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Zero Basal?

Discussion in 'Parents of Children with Type 1' started by Darryl, Jul 22, 2015.

  1. Darryl

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    By now we've pretty much seen it all when it comes to basal rate variations, from times where she needs 5u/hr to needing no basal, but these times usually last a few hours at most.

    The past few days, with her standard basal program (around 1u/hour most of the day), her BG has been constantly in the range of 60 to "low" on the CGM (under 40) despite basal suspended and massive eating. Yesterday she ate 180 carbs (juice, glucose tabs, meals, snacks) between 3 PM and 11 PM with no boluses and basal turned off for all 8 hours. Every time she ate, BG would rise up to 45 or 55 then fall right back down. Finally she at a 60-carb dinner without bolusing and her BG finally came up to 120 around midnight at which point I turned her basal back on and she stayed in a good range until morning.

    Today, she turned off her basal pre-emptively at 9 AM and it is still off now, 19 hours later. Her BG was better, hovering in the 70's most of the day although it dropped low a few times and she needed to eat. She bolused only for her meals today, and post prandials were normal, BG went into the high 100's then came back down.

    She feels fine, no indication of sickness, no eating issues, no digestive issues or any discomfort other than feeling perpetually low. The sensor is good (BG checks match the readings). It's not the pump (omnipod) as the problem has persisted though two pods, including 6 hours in-between pods when she had no pod on at all. She is just tired of having to eat so much food.

    Has anyone experienced this kind of prolonged intolerance of basal insulin with a teenager?
     
  2. quiltinmom

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    I've never heard of anything like it, perhaps with the exception of a newly dx'ed young child.

    Have you talked to your endo about this? Perhaps he/she would have some insights.
     
  3. Theo's dad Joe

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    I read about people who ran low when they had insulin antibodies hold on to insulin for a long time and then releasing it, or who had insulin build up in resistant sites and then released at once. Also celiac preventing absorption. Also muscles can take in glucose with ZERO insulin by a process called non insulin mediated glucose uptake. That could happen during or following intense exercise and is not the same thing as increased insulin sensitivity after exercise (which tends to happen more than 2 hours later).

    Contracting muscles can take in 200+ grams of carbs an hour without insulin by this mechanism (active transport through muscle contraction). Non-insulin mediated glucose uptake has been shown to upregulate during periods of insulin resistance.

    NIMGU is actually the main way that glucose gets into muscle and cells, and gut cells, and really any cells after eating. http://www.jci.org/articles/view/112169
    "We conclude that (a) in the postabsorptive state, NIMGU is the major pathway for glucose disposal"

    Again if someone is becoming insulin resistant there are studies that suggest that non insulin mediated glucose uptake rate increases. (you may have to search for those).

    And I've seen other studies with athletes that runners can move over 200 grams of glucose per hour into cells by non-insulin mediated mechanism, and may continue to do so after exertion for a few hours. Growth of muscles in normal growth of adolescents might also increase it. This all may not apply entirely, but it is important to realize that most glucose enters cells without insulin, even cells that use insulin to bring in glucose.
     
    Last edited: Jul 22, 2015
  4. Christopher

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    So you are saying that even in children with Type 1 diabetes, glucose enters their cells without insulin?
     
  5. Theo's dad Joe

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    Yes absolutely 1000%.

    http://diabetes.diabetesjournals.org/content/39/8/955

    http://nadeem.no/2012/10/07/glucose-uptake-is-not-insulin-dependant/ (cited)

    http://ajpendo.physiology.org/content/255/6/E769.short

    http://physiologyonline.physiology.org/content/20/4/260

    https://books.google.com/books?id=x...8Xwz0#v=onepage&q=endocrinology nimgu&f=false (2/3 of glucose uptake does not use insulin)


    http://www.consultant360.com/articles/pathophysiology-diabetes-elderly
    It has been recognized for years that glucose can stimulate its own uptake in the absence of insulin. This is known as non–insulin-mediated glucose uptake (NIMGU). Under fasting conditions in normal individuals, approximately 70% of glucose uptake occurs via NIMGU, and during a meal, approximately 50% of glucose uptake occurs by non–insulin-mediated mechanisms.

    http://link.springer.com/article/10.1007/BF00265400
    Comparison of values obtained for Vmax and Km in the present studies of Type 1 diabetes with those obtained from non-diabetic subjects indicates that non-insulin dependent glucose uptake in Type 1 diabetes is quantitatively similar to that of non-diabetic subjects.
     
    Last edited: Jul 22, 2015
  6. rgcainmd

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    I don't know if you're completely unaware of the fact that you come off as extremely narcissistic and rude, but you do.

    Your response (quoted above) is a perfect example.

    ETA: Well, you must have realized this, because by the time I posted this comment, you had removed the following: "It is actually chapter 1, lesson 1 of grad school exercise physiology." A good many of your posts come across in this manner. Not a great way to make friends and influence people.
     
  7. Michelle'sMom

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    I'm curious. Where is she in her monthly cycle?
     
  8. Theo's dad Joe

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    Sorry, I read it and it sounded that way so I removed it, but I was just excited and was going to link to an online ex-phys curriculum that everyone could read about and then decided it was time to get my kids lunch cooking and it could wait.

    If i may comment though, I don't understand why you don't ever respond to the content of my posts.
     
    Last edited: Jul 22, 2015
  9. Christopher

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    I don't want to derail Darryl's thread so this will be my last post about this. I don't have time to look at these all right now but if that is true I find it amazing because everything I have always been told and read is that insulin is the "key" that unlocks the cell so that glucose can get in. When that key is not there glucose is not absorbed and you get high blood glucose and basically Type 1 diabetes. If I want to discuss this further I will create my own thread.

    Sorry Darryl!! :cwds:
     
  10. Theo's dad Joe

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    I am posting this one about non insulin mediated glucose disposal because it is on topic of the thread:

    http://www.ncbi.nlm.nih.gov/pubmed/1989854

    "Gram-negative infection increases noninsulin-mediated glucose disposal"

    It is a study with rats, but shows that certain infections increase the rate of removing glucose from the blood in the absence of insulin.

    https://quizlet.com/5349160/list-of-gram-positive-and-gram-negative-bacteria-flash-cards/



    Among other things I've looked at this morning, it looks like the fast acting insulins are not prone to be delayed and released by insulin antibodies.
     
    Last edited: Jul 22, 2015
  11. mamattorney

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    Wow! I've never experienced that - well, not for days at a time. Good luck figuring it out. It must seem like a blessing and curse at the same time.
     
  12. StacyMM

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    That's crazy! I'm stumped. Has she started or stopped any medications? Has she had anything (surgery, procedure, test) that involved anesthesia of any kind? We've had prescription changes impact insulin needs but never to any extent like what you are seeing. And after surgeries, we typically see absolutely beautiful numbers and flat lines for a few days. Any issues with ketones with the hours of missed basals?

    I'm curious - if you ever figure it out, I'd love to hear about it so that I can file that away in the 'diabetes tricks I haven't seen....yet' section of my brain!
     
  13. sugarmonkey

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    We've had random times when we've had to reduce insulin, but not stopping basal altogether. Except illness. I've put it down to coming out of puberty and his insulin needs going down. When he's working he needs very little to no insulin, plus uncovered carbs or he goes low. He has quite a physical job. Neither of these seem to apply to your DD. I hope you figure it out.
     
  14. Darryl

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    Thanks everyone. I suppose that any of this could be the cause. She wasn't exercising to any unusual degree during this time. I don't ask about the time of the month, but it's never happened before so I don't think that's it. Today her basal is around 0.2/hr to keep things level vs. 1/hr typically before. So it will probably get back up to 1u in a day or two. The infection theory sounds most likely at this point, even though she has no symptoms I think some infections can be silent as the body deals with them.

    Christopher, I remember it coming up in the forum years ago that exercise can cause muscles to uptake glucose. It is not clear from the articles that Theo's dad posted whether this can happen with ZERO insulin, or perhaps rather that exercise increases uptake for the same amount of insulin. Remember, before insulin was available, exercise was not found to be a cure. And there are other tissues and organs that do require glucose so even if exercise lowered bg it woudn't be a substitute for insulin. My impression reading the articles is that some insulin is still needed to support the increased glucose uptake during exercise.
     
  15. Theo's dad Joe

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    The last 2 sources show that it works in T1D and requires no insulin. The studies also mention that all tissues take in glucose by diffusion, but not against the concentration gradient.
    1) Some tissues (nerves, brain, retina) can take in all the glucose they need without insulin.
    2) Some take in some without insulin by non insulin mediated diffusion.
    3) Muscle contraction increases the rate of non insulin mediated diffusion.
    4) And on top of that, yes, exercise can increase the effectiveness of insulin in the blood by circulating it more efficiently and improving perfusion AND
    5) on top of that, muscles can become more sensitive to insulin in the 24 hours or so after glycogen depleting exercise.

    The problem with using exercise as a cure is that without insulin the liver release never gets shut down so the liver needs a basal insulin to prevent ketoacidosis (and high blood sugar) and preserve life so exercise can not stand alone. The liver will see no insulin for a while and become more and more sensitive to glucagon. There are new drugs that lower blood sugar but have ended up producing low blood sugar ketoacidosis. So its not about the cells getting energy (muscles can work on 90% fatty acids which go right into the same pathway as glucose, fructose and galactose go into cells without insulin) it is about the liver eventually malfunctioning without any insulin.

    http://www.consultant360.com/articles/pathophysiology-diabetes-elderly
    "It has been recognized for years that glucose can stimulate its own uptake in the absence of insulin. This is known as non–insulin-mediated glucose uptake (NIMGU). Under fasting conditions in normal individuals, approximately 70% of glucose uptake occurs via NIMGU, and during a meal, approximately 50% of glucose uptake occurs by non–insulin-mediated mechanisms."

    http://link.springer.com/article/10.1007/BF00265400
    "Comparison of values obtained for Vmax and Km in the present studies of Type 1 diabetes with those obtained from non-diabetic subjects indicates that non-insulin dependent glucose uptake in Type 1 diabetes is quantitatively similar to that of non-diabetic subjects."
     
    Last edited: Jul 22, 2015
  16. Theo's dad Joe

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    I thought this was a good read, and it is fully cited. Now it still leaves the door open to the possibility that you need some insulin some time to keep all of the other GLUT transports active or upregulated, it is clear to me that you don't need insulin on board for any and all cells to take in glucose. Again the main issue of exercise not being a cure is that lack of insulin will eventually cause the liver to produce uncontrolled ketoacidosis.

    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.

    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: Jul 22, 2015
  17. Michelle'sMom

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    Bearing in mind that my dd has PCOS, I asked about the cycle because prior to her PCOS dx we had days similar to what you've described, although not as long lasting & certainly not to the point of suspending basal. Not that I'm suggesting your dd's situation is the same, but I have an (obviously) personal interest in hormones & their effects on insulin sensitivity.
     
  18. Theo's dad Joe

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    I was actually wondering about PCOS. If someone cycles between higher insulin resistance and lower insulin resistance the first period of time may upregulate the NIMGU which has been shown to go up with insulin resistance, and then if there was a following period of increased sensitivity it might bring the need way down. Does PCOS cause cycles of higher and lower basal needs?

    Oh, and StacyMM did bring up a question, you might want to check ketones with the low. When my son is about to get sick, I'll catch him in the 60s but with medium ketones. I have known he was getting sick a day ahead of time on two occasions because he had ketones after a mid 60s morning number.
     
    Last edited: Jul 22, 2015
  19. Michelle'sMom

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    The monthly cycle alone causes cycles of higher/lower basal needs. One of the many symptoms of PCOS is hormone imbalance, mainly higher testosterone in my dd. The imbalance exaggerates the hormonal effect on basal needs. The treatments, depending upon which medication, vary in their effects on basal needs. Metformin has increased insulin sensitivity remarkably. All of the other meds so far have increased insulin resistance, along with other unpleasant/undesirable side effects. The goal is to reduce the amount of circulating insulin.


    Darryl, I hope you'll update as things progress/change/return to "normal."
     
  20. sugarmonkey

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    I know we've definitely seen this with Phillip. He'll suddenly go high, then his sister gets sick. He hardly ever actually gets symptoms, but I'm convinced the highs are his body fighting illness. I don't think we've seen him go low from an infection though. After he's had a tummy back, yes, but not before.
     

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