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* * * Mildly high blood glucose, or injected insulin? A Risk Managemnt Approach

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  • Ellis2ca
    After I wrote and sent the answer to this post, I kept on thinking about why I choose to use insulin, even IF insulin should turn out to increase risk of
    Message 1 of 2 , Nov 4, 2011
    • 0 Attachment
      After I wrote and sent the answer to this post, I kept on thinking about
      why I choose to use insulin, even IF insulin should turn out to increase
      risk of cancer... I thought and thought about it, and the more I thought
      about it, the more I realized that my answer is correct, but I should have
      given an answer from a Risk Management Approach.

      Risk Management is how insurance agents analyze a risk, and try to
      improve the risk (and thus the premium to be paid) by either eliminating
      the risk, reducing it, or transferring it to the insurance company.

      I should have answered with reference to how likely each decision is to give
      what result...

      So... I have re-written my answer, just editing on top of my previous post, which
      was good and correct. But this revised answer will give you more insight into
      why I think that the use of insulin will give me better results, even if
      it should turn out to increase the incidence of cancer.

      FIRST OF ALL... I checked it... and I DID NOT FIND ANY ASSOCIATION between
      the use of HUMULIN R with an inceased incidence of cancer. The reported
      association is with INSULIN ANALOGUES, particularly "glargine" insulin which
      is LANTUS... Insulin ANALOGUES are "insulin" that has been
      slightly modified in the order of the amino acids, or a substance has
      been added, usually to make it act FASTER or SLOWER than human insulin.

      But I did not find any report in PubMed that claims that Humulin R increases
      the risk of cancer... there are OTHER types of insulin, particularly LANTUS (insulin
      glargine) which have been reported to increase the incidence of breast cancer...

      But I do not use Lantus anymore, since more than one year ago.. I only use
      Humulin R because I want to THINK LIKE A PANCREAS...

      Humulin R is identical to human insulin and I did not find any
      ASSOCIATION between Humulin R and an increased incidence of any kind
      of cancer...

      Humulin R is FAST ACTING and SHORT LASTING... and it is IDENTICAL
      to Human Insulin, in the order of amino acids and shape of the protein.

      But IN ANY CASE, I answer below, ASSUMING THAT PERHAPS any type of
      insulin, including Humulin R, will increase the risk of cancer.

      - Ellis
      =========
      Hello Ellis!

      I have been meaning to ask you for sometime now :

      What do you say in response to those who claim that insulin promotes cancer,
      and therefore, the use of it to keep blood glucose below 90 at all times is too
      risky as a "mere anti aging strategy" for those who are only possibly
      "pre-diabetic" but rarely go above 125 without using any insulin?

      In other words, I think the question boils down to this . . . which is more
      carcinogenic, the mildly high blood glucose, or the injected insulin that is
      necessary to keep it below 90?

      Thanks so much for your excellent pioneering work on these important topics!!!

      Gratefully,

      Garry



      Ellis: Hello Garry,

      There is always going to be SOMEBODY who will say SOMETHING about
      anything we try to do for anti-aging...

      So now... WHO SAYS that INSULIN causes CANCER? I had not read that one yet...

      I looked it up in PubMed (The Library of Medicine of the Library of Congress)
      and I found an article that says that there seems to be an association between
      Insulin Analogues, in particular Insulin glargine, and breast cancer, but not
      with all incidence of cancer... (see abstract below...)

      But let's suppose that all kinds of insulin MIGHT cause cancer (I don't believe
      it does, but let's suppose it might...)

      So now I have to decide which road do I want to travel?

      Shall I go down the road where my blood sugar is "rarely" above 125 mg/dl?

      Or shall I go down the road where my blood sugar is "rarely" above
      100 mg/dl, and according to somebody, perhaps I have a higher risk of
      cancer?

      Well... it all comes down to choosing the lesser of two evils... and quality
      of life.

      Let us start with a little Risk Management. The TWO BIGGEST CAUSES of
      DEATH are: Heart Disease and Stroke, which together kill about 50% of the
      population... and CANCER which kills about 15% of the population.

      That is an amazing statistic... If you can prevent heart disease or stroke,
      and cancer, you avoid the cause of death of 65% or more of the population,
      and you will surely increase your life expectancy by many, many years.

      Other important causes of death are Alzheimer's and Kidney disease and
      diabetes...

      Of course, diabetes.... which "according to Ellis" is caused by high blood sugar
      over many years.

      We KNOW that HEART DISEASE and STROKE are associated to the damage
      CAUSED by HIGH BLOOD SUGAR which damages the circulatory system...

      And we KNOW that sugar is food for cancer...

      An even higher percent of the population suffers at least one heart attack
      or stroke, but does not die of it, but they survive with a lessened quality of
      life... and about 30% of the population gets cancer at some time in their
      life, and about half die and half survive cancer... probably with some
      suffering, even if they survive.

      So those TWO causes of DEATH account for about 65 per cent of all the
      people who are in the cemetery... The other 35% die of kidney disease,
      accidents, degenerative neurological diseases, suicide, etc. including
      "old age" which is probably caused by cells which are unable to repair
      themselves anymore.

      So... If I should get cancer because I take insulin, there is about 50% chance
      that I will be cured... it is even greater chance if I can detect it when it is not
      yet advanced...

      And... If I am to get cancer because I take insulin to keep my blood sugar
      levels low, then at least I am not going to FEED that cancer much sugar...

      Cancer grows better and is more difficult to treat when there is high
      blood sugar, so it seems almost contradictory that insulin should cause
      cancer... but we are supposing that it does...

      But if I have my blood sugar levels 30 or more points LOWER that it would
      have been without insulin, then I am not going to hasten the loss
      of the nervous system, which includes MY BRAIN...

      And I am not going to hasten the loss of my kidneys...

      And I am not going to hasten the deterioration of my circulatory
      system...

      And if I have my blood sugar levels HIGH (that is, "rarely" above 125) I also
      am certain that AFTER I EAT INCORRECTLY it is going to be A LOT higher
      than 125, and I am sure that most people who THINK that their blood sugar
      is "rarely" above 125, do in fact have blood sugar levels way above 125
      VERY OFTEN...

      Because ONE large APPLE will raise my blood sugar to about 140...
      and ONE large glass of ORANGE JUICE juice will raise my blood sugar
      to 160... and ONE large plate of spaghetti will raise my blood sugar to 180...

      So do you know anybody who has an APPLE or a large glass of ORANGE
      JUICE, or a plate of spaghetti, or a whole bun of bread?

      So I don't believe this baloney about "rarely" raising blood sugar above 125...
      it is wishful thinking... if you don't actively prevent blood sugar from rising,
      as I do with a tiny dose of insulin before I eat, then your blood sugar is
      probably hitting way above 125 several times each day, for several hours.

      So... it is: PERHAPS get cancer which has a 50% chance of being cured, or live
      almost certainly with complications of diabetes in the long run, and an increased
      risk of heart attack or stroke or cancer or kidney disease or Alzheimer's...

      I have taken about 20,000 shots of insulin, and if each shot kept me 30
      points lower than I would have been otherwise for about 4 hours on the
      average, that would be ABOUT 80,000 HOURS that I have had less SUGAR
      gumming up my kidneys, and damaging my circulatory system, and
      damaging my nervous system, and raising my resistance to insulin (because
      it is a paradox, but injecting INSULIN results in LESS insulin floating about
      my circulatory system...)

      SO... I think I will CHOOSE TO TAKE INSULIN and RISK GETTING CANCER, if
      in fact taking insulin will raise my risk of getting cancer.

      I take a PSA test, prostate specific antigen... prostate cancer is the most
      common kind of cancer in males, so I will cross my fingers and hope to CATCH
      IT SOON, if I ever get cancer.

      And there is another blood test, the A.M.A.S. (anti-malignin-antibodies-
      in serum) which can detect that there are antibodies to cancer, so there is
      a tumor SOMEWHERE in your body.

      So detecting cancer at an early stage is possible, and we should all try to
      avoid cancer by detecting it with blood tests, but more importantly, we can
      prevent cancer by keeping blood sugar levels controlled.

      I THINK that taking insulin has helped me to AVOID SENILITY, and it has helped
      me to AVOID HEART ATTACKS, and CANCER, and it has helped me to AVOID DIABETES.

      And... IF I SHOULD DIE YOUNG because I take insulin, I have NO COMPLAINTS.

      I am 66 years old now... that is YOUNG compared to the age I would HOPE
      to get to some day... but if I die tomorrow, I have never lived ONE DAY of
      my life as an OLD MAN. I give THANKS to God and to Banting and Best and
      Eli Lilly and all those who have made this incredible hormone available to me.

      Tell that to Tchaikowsky... or to MANY MEN who DIED YOUNGER THAN AGE 66.

      Thanks for writing.

      Ellis Toussier


      ======= ABSTRACT OF STUDY
      Insulin analogues and cancer risk: the emergence of second-generation studies.
      Renehan AG.
      Source
      School of Cancer and Enabling Sciences, University of Manchester, Manchester Academic
      Health Science Centre, The Christie NHS Foundation Trust, Wilmslow Road, Manchester,
      M20 4BX, UK, arenehan@....

      Abstract

      A number of observational studies have linked insulin glargine (A21Gly,B31Arg,B32Arg
      human insulin) with a putative increased cancer risk, particularly breast cancer, but many
      of these 'first generation' studies had study design and analysis flaws, and were
      inconclusive.

      A small number of 'second generation' studies are now emerging in which the applied
      pharmaco-epidemiological principles are more robust. For example, when Ruitar and
      colleagues (Diabetologia DOI: 10.1007/s00125-011-2312-4 ) focused specifically on
      breast cancer rather than all incident cancer risk, they were able to show a positive
      association with insulin glargine for breast cancer although there was no association with all incident cancer risk.

      (snip...)
      ==========ABSTRACT OF STUDY

      Is there a role for carbohydrate restriction in the treatment and prevention of cancer?
      Klement RJ, Kammerer U.
      Abstract
      ABSTRACT: Over the last years, evidence has accumulated suggesting that by
      systematically reducing the amount of dietary carbohydrates (CHOs) one could suppress,
      or at least delay, the emergence of cancer, and that proliferation of already existing tumor
      cells could be slowed down.

      This hypothesis is supported by the association between modern chronic diseases like the
      metabolic syndrome and the risk of developing or dying from cancer. CHOs or glucose, to
      which more complex carbohydrates are ultimately digested, can have direct and indirect
      effects on tumor cell proliferation: first, contrary to normal cells, most malignant cells
      depend on steady glucose availability in the blood for their energy and biomass generating
      demands and are not able to metabolize significant amounts of fatty acids or ketone
      bodies due to mitochondrial dysfunction.

      Second, high insulin and insulin-like growth factor (IGF)-1 levels resulting from chronic
      ingestion of CHO-rich Western diet meals can directly promote tumor cell proliferation via
      the insulin/IGF-1 signaling pathway.

      Third, ketone bodies that are elevated when insulin and blood glucose levels are low, have
      been found to negatively affect proliferation of different malignant cells in vitro or not to
      be usable by tumor cells for metabolic demands, and a multitude of mouse models have
      shown anti-tumorigenic properties of very low-CHO ketogenic diets.

      In addition, many cancer patients exhibit an altered glucose metabolim characterized by
      insulin resistance and may profit from an increased protein and fat intake.

      In this review, we address the possible beneficial effects of low CHO diets on cancer
      prevention and treatment. Emphasis will be placed on the role of insulin and IGF-1 signaling in tumorigenesis as well as altered dietary needs of cancer patients.

      ========
    • Gordon
      I have not followed this debate carefully, but it seems to me that any link between insulin use and cancer must be correlative and not causal. In other words,
      Message 2 of 2 , Nov 10, 2011
      • 0 Attachment
        I have not followed this debate carefully, but it seems to me that any link
        between insulin use and cancer must be correlative and not causal.

        In other words, while it might be true that people who must inject
        insulin have a higher rate of cancer, it does not follow that insulin
        use causes cancer.

        Can anyone show evidence to the contrary?

        Gordon Swobe  


        Ellis: Hello Gordon... It is good to hear from you.

        You are right, it might be true that people who must inject insulin
        have a higher rate of cancer, because they also probably have a
        higher HbA1c... but the association that was found in the study
        was between Lantus ("glargine insulin") and breast cancer, only.

        (note: Lantus is a very long-lasting insulin analog which
        crystalizes beneath the skin when it is injected, and slowly melts
        away in a very even dose of insulin, during about 24 hours.)

        And I did not find any study showing an association between
        Humulin R, which is identical to Human Insulin, and cancer of
        any kind. But I will bet that as you say, there is a higher rate of
        all types of cancer among persons who must use insulin than
        persons who don't have to use insulin, because their average
        blood glucose is probably considerably higher than persons who
        do not have to use insulin.

        And I will also bet that there is a HIGHER rate of cancer among
        diabetics who SHOULD USE INSULIN but DO NOT, because their
        doctors prescribe metformin instead.

        And... I will also bet that there is a LOWER rate of cancer among
        persons (like me) who are not diabetic and do use Humulin R and
        DO NOT HAVE TO USE INSULIN but use it anyways, to keep blood
        glucose lower.

        (I have no way to know how many persons in the world are not
        diabetic but do use insulin... Before I started to use insulin about
        10 years ago, it was probably zero, or close to zero...

        But now it is perhaps 10 persons around the world... it is more than
        just me, because I have received e-mails from about 10 persons in
        different countries around the world, thanking me for opening their
        mind to a radical and life saving idea... And I thank everybody here
        on Rejuvenation, because I learned this idea in the course of discussions
        that we had on this forum.)

        - Ellis





        ___
        From: Ellis2ca <etoussier@...>
        To: Rejuvenation@yahoogroups.com
        Sent: Friday, November 4, 2011 8:11 AM
        Subject: [Rejuvenation] * * * Mildly high blood glucose, or injected insulin? A Risk Managemnt Approach

        After I wrote and sent the answer to this post, I kept on thinking about
        why I choose to use insulin, even IF insulin should turn out to increase
        risk of cancer... I thought and thought about it, and the more I thought
        about it, the more I realized that my answer is correct, but I should have
        given an answer from a Risk Management Approach. 

        Risk Management is how insurance agents analyze a risk, and try to
        improve the risk (and thus the premium to be paid) by either eliminating
        the risk, reducing it, or transferring it to the insurance company. 

        I should have answered with reference to how likely each decision is to give
        what result... 

        So... I have re-written my answer, just editing on top of my previous post, which
        was good and correct.  But this revised answer will give you more insight into
        why I think that the use of insulin will give me better results, even if
        it should turn out to increase the incidence of cancer.

        FIRST OF ALL... I checked it... and I DID NOT FIND ANY ASSOCIATION between
        the use of HUMULIN R with an inceased incidence of cancer.  The reported
        association is with INSULIN ANALOGUES, particularly "glargine" insulin which
        is LANTUS...  Insulin ANALOGUES are "insulin" that has been
        slightly modified in the order of the amino acids, or a substance has
        been added, usually to make it act FASTER or SLOWER than human insulin.

        But I did not find any report in PubMed that claims that Humulin R increases
        the risk of cancer... there are OTHER types of insulin, particularly LANTUS (insulin
        glargine) which have been reported to increase the incidence of breast cancer...

        But I do not use Lantus anymore, since more than one year ago.. I only use
        Humulin R because I want to THINK LIKE A PANCREAS...

        Humulin R is identical to human insulin and I did not find any
        ASSOCIATION between Humulin R and an increased incidence of any kind
        of cancer...

        Humulin R is FAST ACTING and SHORT LASTING... and it is IDENTICAL
        to Human Insulin, in the order of amino acids and shape of the protein.

        But IN ANY CASE, I answer below, ASSUMING THAT PERHAPS any type of
        insulin, including Humulin R, will increase the risk of cancer.

        - Ellis
        =========
        Hello Ellis!

        I have been meaning to ask you for sometime now :

        What do you say in response to those who claim that insulin promotes cancer,
        and therefore, the use of it to keep blood glucose below 90 at all times is too
        risky as a "mere anti aging strategy" for those who are only possibly
        "pre-diabetic" but rarely go above 125 without using any insulin?

        In other words, I think the question boils down to this . . . which is more
        carcinogenic, the mildly high blood glucose, or the injected insulin that is
        necessary to keep it below 90?

        Thanks so much for your excellent pioneering work on these important topics!!!

        Gratefully,

        Garry



        Ellis: Hello Garry,

        There is always going to be SOMEBODY who will say SOMETHING about
        anything we try to do for anti-aging...

        So now... WHO SAYS that INSULIN causes CANCER? I had not read that one yet...

        I looked it up in PubMed (The Library of Medicine of the Library of Congress)
        and I found an article that says that there seems to be an association between
        Insulin Analogues, in particular Insulin glargine, and breast cancer, but not
        with all incidence of cancer...  (see abstract below...)

        But let's suppose that all kinds of insulin MIGHT cause cancer (I don't believe
        it does, but let's suppose it might...)

        So now I have to decide which road do I want to travel?

        Shall I go down the road where my blood sugar is "rarely" above 125 mg/dl?

        Or shall I go down the road where my blood sugar is "rarely" above
        100 mg/dl, and according to somebody, perhaps I have a higher risk of
        cancer?

        Well... it all comes down to choosing the lesser of two evils... and quality
        of life. 

        Let us start with a little Risk Management.  The TWO BIGGEST CAUSES of
        DEATH are: Heart Disease and Stroke, which together kill about 50% of the
        population... and CANCER which kills about 15% of the population. 

        That is an amazing statistic...  If you can prevent heart disease or stroke,
        and cancer, you avoid the cause of death of 65% or more of the population,
        and you will surely increase your life expectancy by many, many years.

        Other important causes of death are Alzheimer's and Kidney disease and
        diabetes...

        Of course, diabetes....  which "according to Ellis" is caused by high blood sugar
        over many years.

        We KNOW that HEART DISEASE and STROKE are associated to the damage
        CAUSED by HIGH BLOOD SUGAR which damages the circulatory system... 

        And we KNOW that sugar is food for cancer...

        An even higher percent of the population suffers at least one heart attack
        or stroke, but does not die of it, but they survive with a lessened quality of
        life... and about 30% of the population gets cancer at some time in their
        life, and about half die and half survive cancer... probably with some
        suffering, even if they survive.

        So those TWO causes of DEATH account for about 65 per cent of all the
        people who are in the cemetery... The other 35% die of kidney disease,
        accidents, degenerative neurological diseases, suicide, etc. including
        "old age" which is probably caused by cells which are unable to repair
        themselves anymore. 

        So... If I should get cancer because I take insulin, there is about 50% chance
        that I will be cured... it is even greater chance if I can detect it when it is not
        yet advanced...

        And... If I am to get cancer because I take insulin to keep my blood sugar
        levels low, then at least I am not going to FEED that cancer much sugar...

        Cancer grows better and is more difficult to treat when there is high
        blood sugar, so it seems almost contradictory that insulin should cause
        cancer... but we are supposing that it does...

        But if I have my blood sugar levels 30 or more points LOWER that it would
        have been without insulin, then I am not going to hasten the loss
        of the nervous system, which includes MY BRAIN...

        And I am not going to hasten the loss of my kidneys...

        And I am not going to hasten the deterioration of my circulatory
        system...

        And if I have my blood sugar levels HIGH (that is, "rarely" above 125) I also
        am certain that AFTER I EAT INCORRECTLY it is going to be A LOT higher
        than 125, and I am sure that most people who THINK that their blood sugar
        is "rarely" above 125, do in fact have blood sugar levels way above 125
        VERY OFTEN... 

        Because ONE large APPLE will raise my blood sugar to about 140...
        and ONE large glass of ORANGE JUICE juice will raise my blood sugar
        to 160... and ONE large plate of spaghetti will raise my blood sugar to 180...

        So do you know anybody who has an APPLE or a large glass of ORANGE
        JUICE, or a plate of spaghetti, or a whole bun of bread? 

        So I don't believe this baloney about "rarely" raising blood sugar above 125... 
        it is wishful thinking... if you don't actively prevent blood sugar from rising,
        as I do with a tiny dose of insulin before I eat, then your blood sugar is
        probably hitting way above 125 several times each day, for several hours.

        So... it is: PERHAPS get cancer which has a 50% chance of being cured, or live
        almost certainly with complications of diabetes in the long run, and an increased
        risk of heart attack or stroke or cancer or kidney disease or Alzheimer's...

        I have taken about 20,000 shots of insulin, and if each shot kept me 30
        points lower than I would have been otherwise for about 4 hours on the
        average, that would be ABOUT 80,000 HOURS that I have had less SUGAR
        gumming up my kidneys, and damaging my circulatory system, and
        damaging my nervous system, and raising my resistance to insulin (because
        it is a paradox, but injecting INSULIN results in LESS insulin floating about
        my circulatory system...)

        SO... I think I will CHOOSE TO TAKE INSULIN and RISK GETTING CANCER, if
        in fact taking insulin will raise my risk of getting cancer.

        I take a PSA test, prostate specific antigen... prostate cancer is the most
        common kind of cancer in males, so I will cross my fingers and hope to CATCH
        IT SOON, if I ever get cancer.

        And there is another blood test, the A.M.A.S. (anti-malignin-antibodies-
        in serum) which can detect that there are antibodies to cancer, so there is
        a tumor SOMEWHERE in your body.

        So detecting cancer at an early stage is possible, and we should all try to
        avoid cancer by detecting it with blood tests, but more importantly, we can
        prevent cancer by keeping blood sugar levels controlled.

        I THINK that taking insulin has helped me to AVOID SENILITY, and it has helped
        me to AVOID HEART ATTACKS, and CANCER, and it has helped me to AVOID DIABETES.

        And... IF I SHOULD DIE YOUNG because I take insulin, I have NO COMPLAINTS.

        I am 66 years old now... that is YOUNG compared to the age I would HOPE
        to get to some day... but if I die tomorrow, I have never lived ONE DAY of
        my life as an OLD MAN. I give THANKS to God and to Banting and Best and
        Eli Lilly and all those who have made this incredible hormone available to me.

        Tell that to Tchaikowsky... or to MANY MEN who DIED YOUNGER THAN AGE 66.

        Thanks for writing.

        Ellis Toussier


        ======= ABSTRACT OF STUDY
        Insulin analogues and cancer risk: the emergence of second-generation studies.
        Renehan AG.
        Source
        School of Cancer and Enabling Sciences, University of Manchester, Manchester Academic
        Health Science Centre, The Christie NHS Foundation Trust, Wilmslow Road, Manchester,
        M20 4BX, UK, arenehan@....

        Abstract

        A number of observational studies have linked insulin glargine (A21Gly,B31Arg,B32Arg
        human insulin) with a putative increased cancer risk, particularly breast cancer, but many
        of these 'first generation' studies had study design and analysis flaws, and were
        inconclusive.

        A small number of 'second generation' studies are now emerging in which the applied
        pharmaco-epidemiological principles are more robust. For example, when Ruitar and
        colleagues (Diabetologia DOI: 10.1007/s00125-011-2312-4 ) focused specifically on
        breast cancer rather than all incident cancer risk, they were able to show a positive
        association with insulin glargine for breast cancer although there was no association with all incident cancer risk.

        (snip...)
        ==========ABSTRACT OF STUDY

        Is there a role for carbohydrate restriction in the treatment and prevention of cancer?
        Klement RJ, Kammerer U.
        Abstract
        ABSTRACT: Over the last years, evidence has accumulated suggesting that by
        systematically reducing the amount of dietary carbohydrates (CHOs) one could suppress,
        or at least delay, the emergence of cancer, and that proliferation of already existing tumor
        cells could be slowed down.

        This hypothesis is supported by the association between modern chronic diseases like the
        metabolic syndrome and the risk of developing or dying from cancer. CHOs or glucose, to
        which more complex carbohydrates are ultimately digested, can have direct and indirect
        effects on tumor cell proliferation: first, contrary to normal cells, most malignant cells
        depend on steady glucose availability in the blood for their energy and biomass generating
        demands and are not able to metabolize significant amounts of fatty acids or ketone
        bodies due to mitochondrial dysfunction.

        Second, high insulin and insulin-like growth factor (IGF)-1 levels resulting from chronic
        ingestion of CHO-rich Western diet meals can directly promote tumor cell proliferation via
        the insulin/IGF-1 signaling pathway.

        Third, ketone bodies that are elevated when insulin and blood glucose levels are low, have
        been found to negatively affect proliferation of different malignant cells in vitro or not to
        be usable by tumor cells for metabolic demands, and a multitude of mouse models have
        shown anti-tumorigenic properties of very low-CHO ketogenic diets.

        In addition, many cancer patients exhibit an altered glucose metabolim characterized by
        insulin resistance and may profit from an increased protein and fat intake.

        In this review, we address the possible beneficial effects of low CHO diets on cancer
        prevention and treatment. Emphasis will be placed on the role of insulin and IGF-1 signaling in tumorigenesis as well as altered dietary needs of cancer patients.

        ========


        ------------------------------------

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