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confused

Discussion in 'Parents of Children with Type 1' started by C6H12O6, Sep 15, 2015.

  1. Theo's dad Joe

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    OK, I see that this is working on a model that there is something uniquely beneficial about having pulsatile insulin doses sent to the liver. I really know very little about that. I DO know that during hyperglycemia, cells are not "low" on glucose, they are actually high on glucose (as glucose has many ways to enter all body cells that do not require having IOB). There is a problem that cells are inhibited from BURNING glucose during hyperglycemia and maybe this inhibition is related to how insulin is delivered. I think euglycemia is not an equation. It is more about providing insulin to tell the liver to act properly in response to meals and counter regulatory hormones.
     
  2. rgcainmd

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    (The bolding is mine.) What? Don't think you've got this right...
     
  3. C6H12O6

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    I think you are perhaps thing of glucotoxicity, which can happen with type 1 or type 2.
     
  4. Theo's dad Joe

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    glucotoxicity kills beta cells, but it also causes runaway insulin resistance (eventual ketoacidosis) which goes away after a period of euglycemia.
     
  5. Theo's dad Joe

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    I PMed you (not too many links). Let me know what you think. I was taught that the concept that insulin was required for cells to take up glucose is an oversimplification.
     
  6. mmgirls

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    So I have to ask/say work this out in my own mind.

    But a BG from a BG meter is showing what is in the blood, not the sugar in the cells. While I do think it is relevant to understand if it is possible for a cell to up take glucose in the absence of insulin, if we have no measure of that what is the point? except for the middle of the night ponderings of, " I wonder if her cells are hyper.?"
     
  7. mmgirls

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    Is it a matter of osmotic pressure?
     
  8. Theo's dad Joe

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    The only point is that cells have more than 1 transport receptor. the Glut4 (I believe) is insulin dependent. Others can let in some glucose. I think that Glut 2 or 3 in the liver is insulin "regulated" because glucose can go into liver cells without insulin but the glucagon push will always tend to push out more than goes in, unless insulin blocks the glucagon levels or activity. Also, also other receptors let in galactose, fructose and protein without insulin. Here are the links just in case you are interested.
    I think that most estimates are that most people's cells take up around 100 grams of glucose a day through insulin independent means, but-OK back to the point-it doesn't matter because the liver will just keep making and spitting our more glucose if you don't have insulin to tell the liver to stop, so you can't prevent hyperglycemia or DKA without insulin.

    Also the point may be that when cells get full of glucose and the body has hypoglycemia, there are mechanisms that impair cells from burning glucose for fuel (insulin also prevents lipids from moving into the blood from the liver and fat cells, so when insulin is low blood lipids go up.

    Oh also, insulin resistant individuals or T2Ds have been found to create more of the non-insulin mediated pathways over time.

    1) http://www.jci.org/articles/view/112169

    "Although insulin is extremely potent in regulating glucose transport in insulin-sensitive tissues, all tissues are capable of taking up glucose by facilitated diffusion by means of a noninsulin-mediated glucose uptake (NIMGU) system. Several reports have estimated that in the postabsorptive state the majority of glucose disposal occurs via a NIMGU mechanism."

    2) http://www.ncbi.nlm.nih.gov/pubmed/20153490

    "In the fasting state, approximately 83% of glucose uptake occurs via non-insulin-mediated mechanisms. A widely accepted static rate for NIMGU is 1.62 mg kg(-1)·min(-1)."

    3) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC424207/


    4) http://nadeem.no/2012/10/07/glucose-...lin-dependant/ (not research, but commentary of an MD, and a very complete explanation of all mechanisms of glucose uptake).

    Edit, the last one is broken (if it is blocked I apologize). And it contends that there is little clinical significance. Here is the text and references: Edit again, notice the bold and underlined part. I am only speculating that this "therapy" may be considered a way to trigger glucose burning which is "outcompeted by fat oxidation. Its off the wall and I am not supporting it and don't know anything about it though.

    Myth: Insulin is needed for glucose uptake

    Abstract: Despite evidence to the contrary, there is a widespread misconception that cells cannot take up glucose without insulin. It is believed that these starving cells, by their inability to absorb glucose, cause hyperglycemia (high blood sugar). This brief review of the available scientific literature intends simply to show that 1) considerable glucose uptake occurs independently of insulin, 2) that hyperglycemia is not caused by cells unable to import glucose, 3) AND lastly THAT CELLS ARE NOT STARVING DURING HYPERGLYCEMIA.

    Important: this text discusses the underlying mechanisms of glucose uptake. It has little clinical significance. Diabetics should continue to use insulin as prescribed by their doctor.

    As a medical student, i’ve been taught that cells need insulin to absorb glucose. Insulin causes a glucose transporter (glut) to rise to the cell surface. This transporter creates a channel for glucose to flow through. There are about 13 different gluts, and the one that needs insulin is glut4 (possibly 12, also). According to the misconception, glut4 is required for glucose uptake, and that is why insulin is necessary. Without insulin, there will be no glut4, and so we’re told that the cell cannot consume glucose, which causes glucose to build up in the blood – hyperglycemia. This is demonstrably false, as many experiments have shown. While insulin does impact absorption by doubling the glucose uptake speed, we’ll see that it is not required. 1

    While it is true that glut4 is largely insulin dependent, it has almost a dozen brothers that function quite well without insulin. 2 take, for example, glut1. It’s nearly everywhere in the body, all the time, and it’s as powerful as the glut4. Glut1 is the day-to-day glucose transporter responsible for basal glucose uptake. It doesn’t need insulin. It has been hypothesized that glut1 alone can sustain an adequate uptake of glucose in muscle. 3 there mere existence of this glut1 is enough to question the notion that glucose uptake must be insulin mediated.

    We’ve quickly established that glucose uptake occurs without insulin, but how much? In 1983, the peer reviewed american journal of physiology published a study which concluded:

    These results indicate that in postabsorptive human subjects 75-85% of glucose uptake is noninsulin-mediated and provide additional support for the concept that insulin may increase glucose uptake merely by providing additional transport sites. 4

    Around 80% of glucose uptake is insulin independent. That’s quite a lot. If you’re inclined to reject this study based on its age, consider the glucose clamp technique they’ve used: developed in 1979, it is still the gold standard today. 5 this means that it has been known for more than 30 years that there is considerable glucose uptake without insulin. Why then do medical schools teach students that insulin is an absolute requirement for glucose uptake?

    In 1994, another study consisting of almost a 100 human subjects, published in the journal diabetes, said:

    We conclude that insulin-independent glucose uptake is a major determinant of intravenous glucose tolerance … 6

    A 2001 review in the journal of endocrinology:

    We now know that there is a sufficient population of glucose transporters in all cell membranes at all times to ensure enough glucose uptake to satisfy the cell’s respiration, even in the absence of insulin. Insulin can and does increase the number of these transporters in some cells but glucose uptake is never truly insulin dependent – in fact, even in uncontrolled diabetic hyperglycaemia, whole body glucose uptake is inevitably increased (unless there is severe ketosis). 7

    The article continues:

    When insulin is administered to people with diabetes who are fasting, blood glucose concentration falls. It is generally assumed that this is because insulin increases glucose uptake into tissues, particularly muscle. In fact this is not the case and is another error arising from extrapolating from in vitro rat data. It has been shown quite unequivocally that insulin at concentrations that are within the normal physiological range lowers blood glucose through inhibiting hepatic glucose production (ra) without stimulating peripheral glucose uptake 8

    Some think that without insulin, glucose just piles up outside the cell, causing high blood sugar and leaving the cell lacking glucose. In fact, during hyperglycemia, there is more glucose inside the cell than during normoglycemia. Again, from the 2001 review:

    Contrary to most textbooks and previous teaching, glucose uptake is therefore actually increased in uncontrolled diabetes and decreased by insulin administration! The explanation for this is that because, even in the face of insulin deficiency, there are plenty of glucose transporters in the cell membranes. The factor determining glucose uptake under these conditions is the concentration gradient across the cell membrane; this is highest in uncontrolled diabetes and falls as insulin lowers blood glucose concentration primarily (at physiological insulin concentrations) through reducing hepatic glucose production. 9

    The liver is the main reason that blood sugars rise 10, and insulin lowers blood sugar by telling the liver to stop releasing sugar into the blood.

    If you still believe that hyperglycemia is due to cells not taking up glucose, consider that hyperglycemia itself causes increased glucose uptake. A 2012 study on rats assessed the effects of hyperglycemia on how much and how fast cells import glucose. Using somatostatin they suppressed insulin and isolated the effects of hyperglycemia. They had this to say:

    … The model detects increases in both interstitial and intracellular glucose concentrations, increases in the maximal velocity of glucose transport and increases in the rate of glucose transport, all in response to hyperglycemia. 11

    Hyperglycemia actually increases glucose uptake, while during hyperglycemia insulin actually decreases glucose uptake.

    We’ve talked about insulin and we’ve discussed hyperglycemia. Now let’s talk some more about glut4. What happens when there is no glut4? Mice who have no glut4 develop enlarged hearts, shorter life-span and growth retardation. But, they do not develop diabetes, and clear up blood glucose just like normal subjects. Here’s a quote from a study published the journal nature:

    The glut4-null mice demonstrate that functional glut4 protein is not required for maintaining nearly normal glycaemia but that glut4 is absolutely essential for sustained growth, normal cellular glucose and fat metabolism, and expected longevity. 12

    Another study, aptly named “normal muscle glucose uptake in mice deficient in muscle glut4″ says:

    Our study demonstrates that deletion of muscle glut4 does not adversely affect glucose disposal and glucose tolerance and that compensation from other transporters may contribute to this unaltered homoeostasis of glucose. 13

    Glut4 does not seem to be as important in glucose uptake as we’re taught.

    Lastly, is the cell starving during hyperglycemia? No. While glucose uptake is increased during hyperglycemia, glucose metabolism is down regulated and out competed by fat metabolism. 14

    I hope you found this article helpful. Please share your thoughts in the comments field below.



    nadqur@gmail.com
    Abonner
    Notes:

    Ludvigsen, C. & Jarett, L. (1980). A comparison of basal and insulin-stimulated glucose transport in rat adipocyte plasma membranes. Diabetes, 29(5), 373-8. ↩
    Zhao, F. Q. & Keating, a. F. (2007). Functional properties and genomics of glucose transporters.Current genomics, 8(2), 113-28., from http://www.Pubmedcentral.Nih.Gov/picrender.Fcgi?Blobtype=pdf&artid=pmc2435356
    Ebeling, P., Koistinen, H. A., & Koivisto, V. A. (1998). Insulin-independent glucose transport regulates insulin sensitivity. Febs letters, 436(3), 301-3. ↩
    Gottesman, I., Mandarino, L., & Gerich, J. (1983). Estimation and kinetic analysis of insulin-independent glucose uptake in human subjects. The american journal of physiology, 244(6), e632-5. ↩
    Hompesch, M. & Rave, K. (2008). An analysis of how to measure glucose during glucose clamps: are glucose meters ready for research?. Journal of diabetes science and technology, 2(5), 896-8., from http://www.Pubmedcentral.Nih.Gov/picrender.Fcgi?Blobtype=pdf&artid=pmc2769796
    Kahn, S. E., Prigeon, R. L., McCulloch, D. K., Boyko, E. J., Bergman, E. N., Schwartz, M. W., et al. (1994). The contribution of insulin-dependent and insulin-independent glucose uptake to intravenous glucose tolerance in healthy human subjects. Diabetes, 43(4), 587-92. ↩
    Sonksen, P. H. (2001). Insulin, growth hormone and sport. The journal of endocrinology, 170(1), 13-25. ↩
    ibid ↩
    ibid ↩
    Defronzo, R. A., Ferrannini, E., & Simonson, D. C. (1989). Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism: clinical and experimental, 38(4), 387-95. ↩
    Huang, H. M., Chandramouli, V., Ismail-Beigi, F., & Muzic, R. F. (2012). Hyperglycemia-induced stimulation of glucose transport in skeletal muscle measured by pet- [(18)f]6fdg and [(18)f]2fdg. Physiological measurement, 33(10), 1661-73. Doi:10.1088/0967-3334/33/10/1661 ↩
    Katz, E. B., Stenbit, A. E., Hatton, K., Depinho, R., & Charron, M. J. (1995). Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in glut4. Nature, 377(6545), 151-5. Doi:10.1038/377151a0 ↩
    Fam, B. C., Rose, L. J., Sgambellone, R., Ruan, Z., Proietto, J., & Andrikopoulos, S. (2012). Normal muscle glucose uptake in mice deficient in muscle glut4. The journal of endocrinology,214(3), 313-27. Doi:10.1530/joe-12-0032 ↩
    see Sonksen, p. H. (2001) ↩
     
    Last edited: Sep 17, 2015
  9. njswede

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    OK. I can follow the reasoning of the Norwegian fellow. But there's on thing I don't understand: If the cells in the body are perfectly well fed with glucose even during a hyperglycemia episode, what causes the ketosis and ketoacidosis? Ketosis, from what I understand, is a metabolic mechanism that kicks in when there isn't enough glucose to feed on. How is that possible if there's plenty of glucose to go around and the cells have ways of absorbing it?

    I think I've seen reasoning somewhere that nerve-cells have different ways of absorbing glucose and that they are the ones to trigger ketosis. Is that the case here too?

    BTW, I think the keyword in the article is this "Important: this text discusses the underlying mechanisms of glucose uptake. It has little clinical significance. Diabetics should continue to use insulin as prescribed by their doctor". This is fascinating research, but it has very little impact on the day-to-day life of a type 1 diabetic.
     
  10. funnygrl

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    Ketoacidosis is caused by insulin deficiency, not resistance.
     
  11. Theo's dad Joe

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    As for the bold part, its not much different than saying that we might be able to get liver cells to make insulin in theory but it has little clinical significance. It may turn out to have significance. In a way we are pioneers in this age of CGM and the underlying principals may turn out to help us understand say why a couple of crackers can shoot someone up to 300. Everyone can keep dismissing the fascinating research for having little impact, or they can ask new questions.

    Second, ketones are made primarily based on what the liver is experiencing. Low liver glycogen causes ketone production. Chronic low liver glycogen can cause nutritional ketosis. In hyperglycemia the liver sees no insulin so it kicks out glucose from glycogen or protein, and it is getting a zero insulin message that carbs are not coming so start turning fat into ketones. It doesn't care that it has glycogen, just that the lack of insulin is telling it to turn to ketones.
     
  12. Theo's dad Joe

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    I meant that ketosis causes runaway insulin resistance (because ketones block the effects of insulin), but you are right in that it is the insulin deficiency caused by glucotoxicity shutting down beta cells that causes the ketones that cause the resistance.
     
    Last edited: Sep 17, 2015
  13. mmgirls

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    Not sure I agree with this with an established T!D.

    Can you explain to me hoe "ketones" cause insulin resistance? I agree anecdotally, but I have never explored why?
     
  14. Theo's dad Joe

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    I want to be clear, its not IR like that in a T2D. (receptors become desensitized).

    When you have other energy compounds in the blood, like lipids and protein and ketones, they get in the way of insulin working on glucose. Insulin works to keep fatty acids in the liver or in fat cells, not just to move glucose, or keep glucose in the liver, http://www.life-enhancement.com/mag...-not-just-blood-sugar-but-fatty-acids-as-well

    It also is USED to prevent the liver from making and releasing ketones. It also can be used up moving protein into cells.

    So if there is anything in the blood that insulin may get used up on other than glucose, there is less of it to move and hold glucose in.

    Very low carb dieters who are in nutritional ketosis actually tend to need higher basal insulin than people who eat moderate amounts of carbs (around 30%).
     
  15. mmgirls

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    o it would be more of a perceived IR, then, the body is actually not not using the insulin it is just not using it towards lowering glucose, instead dealing with ketones and proteins. That makes sense to me as I have lerned with a stomach bug that has high ketones that but low bg the insulin will go towards "turning off" the ketones first and not lowering bg (when already low)
     
  16. Theo's dad Joe

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    It is usually referred to as "physiological insulin resistance" in literature. Lower carb dieters for example tend to have their fasting blood sugar rise because they are using other energy sources, (but not because of pathological "progressive" insulin resistance).

    In general, without underlying pathological insulin resistance, higher carb eaters (45%+) will tend to have fasting blood sugar in the 80s, moderate/low carb eaters (20-30%) will tend to have fasting numbers in the 90s and very low carb dieters will tend to be in the low 100s. This is physiological and just the result of the body saving sugar for the brain and so setting a higher set point on a lower carb diet.

    http://ketopia.com/physiological-insulin-resistance/

    http://high-fat-nutrition.blogspot.com/2007/10/physiological-insulin-resistance.html

    Here is an interesting study (largely because it was done almost 100 years ago) http://www.jbc.org/content/83/3/747.full.pdf

    (I won't promote any particular carb level or diet, but it doesn't hurt to know that what is a normal fasting blood sugar, or a normal blood sugar pattern depends on the makeup of their diet)
     
    Last edited: Sep 19, 2015

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