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  1. #1
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    metforim is used to regulate glycemia in type-II diabete.

    is well known MET regulates glycemia ruducing endogenus glucose production:" Metformin lowered the rate of glucose production in these patients through a reduction in gluconeogenesis."(2)



    the reduction of gluconeogenesis seems to be a good thing for dieting bbers, because it could have a spanning effect on muscles, that during diet are used to produce glucose.



    it's interesting that, while MET reduces gluconeogenesis, increases FFA in skeletal muscle and liver. "The metabolic actions of the anti-diabetic agent, metformin, which include stimulation of fatty acid oxidation, are believed to occur in part via activation of AMP-activated protein kinase (AMPK) in liver and skeletal muscle"(1)



    this

    a)could produce a faster fat-loss, and

    b)could avoid the problem of very low blood glucose, because glucose is spanned increasing FFA oxidation.



    IN SUMMARY:

    METFORMIN can increases FFA oxidation. this should reduce glucose oxidation, producing a more stable glycemia. a more stable glycemia could reduce gluconeogenesis, spanning muscles.

    by the other side, metformin reduces gluconoegenesis by its self, and this could be another factor to figure a muscle-spanning-effect of metformin.

    we can figure that using met during cutting can speed fat loss, while preserving muscles.

    this model could explain why so may bber report good resault using met during cutting.



    (1)METFORMIN STIMULATES MYOCARDIAL FATTY ACID OXIDATION INDEPENDENT OF CHANGES IN AMP-ACTIVATED PROTEIN KINASE ACTIVITY.

    H Parsons, R Wambolt, R Saeedi, M Allard

    Vancouver, British Columbia



    (2)Effects of Metformin on Hepatic Glycogenolysis and Gluconeogenesis in Type 2 Diabetes.

    Diabetes, May, 2000, by Ripudaman S. Hundal, Martin Krassak, Didier Laurent, Vincent Lebon, Visvanathan Chandramouli, Silvio Inzucchi, William C. Schumann, Bernard R. Landau, Kitt F. Petersen
    IT'S NOT ME IN MY AVATAR!

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    Quote Originally Posted by duchaine' date='Mar 7 2004, 11:36 AM
    metforim is used to regulate glycemia in type-II diabete.

    is well known MET regulates glycemia ruducing endogenus glucose production:" Metformin lowered the rate of glucose production in these patients through a reduction in gluconeogenesis."(2)



    the reduction of gluconeogenesis seems to be a good thing for dieting bbers, because it could have a spanning effect on muscles, that during diet are used to produce glucose.



    it's interesting that, while MET reduces gluconeogenesis, increases FFA in skeletal muscle and liver. "The metabolic actions of the anti-diabetic agent, metformin, which include stimulation of fatty acid oxidation, are believed to occur in part via activation of AMP-activated protein kinase (AMPK) in liver and skeletal muscle"(1)



    this

    a)could produce a faster fat-loss, and

    b)could avoid the problem of very low blood glucose, because glucose is spanned increasing FFA oxidation.



    IN SUMMARY:

    METFORMIN can increases FFA oxidation. this should reduce glucose oxidation, producing a more stable glycemia. a more stable glycemia could reduce gluconeogenesis, spanning muscles.

    by the other side, metformin reduces gluconoegenesis by its self, and this could be another factor to figure a muscle-spanning-effect of metformin.

    we can figure that using met during cutting can speed fat loss, while preserving muscles.

    this model could explain why so may bber report good resault using met during cutting.



    (1)METFORMIN STIMULATES MYOCARDIAL FATTY ACID OXIDATION INDEPENDENT OF CHANGES IN AMP-ACTIVATED PROTEIN KINASE ACTIVITY.

    H Parsons, R Wambolt, R Saeedi, M Allard

    Vancouver, British Columbia



    (2)Effects of Metformin on Hepatic Glycogenolysis and Gluconeogenesis in Type 2 Diabetes.

    Diabetes, May, 2000, by Ripudaman S. Hundal, Martin Krassak, Didier Laurent, Vincent Lebon, Visvanathan Chandramouli, Silvio Inzucchi, William C. Schumann, Bernard R. Landau, Kitt F. Petersen
    IIRC, Metformin acts through antagonizing PPAR gamma as well.
    <span style='color:red'>The attentions of others might be said to matter to us principally because we are afflicted by a congenital uncertainty as to our own value - as a result of which what others think of us comes to play a determining role in how we are able to view ourselves. Our sense of identity is held captive by the judgements of those we live among-- Alain de Botton</span>

  3. #3
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    Quote Originally Posted by Spencer' date='Mar 8 2004, 01:23 AM
    IIRC, Metformin acts through antagonizing PPAR gamma as well.
    This is minor. Met's primary effect is increasing AMPK and reducing coenzyme A (CoA), the fuel sensors in many cell types (hepatic, adipose and skeletal muscle). Although Met does reduce body weight and bodyfat, some of the effects are indirect as well as direct. Met also tends to suppress appetite and increase water loss. Compared to other modalities, Met was more favorable than the thiazolidinediones (where increases of bodyfat and body weight were seen), but less favorable than exercise and AICAR. Body fat changes were not 100% deficit in models (human and murine) treated with Met. Some actually gained bodyfat.



    This is information gleaned from a seminar I attended presented by Neil Ruderman, who pioneered AICAR and was the key researcher on mechanisms of AMPK and CoA. I composed a summary of the presentation elsewhere. If there's interest, I might post it here.
    <span style='color:blue'>"The absence of evidence does not mean evidence of absence."</span>

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    Quote Originally Posted by Labrat' date='Mar 14 2004, 08:24 AM
    [quote name='Spencer' date='Mar 8 2004, 01:23 AM']IIRC, Metformin acts through antagonizing PPAR gamma as well.
    This is minor. Met's primary effect is increasing AMPK and reducing coenzyme A (CoA), the fuel sensors in many cell types (hepatic, adipose and skeletal muscle). Although Met does reduce body weight and bodyfat, some of the effects are indirect as well as direct. Met also tends to suppress appetite and increase water loss. Compared to other modalities, Met was more favorable than the thiazolidinediones (where increases of bodyfat and body weight were seen), but less favorable than exercise and AICAR. Body fat changes were not 100% deficit in models (human and murine) treated with Met. Some actually gained bodyfat.



    This is information gleaned from a seminar I attended presented by Neil Ruderman, who pioneered AICAR and was the key researcher on mechanisms of AMPK and CoA. I composed a summary of the presentation elsewhere. If there's interest, I might post it here. [/quote]

    I'm interested. I am diabetic and have been on Metformin for 2 years. (1000mg BID)



    Could you briefly define AICAR? I've never heard of it, but would like to learn about it.





    Greenguy

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    Quote Originally Posted by Labrat' date='Mar 14 2004, 08:24 AM
    [quote name='Spencer' date='Mar 8 2004, 01:23 AM']IIRC, Metformin acts through antagonizing PPAR gamma as well.
    This is minor. Met's primary effect is increasing AMPK and reducing coenzyme A (CoA), the fuel sensors in many cell types (hepatic, adipose and skeletal muscle). Although Met does reduce body weight and bodyfat, some of the effects are indirect as well as direct. Met also tends to suppress appetite and increase water loss. Compared to other modalities, Met was more favorable than the thiazolidinediones (where increases of bodyfat and body weight were seen), but less favorable than exercise and AICAR. Body fat changes were not 100% deficit in models (human and murine) treated with Met. Some actually gained bodyfat.



    This is information gleaned from a seminar I attended presented by Neil Ruderman, who pioneered AICAR and was the key researcher on mechanisms of AMPK and CoA. I composed a summary of the presentation elsewhere. If there's interest, I might post it here. [/quote]

    there is a lot of interest, labrat. thanks for your answer.
    IT'S NOT ME IN MY AVATAR!

  6. #6
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    Quote Originally Posted by duchaine' date='Mar 14 2004, 06:07 PM
    [quote name='Labrat' date='Mar 14 2004, 08:24 AM'] This is information gleaned from a seminar I attended presented by Neil Ruderman, who pioneered AICAR and was the key researcher on mechanisms of AMPK and CoA. I composed a summary of the presentation elsewhere. If there's interest, I might post it here.
    there is a lot of interest, labrat. thanks for your answer.[/quote]

    Fuel Sensing: Exercise beats all.



    Neil Ruderman from Boston University was on campus, the guest of Roger

    Unger, just two days after the media announcement of Unger et al's

    published study on leptin and 'redesigning' the fat cell. Ruderman

    headed the search for the hidden mechanisms behind the common, and

    diverging, pathways of fuel sensing in fat and muscle cells. While

    these pathways are similar in skeletal muscle tissue and adipose

    tissue, they are not quite 'created equal.'



    The common signaling for most of these pathways are reduced mostly to

    a few molecules that serve as 'fuel sensors.' Basically, they sense

    when the cell is low in or replete with energy for the jobs that the

    cell does and then activates switches to compensate. Aside from basic

    cell machinery, muscle cells have the highest demand for fuel, second

    only to the brain. Fat cells have very little fuel requirement.



    The two main role players are enzymes: AMP-activated protein kinase

    (AMPK) and malonyl coenzyme A (CoA). They are largely responsible for

    fuel sensing in the cells, and, ultimately, energy balance. Without

    delving into the sordid molecular details, simply put: increased AMPK

    good, increased CoA bad.



    CoA increases de novo TG synthesis and storage and inhibits glucose

    oxidation. AMPK increases fatty acid oxidation and reduces de novo TG

    synthesis (especially re-esterification of FFAs). They are the

    opposing 'twins.' So anything that increases AMPK and decreases CoA is

    really good.



    Ruderman and others have examined several approaches that achieve

    this: electrical stimulation (the first model), several

    pharmaceuticals, some which may be familiar to you (AICAR,

    thiazolidinediones, metformin, b-AR agonists), a few hormones

    (adiponectin, leptin), and exercise.



    Some examples that demonstrate how these molecules work:



    Skeletal muscle: glucose alone stimulates CoA; add insulin and the

    increase is several fold (additive effect).



    When fuel is low in skeletal muscle (in the form of glycogen), CoA is

    downregulated (lower activity).



    Exercise increases AMPK and decreases CoA.



    Here is what astounded me (and I have reversed my former position): exercise

    not only downregulated CoA and increased AMPK in skeletal muscle, but

    ALSO in the liver and adipose tissue. It is the latter that caught me

    by surprise (as did it he when he made this discovery).



    Comparing several of the pharms mentioned above to exercise, the

    latter came out on top with flying colors in:

    * increasing AMPK, decreasing CoA, reducing body weight, improving

    insulin sensitivity, and reducing risks associated with several

    diseases (inflammation, CVD, etc).

    AICAR was second, metformin third and the thiazolidinediones last

    which increased body weight more than reducing, etc.



    Moreover, when exercise is performed with muscle glycogen somewhat

    depleted, the increase in AMPK is rapid and most significant. (is

    glycogen synthase involved in the signaling pathway, I asked? They

    don't know as yet, but it may be).



    In relevance to the metabolic syndrome, which was the underlying

    impetus behind this seminar and obviously related to energy balance,

    the main message is to increase physical activity. I asked if there

    has been any application of this research to exercise prescription.

    Not yet, but several points are apparent:



    * as little as 20 minutes of treadmill running will induce a shift

    in skeletal muscle cell fuel use.

    * Duration will depend on intensity, but duration may be more

    important than intensity. (there is a recent clinical study and a gene regulation study that supports this)

    * Frequency may be a factor, depending on the beginning fuel status of

    the muscle (related to glycogen content). In other words, don't keep

    the fuel tanks topped off.

    * I asked if duration (and fequency) was related to time required for

    enzyme shift. Probably. Another reason to keep the fuel tanks a bit

    low. In glycogen depleted rats, a shift in AMPK and CoA was seen at 3

    minutes of TM running.



    Take home lesson:

    Exercise. More than just 3 times/week, more than 20 minutes/session.

    Just do it.



    Avoid super compensation of muscle glycogen unless you are going to

    burn it soon (endurance training, etc).



    Avoid lots of carbs (to keep the tank from being topped off and to

    avoid adding pain to injury i.e. additive effects of glucose and

    insulin).



    The sushi and wine at the seminar were wonderfully delicious.
    <span style='color:blue'>"The absence of evidence does not mean evidence of absence."</span>

  7. #7
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    Quote Originally Posted by Greenguy' date='Mar 14 2004, 10:40 AM
    I'm interested.* I am diabetic and have been on Metformin for 2 years. (1000mg BID)



    Could you briefly define AICAR?* I've never heard of it, but would like to learn about it.





    Greenguy
    I, too, am diabetic. I have found that some exercise every day (yes, every day) controls my BG levels. On days where I cannot exericse, I take metformin.



    AICAR is 5-aminoimidazole-4-carboxamide ribonucleoside, a compound that activates AMP-activated protein kinase (AMPK) and demonstrated to stimulate glucose transport. AICAR is metabolized to an AMP-mimetic, ZMP. It is used frequently in research models, but not much in humans. A clinical trial is in phase II stage.
    <span style='color:blue'>"The absence of evidence does not mean evidence of absence."</span>

  8. #8
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    Quote Originally Posted by Labrat' date='Mar 20 2004, 08:05 AM
    [quote name='duchaine' date='Mar 14 2004, 06:07 PM'][quote name='Labrat' date='Mar 14 2004, 08:24 AM'] This is information gleaned from a seminar I attended presented by Neil Ruderman, who pioneered AICAR and was the key researcher on mechanisms of AMPK and CoA. I composed a summary of the presentation elsewhere. If there's interest, I might post it here.
    there is a lot of interest, labrat. thanks for your answer.[/quote]

    Fuel Sensing: Exercise beats all.



    Neil Ruderman from Boston University was on campus, the guest of Roger

    Unger, just two days after the media announcement of Unger et al's

    published study on leptin and 'redesigning' the fat cell. Ruderman

    headed the search for the hidden mechanisms behind the common, and

    diverging, pathways of fuel sensing in fat and muscle cells. While

    these pathways are similar in skeletal muscle tissue and adipose

    tissue, they are not quite 'created equal.'



    The common signaling for most of these pathways are reduced mostly to

    a few molecules that serve as 'fuel sensors.' Basically, they sense

    when the cell is low in or replete with energy for the jobs that the

    cell does and then activates switches to compensate. Aside from basic

    cell machinery, muscle cells have the highest demand for fuel, second

    only to the brain. Fat cells have very little fuel requirement.



    The two main role players are enzymes: AMP-activated protein kinase

    (AMPK) and malonyl coenzyme A (CoA). They are largely responsible for

    fuel sensing in the cells, and, ultimately, energy balance. Without

    delving into the sordid molecular details, simply put: increased AMPK

    good, increased CoA bad.



    CoA increases de novo TG synthesis and storage and inhibits glucose

    oxidation. AMPK increases fatty acid oxidation and reduces de novo TG

    synthesis (especially re-esterification of FFAs). They are the

    opposing 'twins.' So anything that increases AMPK and decreases CoA is

    really good.



    Ruderman and others have examined several approaches that achieve

    this: electrical stimulation (the first model), several

    pharmaceuticals, some which may be familiar to you (AICAR,

    thiazolidinediones, metformin, b-AR agonists), a few hormones

    (adiponectin, leptin), and exercise.



    Some examples that demonstrate how these molecules work:



    Skeletal muscle: glucose alone stimulates CoA; add insulin and the

    increase is several fold (additive effect).



    When fuel is low in skeletal muscle (in the form of glycogen), CoA is

    downregulated (lower activity).



    Exercise increases AMPK and decreases CoA.



    Here is what astounded me (and I have reversed my former position): exercise

    not only downregulated CoA and increased AMPK in skeletal muscle, but

    ALSO in the liver and adipose tissue. It is the latter that caught me

    by surprise (as did it he when he made this discovery).



    Comparing several of the pharms mentioned above to exercise, the

    latter came out on top with flying colors in:

    * increasing AMPK, decreasing CoA, reducing body weight, improving

    insulin sensitivity, and reducing risks associated with several

    diseases (inflammation, CVD, etc).

    AICAR was second, metformin third and the thiazolidinediones last

    which increased body weight more than reducing, etc.



    Moreover, when exercise is performed with muscle glycogen somewhat

    depleted, the increase in CoA is rapid and most significant. (is

    glycogen synthase involved in the signaling pathway, I asked? They

    don't know as yet, but it may be).



    In relevance to the metabolic syndrome, which was the underlying

    impetus behind this seminar and obviously related to energy balance,

    the main message is to increase physical activity. I asked if there

    has been any application of this research to exercise prescription.

    Not yet, but several points are apparent:



    * as little as 20 minutes of treadmill running will induce a shift

    in skeletal muscle cell fuel use.

    * Duration will depend on intensity, but duration may be more

    important than intensity. (there is a recent clinical study and a gene regulation study that supports this)

    * Frequency may be a factor, depending on the beginning fuel status of

    the muscle (related to glycogen content). In other words, don't keep

    the fuel tanks topped off.

    * I asked if duration (and fequency) was related to time required for

    enzyme shift. Probably. Another reason to keep the fuel tanks a bit

    low. In glycogen depleted rats, a shift in AMPK and CoA was seen at 3

    minutes of TM running.



    Take home lesson:

    Exercise. More than just 3 times/week, more than 20 minutes/session.

    Just do it.



    Avoid super compensation of muscle glycogen unless you are going to

    burn it soon (endurance training, etc).



    Avoid lots of carbs (to keep the tank from being topped off and to

    avoid adding pain to injury i.e. additive effects of glucose and

    insulin).



    The sushi and wine at the seminar were wonderfully delicious. [/quote]

    1)when AMPK is reduced, energy expenditure is reduced as well.

    AMPK is related to muscle glycogen, right?

    if muscle glycogen is low, FFA oxidation is increased, but overall energy expenditure is reduced,

    so, I suppose that being glycoen depleted is not a good thing if someone want to decrease bf. Am I wrong, labrat?



    2)low muscle glycogen will icrease IL-6 poduction.

    IL-6 is a signal for liver to incease endogenus glucose production.

    for diabetic people, can this be detrimental to control BG levels?

    and for dieters, can this be bad, bacause it can increase muscle-catabolism?



    3)can u explain me how met can better body composition?



    4)u wrote: "CoA increases de novo TG synthesis and storage and inhibits glucose oxidation." isn't this contradictory? if I reduce glucose oxidation, I should increase FFA oxidation, reducing TG storage.(for the statment: I knew incread CoA should increase gucose oxidation and decrease FFA oxidation)
    IT'S NOT ME IN MY AVATAR!

  9. #9
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    Quote Originally Posted by duchaine' date='Mar 21 2004, 07:01 PM
    1)when AMPK is reduced, energy expenditure is reduced as well.

    AMPK is related to muscle glycogen, right?

    if muscle glycogen is low, FFA oxidation is increased, but overall energy expenditure is reduced,

    so, I suppose that being glycoen depleted is not a good thing if someone want to decrease bf. Am I wrong, labrat?


    Your logic falters in the middle and you reached the wrong assumption. Glycogen depletion enhances fat oxidation/fat loss.



    2)low muscle glycogen will icrease IL-6 poduction.

    IL-6 is a signal for liver to incease endogenus glucose production.

    for diabetic people, can this be detrimental to control BG levels?

    and for dieters, can this be bad, bacause it can increase muscle-catabolism?


    First question: no. Low glycogen correlates with enhanced insulin sensitivity. Yes, high IL-6 does induce heptatic glycogenolysis, but since glucose clearance is enhanced, it's typically a non-issue. Also, unless one is cachexic, IL-6 does not cause muscle catabolism. TNF-a will.



    3)can u explain me how met can better body composition?


    Not sure what you are specifically asking here.



    4)u wrote: "CoA increases de novo TG synthesis and storage and inhibits glucose oxidation." isn't this contradictory?


    No. "CoA increases de novo TG synthesis and storage and inhibits glucose oxidation. AMPK increases fatty acid oxidation and reduces de novo TG synthesis (especially re-esterification of FFAs). They are the

    opposing 'twins.' So anything that increases AMPK and decreases CoA is good."



    if I reduce glucose oxidation, I should increase FFA oxidation, reducing TG storage.(for the statment: I knew incread CoA should increase gucose oxidation and decrease FFA oxidation)


    What?
    <span style='color:blue'>"The absence of evidence does not mean evidence of absence."</span>

  10. #10
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    I use metformin in suppository form. Am I doing it right?? Oh, also, I'm a spammer.

  11. #11
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    Why don't you just look at the website you're promoting in your sig, it willl probably have the questions and answers you're looking for....

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