Another Metformin Question

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Another Metformin Question


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Old 08-14-2012, 03:29   #1
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Default Another Metformin Question

Good Evening All,

I've read countless articles on Metformin. I'm more confused than ever. Some claim it increases insulin sensitivity, or at least it is referred to as an IR med. Others claim it supresses glucose production in the liver. I do not comprehend that as the same thing.

First, please help me and share your understanding of Met's function.

Second, if it does supress glucose production, what happens to all that extra glucose? Does it not need to get dumped eventually?

Thanks in advance!

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Old 08-14-2012, 03:37   #2
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Correct - they are not the same thing, but metformin does do both. The fact that it suppresses glucose production in the liver means that there is no excess glucose to get dumped anywhere. And it increases sensitivity of the insulin receptor in the cells so that they are able to access the insulin which is already in the blood.

Metformin - Wikipedia, the free encyclopedia




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Old 08-14-2012, 14:15   #3
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Correct - they are not the same thing, but metformin does do both. The fact that it suppresses glucose production in the liver means that there is no excess glucose to get dumped anywhere. And it increases sensitivity of the insulin receptor in the cells so that they are able to access the insulin which is already in the blood.

Metformin - Wikipedia, the free encyclopedia
How easy was that! I'm glad you emphasized "production". It suddenly made sense. Thanks loads, Shanny.

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Old 08-14-2012, 17:29   #4
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The reason metformin is such a great drug is because it works on many levels. It works differently than drugs that overstimulate I sulking production in the pancreas. As Shanny said it works in the liver to stop the conversion of glycogen into glucose, so the glucose isn't produced when we are fasting for long periods. It also along with exercise and LC diet makes us more sensitive to the I sulin we do make. Another way it works is in the gut by making us feel full sooner, leading to weight loss in many D's.

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Old 08-14-2012, 19:14   #5
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Originally Posted by wineguy View Post
Good Evening All,

I've read countless articles on Metformin. I'm more confused than ever. Some claim it increases insulin sensitivity, or at least it is referred to as an IR med. Others claim it supresses glucose production in the liver. I do not comprehend that as the same thing.

First, please help me and share your understanding of Met's function.

Second, if it does supress glucose production, what happens to all that extra glucose? Does it not need to get dumped eventually?

Thanks in advance!
No, it can just stay where it is stored as "sugar water" (glylcogen) in the liver. Most people (on most diets) walk around with between 3 and 10 pounds of this water-glycogen mixture stored in their liver all the time. Non-diabetics only "dump" from this store when appropriate. Some diabetics (whose livers aren't "listening" to the signals due to hepatic insulin resistance) experience dumps which raise glucose at innappropriate times.

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Old 08-14-2012, 21:52   #6
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No, it can just stay where it is stored as "sugar water" (glylcogen) in the liver. Most people (on most diets) walk around with between 3 and 10 pounds of this water-glycogen mixture stored in their liver all the time. Non-diabetics only "dump" from this store when appropriate. Some diabetics (whose livers aren't "listening" to the signals due to hepatic insulin resistance) experience dumps which raise glucose at innappropriate times.
This is not accurate. While both the mechanism(s) and off-label therapeutic potential for metformin is still a relatively active area of research, the benefit to diabetics generally has nothing to do with glycogen (and I've never heard of it referred to as "sugar water" before). The most well-established effect of metformin is to block liver production of glucose from scratch using amino acids as the source material (gluconeogenesis). This was thought to be due to activation of AMPK until fairly recently where is becoming clear that it does both (activating AMPK and inhibiting gluconeogenesis) by blocking the electron transport chain which increases AMP/ATP ratio (cellular energy charge). This directly blocks gluconeogenesis and stimulates glycolysis to generate more ATP. While there is a group at Vanderbilt that has published a couple of papers describing effects of metformin on glycogen in dogs, the effect is likely secondary.

Metformin also decreases insulin resistance, although the mechanism not fully understood and is still under investigation. The problem with resistance to insulin is that glucagon is the dominant hormone, and glucose production in the live is regulated by the ratio of the two (glucagon+epinephrine tell the liver to make glucose when insulin is low or perceived to be low). The jury is still out on the precise effect of metformin on insulin resistance. However, it is becoming clear that another therapeutic effect of metformin for us diabetics is to increase GLP-1 production.

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Old 08-14-2012, 23:45   #7
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This is not accurate. While both the mechanism(s) and off-label therapeutic potential for metformin is still a relatively active area of research, the benefit to diabetics generally has nothing to do with glycogen (and I've never heard of it referred to as "sugar water" before). The most well-established effect of metformin is to block liver production of glucose from scratch using amino acids as the source material (gluconeogenesis). This was thought to be due to activation of AMPK until fairly recently where is becoming clear that it does both (activating AMPK and inhibiting gluconeogenesis) by blocking the electron transport chain which increases AMP/ATP ratio (cellular energy charge). This directly blocks gluconeogenesis and stimulates glycolysis to generate more ATP. While there is a group at Vanderbilt that has published a couple of papers describing effects of metformin on glycogen in dogs, the effect is likely secondary.

Metformin also decreases insulin resistance, although the mechanism not fully understood and is still under investigation. The problem with resistance to insulin is that glucagon is the dominant hormone, and glucose production in the live is regulated by the ratio of the two (glucagon+epinephrine tell the liver to make glucose when insulin is low or perceived to be low). The jury is still out on the precise effect of metformin on insulin resistance. However, it is becoming clear that another therapeutic effect of metformin for us diabetics is to increase GLP-1 production.
It's the same. Metformin reduces "production" of glucose by the liver. It doesn't deplete it. It's still there. It just doesn't dump as much and doesn't increase (or decrease). This could be "front-end" or "back-end" it doesn't really matter. The end result is the same.

Front-end: reduces the amoung of glycogen made. System somehow senses glycogen is not being added and therefore is less inclined to "dump" (produce or send to circulation).

Back-end: causes the liver to behave as it should and NOT dump glucose into blood when insulin is present (overcomes hepatic insulin resistance). System senses glycogen is still "stoked" and so refrains from making more via gluconeogenesis.

I believe the second one is more plausible but I don't think the answer is known. Maybe it's both.

You mentioned the hormones which tell the liver "go" but don't forget the one which tells it to "stop and hold". That hormone is insulin. Imbalances in any of these hormones - or the livers responsiveness to them can cause detrimental behavior. Hepatic insulin resistance will result in liver dumping at levels of insulin where it shouldn't happen without necessarily any change in other hormones.

Glycogen (slightly modified glucose) is stored in the liver as one part glycogen with 16 parts water. That's why it weighs so much. 5 - 10 pounds of pure glucose/glycogen would be HUGE. "Sugar water" is my term but I think its pretty descriptive and accurate. OK, I admit, it also reflects how I feel about it.

Metformin's effect on insulin resistance is not just still being "studied", it is disputed. A good number of clinical studies disprove this claim but others seem to say otherwise. It is not a proven effect of Met, although it is repeated endlessly.

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Old 08-15-2012, 04:12   #8
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Does all of the 10 lbs get stored in the liver ? From what I read the liver stores 90 gms and muscles store about 300 gms. That would be the glycogen in it's pure form. With the water retained (16 parts) it would all add up to 10 lbs, but I'm not sure that the liver storage would be 10 lbs.

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Old 08-15-2012, 16:39   #9
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Does all of the 10 lbs get stored in the liver ? From what I read the liver stores 90 gms and muscles store about 300 gms. That would be the glycogen in it's pure form. With the water retained (16 parts) it would all add up to 10 lbs, but I'm not sure that the liver storage would be 10 lbs.
10lbs of glycogen is not accurate, your numbers are more realistic. The liver has around 6-8% fresh (hydrated) weight as glycogen in the "fed state", which is close to 100 g usually. The skeletal muscle stores less; about 1-2% of fresh weight (about 400 g), but of course most folks have significantly more muscle mass than liver mass. Other tissues also store glycogen (10% of total) including most muscle cells (including heart), kidney and small intestine. The muscle glycogen is an internal energy source whereas the liver (and kidney) glycogen is used to buffer blood glucose.

However, it is not "sugar water" and it is not "slightly modified glucose". Glycogen in it's simplest form is a polymer of glucose, highly branched and exists as granule or balls containing an equal amount of protein. The synthesis and degradation is a highly controlled process.

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Old 08-15-2012, 18:45   #10
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I bet my doctor doesn't know all this. You guys are no joke.

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