Insulin Paradox.Has any one heard about it?

I am sure no body has heard about it. Actually it is me that is coining the word for first time.

What every body know is that in type 2 diabetes ,there is insulin resistance. So even if pancreas is working normally and there is enough insulin or may be there is hyperinsulinemia ,still insulin is not doing its work of lowering blood sugar properly. So there is hyperglycaemia .

Now, the same person who has high blood sugar level due to insulin resistance ( endogenous insulin becoming ineffective ), when given insulin from outside ( exogenous insulin ) ,responds quickly and high blood sugar level goes down. Meaning external insulin works while internal insulin is in effective. IS IT NOT A PARADOX ?

27 Replies

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  • Mr.Rao, let us drop "Mr.".

    Even though you have written about French dietary ritual,in a lighter vein,it has reminded me our own dietary customs. It postulates that each bite of food should be chewed 32 time before swallowing. If we could revert back to and follow that system of eating,we could perhaps surpass the French lunch duration. If that happens there will be no need for effort,internal or external,and pharma industry will go into a stage of shock.

    By the way,any thought on how to solve Insulin Paradox puzzle ?

  • Rao,I am inclined to agree with Indiacratus. Falling requirement of insulin might point an accusing finger at kidney. But if your doctor says all is well, then there is no concern to worry. May I suggest a Doppler CT scan of kidney to rule out any initial renal damage . Well you are the best person to judge.

  • Good for you,nothing to worry as far as kidney is concerned.

  • Btw, can you you quote your blood sugar levels fasting and pp and also HbA1C.your BP .sorry, if it encroaches upon your privacy.you are at Liberty not to make your medical reports public.

  • Your reports are wonderfully good.please continue what you are following . If you have any thing specific in mind please come out with it.Will try to clear any doubts with our limited knowledge.

    Thank you for sharing your reports.

  • I come from North India. No secrets.

  • I must compliment you on your fine health. Even at the the age of about 82 yrs ,you are physically and mentally very active. I have also seen a few diabetics,on oral hypoglycemics,eating every thing including a lot of sweets,I repeat a lot of sweets,still hale and hearty and without any complications. They all are 80+ age group. I have not tried to look for the reason behind that. There must be some thing more than the diet and walking. I have also known diabetics who despite proper diet and excercise and medication including insulin, have failed to control their blood sugar.

    That is why I want to understand the phenomenon of insulin paradox as clearly as possible.

    Thanks for sharing your diabetic history.

  • It may be due to tension free life & happiness

  • Indiacratus,something new for me,insulin is altered when it enters into blood from pancreas?

    The said explanation for insulin paradox never satisfies me . It is too simple . It's just like putting a crowed at a barrier, hoping some might sneak in ! It fails to explain many things. A more detail understanding of the whole subject is required.

  • Indiacratus, to get to the bottom of things is my habit since younger age. There fore I have developed expertise to understand complicated things in many discipline . Once upon a time puzzle solving was my past time.

    So the crux of the matter is to understand insulin resistance . And I am not going into those details here.

  • What is a paradox. As per dictionary meaning "a seemingly contradictory statement but found to be true." Now on the basis of this meaning, if I say insulin paradox, is it not correct ?

    Please look at from another angle, is any of the statement made is factually incorrect ? So statement seem contradictory but is based on sound logic.

    Here we are not concerned with any correction factor or questioning the efficacy of insulin. The contradiction is that in the same environment that is blood, endogenous insulin is not effective despite there being very high level of it (hyperinsulinemia ), while in the same environment external insulin is in real life practice is effective.

    So the PARADOX is that the same insulin produced internally is not doing its job,but same insulin when given from outside does its job efficiently. It needs no reminder that both insulin ( internal and external ) are structurally the same.

  • I know about clamp test since long. The paradox is not about comparing the efficacy of exogenous and endogenous insulin. I am sorry to say that you are thinking is differen and in different direction.

    When you talk about French paradox,you simply say that both French and Americans are both taking high fat diet,but French are slim and have little cardiac complications,while Americans become obese and with it all related complications. So it is paradox. Same fat different result.

    In the same way ,as natural insulin is unable to cope with the rising blood sugar level (please remember insulin is available in abundance ,much, much more than what is required ) ,the artificial insulin is effective. I may point out that whatever the cause of failure of endogenous insulin to function properly,is still there when exogenous insulin is administered.

    In vitro, while functionally and structurally both types of insulin are same,there is no two opinions about that,but in vivo in diabetics reasons unknown ,results everybody know exogenous insulin does reduce blood sugar levels. That is the paradox. Same insulin different result.

  • Just following what white collared scientists say in lab doesn't mean one is rational. Rational guys weight both sides of the story without bias or prejudice and more often that not that's done based on personal experience.

    Just take a look at LUPUS forum. I just follow that forum to see how decently guys and gals behave even when they go against the so called science. No one starts bashing anyone who criticizes the mainstream. Many even say that the amount of new things that they learned no doctor could ever tell. This is how FORUM should be and not what you think it should be.

    I have read about this whole insulin paradox with half side of the story

    Was insulin in blood of the subjects measured?

    What is triglycerides level?

    How bad is IR?

    What are other drugs taken? Because STATINS are known to increase insulin resistance.

  • Indiacratus, agreed in French paradox ,ethnicity is same and the reason, perhaps is the difference in the quality of fat.whatever might be the reason,which is immaterial,only both eat high fat and result is different,so it is paradox,and we all accept it.

    Now ,function of insulin,reduction of blood sugar,universal truth.

    Hyperinsulnemia precedes development of first prediabetes and then full blown diabetes, widely accepted fact.

    Endogenous insulin,for whatever reason fail to control blood sugar level, accepted fact.

    Exogenous insulin ,when administered,reduces blood sugar,irrespective of level of insulin in blood or lipid profile data ,irrespective of ethnicity ,race or genetic profile. Accepted universally.

    So ,both endogenous and exogenous nsulin is behaving differently,in exactly in the same condition,and that also without exception. An undisputed fact.

    Is it not a PARADOX ?? It has much stronger case as it is a global phenomenon and not limited to a small group as in French paradox.

  • Dear Indiacratus , here we are talking about insulin and NOT diabetes. Secondly ,when I say irrespective of insulin level in blood,it is quite correct ,whether there is high level or low level external insulin is effective,so no need to measure insulin. We are not talking about even insulin resistance. You may be right when experimenting in normal subjects,but not in a diabetic,who require external insulin.

    Physiolathogenesis of insulin secretion and. It's role in glucose homeostasis in normal condition and in diabetic condition is very complicated and will need lot of time and energy to understand.

  • Sigh, the reason the American diet is bad is because it contains man-made fats, harmful carbohydrates and additives.

    Too much insulin is worse for health than hyperglycaemia; see the ACCORD study. Don't eat more carbohydrate than you use.

  • "Don't eat more carbohydrate than you use."

    Scientists say eat 60% CARBS and only 7% saturated fat and then walk 5 miles. Ridiculous.

    Everything is on the up (diabetes, obesity, cancer, cvd, chd, autism, ibs, etc after this recommendation :( :(

  • One has to understandthe inter-relation of glucose as it is insulin secretogogue. on arrival of glucose insulin released. Its action is on insulin receptor for uptake of glucose intotargeted tissue. If understands this interaction ,then one can appreciate of the pardox posed.

    Let me clarify the dynamism invovled because I worked on this extreemly useful concept.on digestion of polysaccarides at the gut enzymes, glucose is liberated ,which is absorbed by the blood, remember that they are spefic transporters,there is increase in the glucose which signals beta-ilet cells to secrete insulin.This secretion is intune with glucose concentration as the glucose levels go up insulin increases but as glucose tapper the insulin levels do.After about two hours the blood glucose levels reach around120-140mg/dl.so also insulin levels reaching to minimum but, secretion continues at lower level.After 4-5 hours of carbohydrate ingestion glucose levels reach much lower causing hunger and one take food.

    Maintance of glucose is very important since brain depends on glucose as source of energy, otherwise it leads to fatality.

    It is OK in day time, one feels hungry and takes carbohydrate food. As again this in night this is different. Liver gluconeogenisis takes place to maintain blood glucose levels to feed the brain.

    In type 2 diabeties gluconeogenisis is thrice higher, thus leading to higher glucose out put causing higher insulin secretion.

    This is particularly observed in fasting glucose and fasting insulin levels. This is used as marker of on set of type2 diabeties. This is calculated as HOMA values.

    So there is higher insulin but not acting, this is the pardox.

    For better understanding of this one must know the basic interlation of insulin&insulin receptors.

    For pushing glucose into target tissue, insulin acts on specific protein on cell membrane called insulin receptor.More details are not given except the fact that reaction is though one to one, the interaction is not linear to insulin concentration in blood. What this means higher the insulin ,the availability of insulin receptors on cell membranes ćome down because of internalization of insulin&insulin receptors, thus accumating more insulin in blood.This is known ad inverse relation of ligand and receptor in molecular endocrinology. It applies generally as ligand receptors complex. The net result is higher insulin less glucose is pushed. For better clearance if insulin is less then better is exposure of insulin receptors. This is insulin sensitization so many antidiabetic drugs are based on metformin like drugs which causes increased number of înśulin recptors without altering insulin levels.it essentially means the number of insulin receptos are more per molecule of insulin.

    Contratry to this in sulin resistance the number of insulin receptors levels are far less.Thus this leads less insulin receptors due to internalization thus leaving more insulin in blood, but due to shear mass action it tries to act and push glucose.

    Finally,take home point is that relation between insulin and insulin receptor is like yin-yang . Hence this distinction"

    Mapalli.

    Dr. m.K.Janardanasarma. Ph.D(IISc)

    Molecular endocrinologist.

    Deputy Director(Retd)

    National Institute of Nutrtion,p

    Indian Council of Medical Research,

    Hyderabad,500007

    Contact number 09866822770

  • "So there is higher insulin,but nor working." That is the paradox. You clearly got to the crux of the matter. Let me explain, in diabetics, higher levels of endogenous insulin in blood is unable to act on or act insuffiently on circulating glucose,while exogenous insulin is effective . That is the paradox.

  • Actualy in type 2 diabeties, there is higher insulin in fasting state not on response to glucose load.please check what is called area under the curve of insulin rełeased called AUC for that period of time of glucose absorption from villai of intestine. Repeated ingestion of high carbohydrates results high demand on insulin secretion repeated. This causes exhustion of insulin,since the synthesed insulin is stored granules. On emptying these granules new insulin has to synthesised which takes time. Thus there is lag period. This lag period if it becomes too short if beat the beta ilets cells repeatedly with high food in take, thus resulting type 2 diabeties. This is always"less. We have repeated this in laboratory on human diabetic voluteers compared to normals.AUC of insulin falls shorter over period of time. So one is put on insulin secrtoguge to increase levels as treatment regime.

    The important point is the number of insulin receptors molecules avaible per molecule of insulin.This is crucial as pointed out,higher is the number of insulin receptors available per molecule better is glucose clerance. On the contratary as in type -2 diabeties since gluconegenis is three times higher, this leads to more fasting insulin secretion, which leads to down regulation of insulin recptors. We have actually quantifed the number of insulin receptors per molecule of insulin. In cases number of insulin receptors permolecule is so low that it corresponds to high level of glucose in plasma.

    Again inverse relation between insulin and insulin receptors is crux of pardox.

    By feeding high fiber we are able to reduce AUC of insulin,but the number of insulin recptors jumped ten to fifteen times and glucose is cleared .This is basis of using highfiber diet or lowglycemic index diet.

    All these finding editorial comments are published by in Journal of Diabeties and Metabolism 2011Sep, under title "insulin sensitization and insulin resistance quantative moleculár model in prediabetic mouse model

    Mapallihh

  • ""So there is higher insulin,but nor working." That is the paradox"

    Definitely not. The higher insulin is insufficient due to Insulin resistance.

    If IR increases even external insulin dose needs to be increased.

    So no paradox anywhere.

    Get TG/HDL close to 1 and same insulin will have far better sensitivity.

  • I am sorry to say that every one is missing the point. It is not about insulin resistance. Resistance is a common factor for both internal and external insulin. Paradox is while endogenous is ineffective or only partially effective, insulin when given from outside it works.

    If cause is set as parameter then there is no French or obesity paradoxes.

  • The quantity injected/needed is also dependent on IR. With reduced IR even endogenous insulin works better thus needing less and less of exogenous shots. Exogenous works as it makes up for the shortfall. Even exogenous shots keep increasing. Why? It's all about TG/HDL ratio and insulin deficiency. No paradox here.

    In addition, even STATIN drugs add to the woes, as it forces IR.

    French or obesity paradoxes are there because of failure to recognize the cause -- Higher INSULIN in blood -- because High Carb diet has to be pushed as healthiest diet under the sun. People don't see the main reason and talk about sedentary lifestyle ie blame the patient and not the system.

  • Gluconegenisis is higher in type -2 diabeties.be it from stored glycogen or from aminoacids. Kindly refer to all articles on mechanism of action of metformin.

    Returing to the question of insulin and insulin receptors, the interaction of insulin on it receptors causeses cascade of reaction first being of autophorphorylation of tyrosine residues, then othere cell proteins called IRS-1,IRS-2 which again leads to translocation of glucose transporters from cytosol to cell surface membrane, this glucose transporter translocates glucose from blood to cytosol, eventuallt the complex of insulin and insulin receptors are englued into cytosol forming what is called clatharin pits, thus there is deprivation of insulin receptors at cell surface. The entire process is called down regulation of insulin receptors. For fresh receptors to appear on cell surface it takes lag time. Hence appearnce of new receptors would dispose fresh insulin to act upon.

    The ying-yang theory is well established in endocrinology system. For better understand let me ilustrate smelling where the odour on intital contact to nose smells, but on constant exposure smelling come down. So do nuerotransmitters, drugs used in the nervous syt.

    Kindly refer to the my article referred in the previous reply. Where there quatification of Insulin receptor per molecule of insulin,which clearly shows that number of molecules of insulin receptors per molecule is far higher compared insulin resistances where the Insulin recptors are far less per molecule of insulin.this elebborated well editors of journal.

  • "Maintance of glucose is very important since brain depends on glucose as source of energy, otherwise it leads to fatality."

    Brain can run on ketones equally well.

    Certain drug resistant epilepsy is treated with ketogenic diet where carbs are 10% or less.

  • Yes gluconegenis is three times higher in type-2 diabeties. It is synthesis of glucose from other sources. The entire story of type-2 diabeties starts from this phenonemena.Hence the first line of treatment type 2 diabeties supression of gluconeogenisis by drugs like metformin sothat there is normalization of fasting glucose. Refer to mechanism of action of metformin in good scientific journals or wikipedia.

    Mapalli

  • Indiacratus and mapalli, paradoxes are based on effects and not on causes. Nevertheless ,it was a good, meaningful and very informative discussion. After a very long time a discussion has taken place in a congenial and peaceful environment. Thanks to all members who participated as well as contributed. Hope it has helped the members in understanding different aspect of insulin metabolism. Thanks again .

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