swallowing a small animals, there’s this bulge as a RBC

passes along it and RBC even when folded in half bulge a small capillary to a certainextent. So the capillaries have to remain flexible. If they get rigid, they will burst or leak

and they will not let the blood flow through. And so excessive glucose in the plasma can

cause capillary malfunction. Now if you think about tissue that have a lot of capillaries in

them…what comes to mind? Kidney and the retina, which we didn’t really go into thatmuch. That’s where the malfunctions occurs either blood leaks out of the capillaries and

into the tissue or the blood doesn’t get through. Circulation to the retina is inadequate to

maintain the rods and cones and various neurons of the retina and THEY DIE. Diabetesuntreated or inadequately treated which involves high glucose level is the single largest

cause of blindness. Especially if you stay out of the Nile, where there are parasites that

can crawl into your eyeball, locally can be a even greater cause of blindness. Second is

the kidney where all these capillaries get mucked up, you lose kidney function. Diabetesuntreated with high glucose levels is the major cause of kidney failure. Think about 2

other effects of that. If your kidneys go, you’re not able to make erythropoietin so you

become anemic and if your kidneys die, you’re not able to maintain your blood pressure because you can’t produce renin. And third, if your kidneys die, you can’t convert 25-

hydroxyvitamin D into 1,25-dihydroxyvitamin D which we will be getting to in the 2nd

hour today. So you fall into a syndrome where you don’t have enough calcium in your plasma and you begin to get bone loss. So it’s a good idea to keep the plasma glucose

levels low and but now too low. You wanna stay ideally within that range.



Insulin

Now, there are four hormones that get involved in the regulation of glucose: insulin,

glucagon, epinephrine, cortisol. Epinephrine is released from adrenal medulla generally

as a part of the sympathetic system, when you have increase sympathetic activity,sympathetic pre-ganglionic fibers go to adrenal medulla and activate chromaffin cells

which release epinephrine and norepinephrine into the blood stream and the increased

epinephrine steps up metabolism, it’s a part of the stress reaction. When you’re nervous,your epinephrine goes up. The tiger has come around the corner, that’s also a stress

reaction, you want to increase your blood glucose levels a bit so that you can have

enough energy in your muscle to get the hell away from the tiger. Cortisol, which acts

through the liver to increase plasma glucose levels. Now you notice the effects of thesehormones are to increase glucose except for insulin. But you have to think about in terms

of the normal activity of these hormones. Generally, insulin, which is secreted by beta-

cells of the pancreas (islets of Langerhans) in response to high blood glucose. The higherthe blood glucose goes the more insulin you secrete. The opposite effect is related to

glucagon, which is secreted by alpha cells of the islets of Langerhans of the pancreas, has

the effects of raising blood glucose. Now I’m going to be talking about mechanisms here.Glucagon secretion is stimulated by low blood glucose. As the glucose concentrations go

up, you stop secreting glucagon. So you have a sort of balance here where if your plasma

glucose is at its normal level (5mM or 90mg/dl), you’re producing a little insulin and

glucagon. If your glucose levels should go higher, you start producing more insulin. If

your glucose levels get low, you start secreting more glucagon and that raises your plasma glucose levels. So it’s a negative feedback regulation that tends to keep the

glucose at or close to the middle of that glucose range (5mM or 90mg/dl). This is sort of

normal negative feedback control. A deviation either way causes one hormone to besecreted more and the other less and it tends to shift the glucose concentrations back to

the setpoint. I’ll get to the other hormones a bit later.



Mechanism of insulin and glucagon

How does insulin lower your blood glucose levels and glucagon raise your blood glucose

levels? Well, it depends on what kind of tissue you’re looking at. Let’s say you have askeletal muscle cell, it does work and it need glucose to metabolize and eventually feed

into the mitochondria to make ATP to do work. Skeletal muscle is also capable of storing

glucose as a polymer in the form of glycogen. So what you have here is a storage ofglycogen and to the extent that there’s any glucose in the cells (labeled by G inside thecell picture), insulin promotes storage of glucose as glycogen. Insulin also tells the cell,

well you need some energy to do your normal function (work), burn glucose which we

would normally do anyways. As a result, whatever glucose is in the cell is used up. It’seither metabolized or stored away as glycogen when there’s insulin. How does a cell get

its glucose. Well glucose which is present in capillaries that pass by the cells gets into the

cell through glucose transporter molecules, these are basically your Na/glucose

cotransporter that we saw in the PCT of the kidney. But here what’s happening is yourcell is using up or locking the glucose, so now the glucose concentrations in the cell is

lower than it normally is, therefore the capillary plasma has a downhill route to move

glucose into the cell. You notice what’s going on here. There’s probably also a certaincomponent of this work drives a Na/K ATPase which is driving sodium out of the cell so

that tends to move the Na in and the Na/glucose transporter works better. The thing is

this, muscle cells are capable of doing this because they have a particular glucose

transporter molecule which is called GLUT4. There are multiple types of glucosetransporter molecules some which are characteristics of different tissues. And what

happens is insulin, when it gets into the cell, triggers the transcription of the gene that

encodes your glucose transporters and you make more glucose transporters. What’s moreimportant is this, muscle cells are constantly making glucose transporter molecules but

most they float around in the cytoplasm. Now if you think about this for a

minute…something that moves something from one side to another…if it’s floating

around in the bath…it’s totally useless. If you’re sitting in the bathtub and you take ahandful of water here and you put it over there…what have you accomplished? A

transporter molecule only works when it’s sitting in the membrane because then there’s a

one side and another side. So there’s 2 things that insulin does. One it promotes thesynthesis of these Na/glucose transporters but the 2

nd thing that it does is it tells the cell to

take these transporters which are in the cytoplasm and insert them into the membrane so

you have more and more of them. And therefore, this cell is capable of taking glucose into store as glycogen or to burn for metabolism.

Skeletal Muscle Cell (refer to picture Dr. Schiff drew)

At least in the case of muscle cells, what you’ve got here is NOT that insulin is saying“let’s get the glucose out of the plasma”. It’s saying “skeletal muscle cell, YOU need

glucose and here’s how you get it into the cell so you can use it” and as a byproduct you

lower plasma glucose levels. So the lowering of plasma glucose is a byproduct compared

to what its main purpose is in terms of the skeletal muscle cell and that is to enable thecell to get the glucose it needs to function.



Liver cell (refer to Dr. Schiff’s drawing)

Let’s look at another cell (liver cell – hepatocyte). Again, you have glucose in the cytosoland you can store the glucose as glycogen. You also are doing all sorts of good thing and

“working” so you also metabolize glucose for energy. In fact, what happens is liver cells

have a different glucose transporter molecule (GLUT2). Insulin does NOT triggertranscription of the GLUT2 genes. So your liver cell is going to have to deal with

whatever transporters it already has in its membrane. This is a little less efficient perhaps

but the liver does so much more because in addition to making glycogen and doing its

metabolism, the liver can also produce glucose out of the blue by gluconeogenesis (fromamino acids or fats) which tends to make glucose and that increases the glucose inside the

cell. So what’s likely to happen with a liver cell? It can take some glucose in throughthese transporters but what it can also do is make glucose and then let it out. So whereasmuscle is only a sink for glucose, the liver most of time is actually producing glucose to a

certain extent and releasing it. Now there’s other thing going on here. Remember I said

that there is a balance between insulin and glucagon with that graph. Glucagon tells yourmuscle cell to breakdown glycogen into glucose which raises the cell’s glucose levels and

might actually cause the cell to release glucose but either way it’ll tell the cell not to use

up the glucose, get some more glucose from the glycogen, and then use it for your

metabolic needs and don’t take in any more from the outside. So in the presence ofglycogen, muscle does not take glucose out of the bloodstream. In fact, it can even

release some. This whole balance is shifted. In the liver even more so because glycogen

promotes gluconeogenesis and it also promotes breakdown of glycogen. So it promotesrelease of glucose into the blood stream and raises blood glucose levels. What’s it doingis changing the metabolism of the cell so that you raise cytoplasmic glucose levels and

therefore glucose will diffuse outward.



Fat cell (refer to Dr. Schiff’s drawing)

Let’s look at a fat cell or adipocyte. Fat cells don’t make glycogen, only muscle and liver

cells do that. Fat cells do store fat. They have a certain amount of glucose in their

cytoplasm. They have GLUT5 transporters. Fat cells are capable of taking glucose in ifthey need it. Now what insulin does is for all the work that the fat cell does, insulin tells it

to use glucose and don’t burn the fat/store the fat…and that way the fat gets stored andglucose is used metabolically so now the fat cell takes in glucose because the cytoplasmicglucose is lowered. In the presence of glucagon, it says NO. Glucagon tells the cell to

metabolize fat for the energy needs. And therefore, whatever glucose it has in the

cytoplasm stays there and it doesn’t take up any more glucose. So what glucagon is doingis it’s telling the liver cell to make and release glucose. It’s telling the muscle cells to

break down its glycogen and use that for your metabolic need…don’t take up glucose.

It’s telling the fat cells to burn your stored fat for energy and don’t take up more glucose.So that’s why these hormones have the opposite effects on your plasma glucose. Insulin

as a byproduct of everything it does has the muscle/liver/fat cells take up glucose because

it uses up the cytoplasmic glucose metabolically and as a byproduct you’re lowering

plasma glucose levels. Glucagon essentially reverses all of that and tells the liver as wellto make more glucose. Now all of this is normal minute to minute

regulation/homeostasis. If you’re blood glucose goes up, you make more insulin and it

does stuff to make muscle/liver/fat cells to take in more glucose. If your blood glucose

goes down, you get glucagon secretion and that tells your liver to start releasing glucose,it tells your muscle cells to stop taking in glucose but instead use glycogen, it tells your

fat cells to not take in more glucose and instead use your fat.



Epinephrine

Epinephrine does a couple of things. The most relevant one here is epinephrine stimulatesthe secretion of glucagon by the alpha cells. What you’ve got is more glucagon secretion

when you have a sympathetic nervous system step up because you’re nervous you just

saw the tiger coming towards you, the epinephrine that you’re secreting from your

adrenal medulla tells your pancreatic alpha cells to secrete glucagon and get some moreglucose into your bloodstream

CortisolCortisol, unless you have Cushing’s or something, DIRECTLY acts on liver and does all

things that glucagon does. It tells it to carry out gluconeogenesis, break down glycogen

and release glucose into the blood. It’s a stress hormone. It’s a little slower acting than

epinephrine but unlike epinephrine which acts through glucagon, cortisol acts directly onthe liver.

Diabetes MellitusSo you’ve got this normal feedback regulation between glucagon and insulin and then

you’ve got stress response where you might need more glucose involving the liver

through cortisol and through glucagon and increasing the blood glucose levels. Wheredoes all of this lead to the symptoms of diabetes mellitus indirectly? Diabetes mellitus isa syndrome in which there’s glucose in the urine and polyuria (large amount of urine

going out). As a result of the polyuria that leaves the person dehydrated somewhat, so

there’s also a symptom called polydipsia, which means they drink a lot of water. Andthat’s the symptom correspondence we referred to as diabetes mellitus. Diabetes is a

reference to a siphon, a tube you use to transfer liquid from one container to another,

because a person with diabetes takes in a lot of water and seemingly passes right out in



urine. Mellitus of course means sweet because there’s glucose in the urine. If you raise

the plasma glucose levels, how does that lead to glucose in the urine and polyuria?

What’s going on with glucose in the kidney? It’s all reabsorbed under normal conditionsin the PCT. So we start off with a plasma glucose level at 90mg/dl, up to that point how

much glucose is filtered at the glomerulus? Glucose is freely filtered, so whatever the

concentration is times GFR gives you the amount of glucose filtered. So this is like astraight line (refer to graph). When you pass through the PCT, how much glucose isreabsorbed…all of it. But how is it reabsorbed? It’s reabsorbed by use of a carrier, the

Na/glucose cotransporter. So the amount reabsorbed is essentially 100% of what was

filtered…to a point. There’s two things characteristics of carrier -mediated transporter.One is they facilitate things so that you get very efficient transport of glucose up to a

point at which there aren’t enough carriers. If glucose gets too high in the filtrate, your

glucose/Na cotransporters are doing all they can already. They can’t transport any more

glucose out of the filtrate. So what happens is the amount reabsorbed someplace here(referring to graph) levels off in the PCT. There’s a maximum rate at which you can

reabsorb glucose from the filtrate. Now the thing is in this situation, all of this additional

glucose that was filtered is still in the filtrate. And by the way, this start to happen abouttwice the normal level (180mg/dl). So as long as you can keep your plasma glucose levels

below ~160ish, you’re not going to spill glucose in your urine. Now anything that gets

past the PCT, there are no more glucose transporters in the nephron. So it’s gonna come

out in the urine. So the amount of glucose lost in the urine will start around here (refer tograph). If you get beyond this maximum ability of the PCT to reabsorb glucose, you end

up with glucose in your filtrate and urine. So how does that lead to polyuria?



Polyuria

Remember the last adjustment of the urine volume occurs, assuming under the presence

of ADH, in the collecting ducts where you have about 18 L a day going into thecollecting ducts and comes out about 2L a day of urine. 16L of water is reabsorbedosmotically. You now have hypertonic filtrate because of all this glucose in it. So now

there’s less osmotic force promoting reabsorption of water. The glucose has its ownosmotic pressure that’s keeping the water in the collecting ducts. So that extra water inthe urine leads to polyuria.

Polydipsia and cause of diabetes type IPolydipsia is you’re getting dehydrated so you’re getting thirsty. And that’s how about it.

What causes diabetes mellitus? What causes this constellations of symptoms involving

glucose in the urine, polyuria, and polydipsia and high plasma glucose levels with all the

side effects that occurs like losing your kidney or getting blind. The other thing is insome of the large descending vessels, you lose the elasticity of your veins in your legs, so

you end up with poor circulation in your legs and that can lead to gangrene, death of cells

in the legs, and also the major cause of lower-limb amputations other than trauma. Whatcauses this to happen? One possibility is and this is called Type I diabetes, it’s an

autoimmune disease in which your body starts making antibodies to the beta-cells in the

pancreas which produce insulin so you can’t produce insulin. Without insulin, your

plasma glucose levels is going to go up. In fact, your muscle may waste because they’renot getting enough energy or glucose to do their job. So what’s gonna happen with a

Type I diabetic? These often occur early in childhood though they can have a late onset in

adulthood. You have to replace insulin. That’s a problem in of itself. For many years, the problem was getting the insulin to inject because in the early day, they would take pig or

beef pancreas and isolate the insulin from there and inject it into people. Two problems.

One is that they’re not identical to human insulin and your body can begin to react after

awhile since this is a foreign protein and attack it. Nowadays, they essentially synthesizethe gene to human insulin and create a bacteria culture which makes recombinant human

insulin (identical to human insulin except it comes from bacteria) and you isolate/remove

everything except the insulin and inject that. Inject is the key word because that’s the 2nd

problem with replacing lost insulin of Type I diabetes. You can’t take it orally. Insulin is

a peptide and you can’t take it orally because the acidity/peptidases in the stomach will

destroy it. By the way, a word about insulin, insulin is synthesized from a single gene butit’s double stranded protein, how does that happen? Well your genes create a single

strand proteins that loops around and forms a couple of disulfide bonds between cysteine.

And then this part gets cleaved leaving the double stranded proteins referred to as A and

B strands which are different. The C protein, which was cleaved may or may not have afunction. It’s still being studied. Of course, the process of purification of bacterially

recombinant DNA derived insulin gets rid of the C protein also. So whatever good it

might do to have the C protein pr esent, people who are injecting insulin don’t have it.

This is a side message here.

Type II diabetes

There are other forms of diabetes mellitus. Like I said, this is a symptom not ADISEASE. There are a group of diseases that produce diabetes mellitus. Another form is



what’s referred to as inadequate insulin intolerance. Basically what happens is in order

for insulin to do all these nice things that it does, it has to bind to a receptors and second

messengers are created and all sorts of things are going on inside the cells, which I’m notgoing into any details. But if the receptors have a problem or if the enzymes that make

the 2nd

messenger has a problem, or the G-protein may have a problem that links them,

the insulin may be perfectly good but not do enough. Or there’s a possibility throughsome mutation, you make defective insulin. What you’ve got here is a # of things that aregenerally lumped together as Type II diabetes in which you’re making insulin but the

insulin is not doing its job because something downstream along the process is not

working. Those syndromes are initially treated by drugs that increase your beta cells’ability to secrete insulin because if you made a little bit more, even with the defective

receptors, it could do its job. So a lot of treatment of Type II diabetes is with drugs that

stimulate beta cells to produce more insulin. The problem is you’re beating a tired horse.

And there’s a point at which it can’t push it no more and it dies. And now effectively, youhave Type I diabetes…it takes years but there’s another treatment for Type II diabetes

that seems to actually work best…and that is there’s a drug that prevents the

gluconeogenesis in the liver because if you eliminate the source of glucose in the bloodstream, then your insulin for Type II diabetes has less to oppose so it doesn’t have

to “fight so hard”. One other thing is that Type II diabetes seems to be linked to obesity

which is why it’s growing in incidence in the US and the rest of the western world. We

eat too much fat. For some reason, when you have too many fatty cells, you need moreinsulin than you’re able to produce so effectively you develop Type II diabetes. You’re

making insulin and your beta cells are fine BUT it’s not enough to handle all the insulin

receptors on the fat cells. So there’s this obesity link.

Gestational Diabetes

Incidentally, there’s a pregnancy-linked diabetes, gestational diabetes, in which

pregnant women will develop a sort of temporary diabetes mellitus, which at the end of pregnancy can go away OR NOT. What happens is with successive pregnancy, if you

have it in the 1st pregnancy, it gets worse the 2

nd time and so on and it can even become

permanent. And of course, there’s the diabetes mellitus produce by Cushing’s disease.We ran a little over but we’ll take 5 and do calcium regulation

45: glucose regulation

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