Carbohydrate metabolism...how does it know?

[kmortis]

Ok, as some of you know, I was diagnosed with Type 2 diabetes last year. I have learned more in the last year about insulin, insulin uptake, sugar structures and their effects on the body; all good stuff. The one thing I haven't been able to find out is - how does the body know know that there are sugars present?

I mean, insulin production Is proportional to sugar concentration. So, how does the body detect the sugar?

[stup_id]

The place where insulin is produced, langerhans islets, is also responsible of detecting blood sugar levels , they monitor these levels and the beta-cells release insulin when is high, and alpha cells release glucagon when is too low

[Adam Ferguson]

That is what politicians call a "good question"!

As far as textbook level study goes; to some extent the B cells of the pancreas can be controlled from without through the action of the parasympathetic nervous system via the vagus nerve and the digestive system via glucose-dependent insulinotropic peptide (GIP), released from enteroendocrine cells in the wall of the small intestine in response to a high level of glucose in a meal. It can also be contolled through paracine action (that's other local hormones like glucagon and somatostatin) and some amino acids.

As you point out however it is mostly controlled through direct detection of the plasma glucose level by the B (or beta) cell itself. The question I think you are asking however is "How?", and to quote Rhodes and Bell, (2009), "Wheras detailed molecular steps by which glucose metabolites regulate insulin secretion have emerged, the molecular basis of glucose-regulated insulin biosynthesis is not entirely clear".

What that means is we essentially don't know for certain. So far as I can gather cell surface receptors are more active in non human animals like mice and the human system tends to use levels of carbohydrate metabolism within the mitochondria to somehow release biochemical markers from the membraine of this organelle to stimulate insulin biosynthesis and secretion. Though to have any idea of the mechanism you have to go to primary research papers and look through several models, I think there are a number of scientists on this forum who can furnish you with more detail.

Hope that's some help.

[casebro]

I do know that alcohol lowers blood sugar. I believe it does because the alcohol break down products are the same as fat breakdown product- acet-a-this-or-that. Acetaldehyde? Anyhow, the breakdown products would indicate that the cells are burning fat, after using up their sugar. So the body produces insulin to replenish the cells. So, I trick my body ever dinner with a glass of wine. My sugar is lower after dinner than before.

I'll drink to that!

But the medicos, they want me to exercise to lower my sugar. They want me to take pills to lower my sugar. They want me to take injections to lower my sugar. BUT they don't want me to drink alcohol, because it lowers my sugar?

I rooted around the net and figgered it out. Low sugar episodes are similar to drunkeness. You might have a drink, go low, and the people who might help you, will just think you are drunk, not having a hypoglycemic incident. I'd call that a social problem, not a medical problem, since it depends on other people.

Anyway, I've calibrated my self. Big dinner, + big glass of wine. = down 25 points. So I take my quick acting insulin after dinner, not before.

[casebro]

Kmortis, have you tried going low carb? Sure helped me. What with lots of exercise, I was off the insulin for several months. Down from 220 units/day.

Adam F. mention Mitochondria. I know of one study that showed that about 17% of type ii diabetics had one of a couple different Mito DNA defects. I don't know which one I have, but a muscle biopsy showed the effects. Now I'm having lots of tendon probs. Common in Diabetics, like 17% perhaps? Type two for 30 years out of 57. But the medicos down play the genetic angle.

[kmortis]

Thanks for the replies. Let me rephrase in my engineerese to make sure I understand, k?

You eat, sugar enters blood stream. The B cells have some kind of glucose sensor (is it just glucose, or any monosaccaride?) that determines through a yet undiscovered process the concentration and [strike]cries havoc and[\strike] lets loose the insulin which then goes on and tells the body's cells to have at. Is that about it?

Casebro, I don't take insulin. I do take Metformin and no refined sugars. In six months, I took my A1C from 14 to 6.2. My doc was very impressed. I should eat less carbs, but since I maintain that A1C with my current diet, I'm hesitant to change it to something that I'd find difficult to stick to. I'm in the process of reducing my salt intake to lower my BP (which is another mechanism that I'd like to understand, but I understand that it's not clear ATM). I'll probably never eliminate salt totally...I have to die from something, might as well be heart disease.

[Adam Ferguson]

You're an engineer?

That explains why you honed in on the one area that all the textbooks skim over while being obsfuscatingly full of detail elsewhere! You will need to ask someone with more molecualr biology than me weather it just responds to glucose, though the liver should have processed any other blood sugars before they get to the pancreas.

casebro; my knowledge is only really textbok level, while I'm aware there are genetic links I don't know that much about them. Perhaps since there is little theraputic manipulation AFIK available for genetic factors; medical textbooks spend more time on factors that affect the presentation or treatment of the disease more?

If you can remember where you read it I'd be interested in looking at that paper.

[casebro]

Hard to find that paper. I'll try googling it up again later. It was an NIH study, done in Japan. <japan study mitochondrial genetic diabetes> ?

The numbers were IIRC: 250 diabetic subjects, 250 controls. Mito gene anomaly was found in 42 subjects, and one control- who wasn't diabetic YET.

[kmortis]

Originally Posted by Adam Ferguson

You're an engineer?

That explains why you honed in on the one area that all the textbooks skim over while being obsfuscatingly full of detail elsewhere! You will need to ask someone with more molecualr biology than me weather it just responds to glucose, though the liver should have processed any other blood sugars before they get to the pancreas.

casebro; my knowledge is only really textbok level, while I'm aware there are genetic links I don't know that much about them. Perhaps since there is little theraputic manipulation AFIK available for genetic factors; medical textbooks spend more time on factors that affect the presentation or treatment of the disease more?

If you can remember where you read it I'd be interested in looking at that paper.

Yup, I be an engineer

I'm thinking that the B cells might just detect glucose, as fructose doesn't get digested like glucose does, at least that's what the Wiki article on Fructose indicates.

[lenox7]

The pancreas couples blood glucose to insulin secretion through glucose metabolism. Glucose in the blood enters the pancreatic beta cell and is phosphorylated to glucose 6 phosphate by the enzyme glucokinase. This is the rate limiting step in glucose metabolism, so glucokinase has been described as the "glucose sensor". Several activators of glucokinase, which enhance insulin secretion, are now in clinical development for treatment of type 2 diabetes.

The ATP generated from glucose metabolism (glycolysis and then complete oxidation in the mitochondria) is the signal for insulin secretion. ATP inhibits the activity of a plasma membrane K+ channel (reducing K+ efflux out of the cell), causing the beta cell to depolarize (more positive). This K+ channel is the target of currently used drugs for type 2 diabetes called sulfonylureas.

Depolarization activates voltage-sensitive Ca++ channels. The increased Ca++ concentation in the beta cell stimulates the fusion of insulin-containing vessicles in the cytoplasm with the plasma membrane, releasing insulin into the blood.

Chronically elevated glucose appears to impair the glucose sensitivity of the beta cell. This, combined with the need to secrete more insulin to compensate for insulin resistance in the insulin sensitive tissues, eventually results in a progressive decline in the beta cell's ability to regulate blood glucose.

[kmortis]

Originally Posted by lenox7

The pancreas couples blood glucose to insulin secretion through glucose metabolism. Glucose in the blood enters the pancreatic beta cell and is phosphorylated to glucose 6 phosphate by the enzyme glucokinase. This is the rate limiting step in glucose metabolism, so glucokinase has been described as the "glucose sensor". Several activators of glucokinase, which enhance insulin secretion, are now in clinical development for treatment of type 2 diabetes.

The ATP generated from glucose metabolism (glycolysis and then complete oxidation in the mitochondria) is the signal for insulin secretion. ATP inhibits the activity of a plasma membrane K+ channel (reducing K+ efflux out of the cell), causing the beta cell to depolarize (more positive). This K+ channel is the target of currently used drugs for type 2 diabetes called sulfonylureas.

Depolarization activates voltage-sensitive Ca++ channels. The increased Ca++ concentation in the beta cell stimulates the fusion of insulin-containing vessicles in the cytoplasm with the plasma membrane, releasing insulin into the blood.

Chronically elevated glucose appears to impair the glucose sensitivity of the beta cell. This, combined with the need to secrete more insulin to compensate for insulin resistance in the insulin sensitive tissues, eventually results in a progressive decline in the beta cell's ability to regulate blood glucose.

Wow. Cool. You always hear that potassium and calicum are important to the body, but rarely (other than Ca & bones) do you hear why.

So, again I'm going to attempt a translation into engineerese to see if I've gotten it.

Blood flows through the B cells, where an enzyme acts upon it. This enzyme is the limiting reagent in glucose metabolism, it can only process so much glucose (so, does the excess get dumped to the kidneys?). This process, in turn, makes ATP which tells the pancreas to make (via the K+ channel)/release (via the Ca++ channel) insulin. Is that about it?

***ETA***
Wait, I thought that the pancreas didn't process the glucose itself, but rather the insulin told the rest of the body that glucose was present so have at. Or, am I misreading your statment and the glucokinase is only processing a small, representative amount, to act as a trigger to insulin production?
***/ETA***

And to your final paragraph, isn't that how Type 2 Diabetes comes about? The body stops responding to the insulin, therefore it stops taking up the glucose, and the blood glucose levels raise, making the pancreas produce more insulin...and more...and more....


ETA: I just realized that was your first post here. Thanks, and welcome.

[casebro]

"if you think you understand cellular respiration, you've missed something".

It's a pretty complicated bit of bio-chemistry. But thanks Lenox, for the effort. How I'll go re-read it several times, and see if any soaks in. I use the Osmotic System of learning...

[kmortis]

Originally Posted by casebro

"if you think you understand cellular respiration, you've missed something".

It's a pretty complicated bit of bio-chemistry. But thanks Lenox, for the effort. How I'll go re-read it several times, and see if any soaks in. I use the Osmotic System of learning...

Kind of like Bohr's comment on Quantum Mechanics? "If quantum mechanics hasn't profoundly shocked you, you haven't understood it yet."

[lenox7]

Kmortis and casebro, thanks for your replies. Kmortis, I think I can answer your questions.

You are correct, the pancreas is not a major contributor to glucose uptake and processing, like the skeletal muscle or liver. The amount of glucose metabolized by the pancreas is relatively very small - it will not reduce blood glucose. You can think of the pancreas as as "sampling" the blood for the concentation of glucose. However, it does still use the ATP generated from glucose for its own energy needs as well as for the regulation of insulin secretion.

The important aspect of this system is that the ATP generated in the beta cell is a function of the concentation of glucose in the blood. More glucose, more ATP, more insulin secretion.

And yes, this is the current model for the development of type 2 diabetes. Insulin resistance places a greater demand on the beta cells of the pancreas, which cannot keep up, and in addition, chronically elevated glucose is actually toxic to the beta cells, which diminishes their function and actually causes cell death.

Sorry, I cannot post links yet, but if you use google image for "insulin secretion", you will find some good cartooon figures from review articles.

[lenox7]

I forgot to mention another important aspect of glucose sensing. The pancreas also responds to glucose concentration in the intestine as well as the blood. Increased glucose in the intestine stimulates the instestinal secretion of incretin hormones into the blood, which act on the pancreas to augment the glucose dependent secretion of insulin.

I think this is a really cool regulation, in which the presence of glucose in the intestine gives the pancreas an early signal that blood glucose is going to increase soon.

This intestinal signaling system is also targeted in diabetes treatment with drugs like Januvia or Byetta.

[kmortis]

Well, I can post links, so here we go.

Google Image Search for "isnulin secretion"

The first one gives us (from http://www.betacell.org/content/arti...hp?aid=1&pid=2)


And while I don't understand everything on that picture 100%, I don't get that woozy feeling when I see it like my brain will leak out my ears. For example, I was going to ask "but where's the glucophage release mechanism in that pic?" when I remembered that insulin is produced in the beta, glucophage in the alpha cells. I'm a'learnin' already.

[kmortis]

Originally Posted by lenox7

I forgot to mention another important aspect of glucose sensing. The pancreas also responds to glucose concentration in the intestine as well as the blood. Increased glucose in the intestine stimulates the instestinal secretion of incretin hormones into the blood, which act on the pancreas to augment the glucose dependent secretion of insulin.

I think this is a really cool regulation, in which the presence of glucose in the intestine gives the pancreas an early signal that blood glucose is going to increase soon.

This intestinal signaling system is also targeted in diabetes treatment with drugs like Januvia or Byetta.

So, does incretin work like insulin, or does it just tell the pancreas that there's too much sugar in the intestines and something should be done about it?

Does it do anything about fructose? I know that fructose is digested in the intestines, and doesn't trigger the whole insulin/glucophage cycle. So, I'm guessing that fructose wouldn't trigger incretin.

[kmortis]

Originally Posted by lenox7

And yes, this is the current model for the development of type 2 diabetes. Insulin resistance places a greater demand on the beta cells of the pancreas, which cannot keep up, and in addition, chronically elevated glucose is actually toxic to the beta cells, which diminishes their function and actually causes cell death.

Hold onna sec, I missed this the first time around. So, glucose is toxic to beta cells which are there to detect/deal with it? How so? Is it just burn out (uses up all the enzyme or something)? I assume since you said that chronically elevated levels of glucose are toxic to it, that means to me that glucose is damaging to beta cells, but that at normal levels (or transient spikes) the cells can be repaired quick enough where the damage is not harmful to the organism as a whole. Is that a correct assumption?

[lenox7]

"So, does incretin work like insulin, or does it just tell the pancreas that there's too much sugar in the intestines and something should be done about it?"

Incretins just tell the pancreas to make more insulin in response to a given amount of glucose. Incretins also act on the alpa cells of the pancreas to suppress the secretion of glucagon. Incretins have a lot of other functions, such as on appetite.

Here is a good review article on incretins by one of the leading guys in that area. If you search it on PubMed, you can download it for free.
Nauck MA, Baller B, Meier JJ. Gastric inhibitory polypeptide and glucagon-like peptide-1 in the pathogenesis of type 2 diabetes. Diabetes. 2004 Dec;53 Suppl 3:S190-6.

To your question about fructose, I don't know. But you got me thinking, so I'm going to look into that.

"I assume since you said that chronically elevated levels of glucose are toxic to it, that means to me that glucose is damaging to beta cells, but that at normal levels (or transient spikes) the cells can be repaired quick enough where the damage is not harmful to the organism as a whole. Is that a correct assumption?"

Exactly. Only chronically elevated glucose causes the damage, which may be through increased oxidative stress.

Here is a good review of the effects of chronic glucose on the beta cells. If you search it on PubMed, you can download it for free.
Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes.J Biol Chem. 2004 Oct 8;279(41):42351-4.

There is also evidence that chronically elevated glucose worsens insulin resistance. This may be the reason for the progressive nature of diabetes: High glucose begets high glucose.

[casebro]

But there is still hope. After 30 years of being type II, enough exercise and a low carb diet did enable me to go without insulin for several months. Until my tendinopathy got too bad for me to work that hard.

Kmortis, did you confuse 'glucophage' with 'glucagon'? One is a treatment that lowers sugar, the other a hormone/signal that raises sugar.

I think furctose is left-handed glucose. Needs to be turned by enzymes in the liver before being used as glucose.

[kmortis]

Originally Posted by casebro

But there is still hope. After 30 years of being type II, enough exercise and a low carb diet did enable me to go without insulin for several months. Until my tendinopathy got too bad for me to work that hard.

Kmortis, did you confuse 'glucophage' with 'glucagon'? One is a treatment that lowers sugar, the other a hormone/signal that raises sugar.

I think furctose is left-handed glucose. Needs to be turned by enzymes in the liver before being used as glucose.

It appears that I did get my diabetes med and pancreatic hormone mixed up. Good catch.

Fructose is not L-Glucose, it is very similar, to the point of being an isomer of glucose, but it's not as simple as L- & D-glucose. In fact, both fructose and glucose as used by the body are both right handed.

Congrats on the control, m'man. Keep up the good work. I really need to add exercise into my daily routine, not just because I'm diabetic. I'm just a fat-ass.

[kmortis]

Originally Posted by lenox7

"So, does incretin work like insulin, or does it just tell the pancreas that there's too much sugar in the intestines and something should be done about it?"

Incretins just tell the pancreas to make more insulin in response to a given amount of glucose. Incretins also act on the alpa cells of the pancreas to suppress the secretion of glucagon. Incretins have a lot of other functions, such as on appetite.

Here is a good review article on incretins by one of the leading guys in that area. If you search it on PubMed, you can download it for free.
Nauck MA, Baller B, Meier JJ. Gastric inhibitory polypeptide and glucagon-like peptide-1 in the pathogenesis of type 2 diabetes. Diabetes. 2004 Dec;53 Suppl 3:S190-6.

To your question about fructose, I don't know. But you got me thinking, so I'm going to look into that.

"I assume since you said that chronically elevated levels of glucose are toxic to it, that means to me that glucose is damaging to beta cells, but that at normal levels (or transient spikes) the cells can be repaired quick enough where the damage is not harmful to the organism as a whole. Is that a correct assumption?"

Exactly. Only chronically elevated glucose causes the damage, which may be through increased oxidative stress.

Here is a good review of the effects of chronic glucose on the beta cells. If you search it on PubMed, you can download it for free.
Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes.J Biol Chem. 2004 Oct 8;279(41):42351-4.

There is also evidence that chronically elevated glucose worsens insulin resistance. This may be the reason for the progressive nature of diabetes: High glucose begets high glucose.

When I get home from work, I'll look those up. Hopfully, they won't make my brain melt.

[kmortis]

Originally Posted by lenox7

"So, does incretin work like insulin, or does it just tell the pancreas that there's too much sugar in the intestines and something should be done about it?"

Incretins just tell the pancreas to make more insulin in response to a given amount of glucose. Incretins also act on the alpa cells of the pancreas to suppress the secretion of glucagon. Incretins have a lot of other functions, such as on appetite.

Here is a good review article on incretins by one of the leading guys in that area. If you search it on PubMed, you can download it for free.
Nauck MA, Baller B, Meier JJ. Gastric inhibitory polypeptide and glucagon-like peptide-1 in the pathogenesis of type 2 diabetes. Diabetes. 2004 Dec;53 Suppl 3:S190-6.

To your question about fructose, I don't know. But you got me thinking, so I'm going to look into that.

"I assume since you said that chronically elevated levels of glucose are toxic to it, that means to me that glucose is damaging to beta cells, but that at normal levels (or transient spikes) the cells can be repaired quick enough where the damage is not harmful to the organism as a whole. Is that a correct assumption?"

Exactly. Only chronically elevated glucose causes the damage, which may be through increased oxidative stress.

Here is a good review of the effects of chronic glucose on the beta cells. If you search it on PubMed, you can download it for free.
Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes.J Biol Chem. 2004 Oct 8;279(41):42351-4.

There is also evidence that chronically elevated glucose worsens insulin resistance. This may be the reason for the progressive nature of diabetes: High glucose begets high glucose.

I added the linkies to the abstracts for you.

[John Jones]

Originally Posted by lenox7

"So, does incretin work like insulin, or does it just tell the pancreas that there's too much sugar in the intestines and something should be done about it?"

Incretins just tell the pancreas to make more insulin in response to a given amount of glucose. Incretins also act on the alpa cells of the pancreas to suppress the secretion of glucagon. Incretins have a lot of other functions, such as on appetite.

Here is a good review article on incretins by one of the leading guys in that area. If you search it on PubMed, you can download it for free.
Nauck MA, Baller B, Meier JJ. Gastric inhibitory polypeptide and glucagon-like peptide-1 in the pathogenesis of type 2 diabetes. Diabetes. 2004 Dec;53 Suppl 3:S190-6.

To your question about fructose, I don't know. But you got me thinking, so I'm going to look into that.

I'm type 2 as well. The role of fructose in the diet has me confused also. i'm a chemist, and actually test for mono and disaccharides. The library at the lab offers research papers reaching contradictory conclusions about fructose.

I'm interested in what you find out.

John Jones.

[plumjam]

Deleted