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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.


  1. Ludvigsen, C. & Jarett, L. (1980). A comparison of basal and insulin-stimulated glucose transport in rat adipocyte plasma membranes. Diabetes, 29(5), 373-8.
  2. 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
  3. Ebeling, P., Koistinen, H. A., & Koivisto, V. A. (1998). Insulin-independent glucose transport regulates insulin sensitivity. Febs letters, 436(3), 301-3.
  4. 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.
  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
  6. 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.
  7. Sonksen, P. H. (2001). Insulin, growth hormone and sport. The journal of endocrinology, 170(1), 13-25.
  8. ibid
  9. ibid
  10. 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.
  11. 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
  12. 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
  13. 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
  14. see Sonksen, p. H. (2001)

  • Milind Watve

    Congratulations Nadeem for the article. It did not surprise me.

    Not only the dependence of muscle glucose uptake on insulin, the current theory of insulin resistance and diabetes is plagued with a large number of misconceptions, which are coming to light now with knockouts and other tools. It seems to me that the entire theory is collapsing, rather has already collapsed but people will take some more time to realize that it has collapsed. But see my recent book, “Doves, diplomats and diabetes: A Darwinian interpretation of type 2 diabetes and related disorders” by Springer ( which reviews the current status of the theory and the possible alternative ways of thinking.

    • Thanks Milind, I really appreciate your comments. Please feel free to expand upon the misconceptions to which you are referring.

    • I really value your comments, Milind. Thanks!

      Feel free to expand on the misconceptions to which you are referring.

      I’ve looked up your publications using ReadCube, and look forward to reading them.

      Your book is a bit pricey, but I’m captured by both the premise and the promise of the book.
      I will try to get it.

  • Johannes

    Hi Nadeem! I found your text really interesting, and somewhat informative. Asking questions is important for the development of modern medicine.

    It is possible that my understanding of this is colored by the information obtained as a medical student; but I think this was a bit too simplyfied. Correct me if I’m wrong, but it seems as though you are neglecting GLUT4’s ability to lower blood glucose. Isn’t it a possibility that this is accomplished through a network of different mechanisms? After all, before the discovery of insulin, all diabetics died only years after onset…I find it somewhat diffucult believing that inhibition og gluconeogenesis is the only way in which insulin is able to lower blood glucose levels.

    Anywho, this is a really interesting topic, and it’s is possible that medical schools are focusing too much on GLUT4!

    • Thanks for your comments, Johannes. They are precious to me.

      You’re right: I did not focus on GLUT4 nor it’s abilities, except indirectly.
      I chose not to talk about GLUT4 in-depth, as it was not the subject of this article
      During hyperglycemia, it won’t matter how able the GLUT4s are, or how many there are of them – there will be no net glucose uptake.

      You’ve misunderstood. I did not say that inhibition of gluconeogenesis is the only way to lower blood glucose levels.

      Under normal conditions (normoglycemia), insulin & GLUT4 along with inhibition of gluconeogenesis will regulate blood glucose levels.

      Hyperglycemia, however, is another story. The cells are now already filled with as much glucose they can take.
      Here, GLUT4 is not going to help. How could it?

      I also think this subject is interesting. Looking forward to your response :-)

      • Johannes

        I see!

        But if cells are stuffed with glucose in a hyperglycemic situation, how can insulin be used to treat hyperglycemic patients with diabetes? I see your point, whitout the presence of a concentration gradient, facilitated uptake (like GLUT4) would not be effective.

        • Thank you, for your question. I will try to answer it briefly.

          When insulin is administered during hyperglycemic conditions, it lowers blood sugar levels by:

          1) Suppressing hepatic gluconeogenesis. This shuts off the supply of glucose to the blood from the liver.
          2) Suppressing lipolysis and ketogenesis. This allows cells to burn more of the glucose they have, so that they can take in more.
          3) Increases lipogenesis, a process in which glucose is a substrate.

          All these factors work together to diminish hyperglycemia, and this why we use insulin in diabetics.

          I highly recommend that you read the section labeled “Insulin Physiology”, pages 14 and 15, in the pdf linked below.
 – This is a 2001 paper published in the Journal of Endocrinology.

  • kristina

    you should check some of the recent papers coming out of roger unger’s lab at UT Southwestern. in mice where glucagon signaling is abolished (glucagon-receptor knock-outs), insulin is basically dispensable! without glucagon action, you can in fact not make a mouse diabetic. remove all the insulin and the animal is still normal-glycemic. so i think that insulin’s basic role is to oppose glucagon. glucose uptake into glut4 cells is a secondary function.

    • Thanks for the tip :-)

      Is this the one?

      This study is very telling indeed!

      I think that the organ that most significantly impacts glycemia is the liver.

      Are you a medical student as well?

      I will try to incorporate your observations in my article.

      • kristina

        no, i’m a postdoc working in mammalian glucose homeostasis.

        when you have no insulin (T1D) or insulin resistance (T2D), glucagon action is unopposed. the consequences are as we know.

        • It’s very encouraging to get comments from someone as highly educated as you.

          Did you notice any factual errors in my article?

  • Brick M

    If he is correct, then diabetics (assuming you mean type 1) died soon after the onset of the disease because they cannot produce insulin. Since they cannot produce insulin, the liver is never “told” to synthesize glycogen instead of releasing glucose into the blood. This does leave me wondering how excess glucose is excreted from the body, though. Is it simply filtered through the kidneys because it oversaturates the transporters?

  • MaxsterBaxsterBailey
  • Colin Nordstrom

    Hi Nadeem,

    I recently sent this email to Todd Becker (author of excellent blog post called “Obesity starts in the brain”):

    the last month, I have been racking my brain over a 3rd possible
    pathway to hypothalamus inflammation. I wholeheartedly agree with the
    fructose/palmitic acid/leptin resistance and the bad fatty acid/insulin
    resistance pathways, but a 3rd one was eluding me. I kept coming back
    to this insulin-driven pathway, however the thought of the insulin
    sensitive Sumos pushed me away from it. Then last night everything came
    together, and was confirmed by a Dr. Sears article on Arachidonic Acid.

    the day progresses, insulin sensitivity decreases. The Sumo
    interestingly fast throughout the morning, have a crazy workout, and
    then gorge on rice post workout. But why do they remain insulin
    sensitive? They remain insulin sensitive because they signal what is
    called a Glut4 insulin-independent mediated pathway. Normally Glut4 is
    an insulin dependent pathway, but resistance training circumvents the
    insulin signal and gets glucose out of the bloodstream.

    what about a couch potato who downs a starch heavy dinner? This is
    where insulin sensitivity works against this person and creates a 3rd
    inflammatory pathway. Because insulin sensitivity is lowest at the end
    of the day, glucose has a hard time leaving the bloodstream because Glut
    4’s aren’t being activated. No insulin, no Glut4. So what is getting
    glucose out of the bloodstream? Mainly the Glut1 and Glut3 transporters
    (Glut 2 are mainly in hepatocytes and beta pancreatic cells), but they
    are slower to get the glucose shuttled out. Thus, insulin levels remain
    elevated, and arachidonic acid rears its ugly head.

    am proposing, just as palmitic acid leaks over to the insulin resistance
    pathway, similarly arachidonic acid also leaks over to the insulin
    resistance pathway. I also feel chronically elevated insulin levels
    with whole grains and late night carbs are driving testosterone levels
    into the dump, which could also be playing into this insulin resistance.

    interesting fact, the brain mainly consists of Glut1 and Glut3
    transporters, however the hypothalamus is predominantly Glut 4, thus
    insulin is acting on it. Another reason why this 3rd pathway is posing a

  • A.Manimaran

    I really liked the way GLUT4 and insulin dependency is put forth by you. I too am having lot of misconceptions about the so-called ‘Diabetes’. But how could you reconcile with the fact that the glucose travelling around the blood in high concentration. Does it cause any other problems, like excess urine, excess hunger or neuropathy. Do you think ‘diabetes’ and peripheral neuropathy is linked really? If we can decipher this, I think we can easily debust the ‘disease of diabetes’ theory once and for all. I am an acupuncturist.

  • Nostents4me

    Above findings largely go along the lines of Dr Jason Fung’s. He recently wrote an article stating that “insulin resistance is protecting the cells” from getting too much sugar pointing to research similar to above, that cells do not starve during hyperglycemia. The conclusion after reading also above is that insulin resistance is protecting the liver from filling up with more glucose, producing more fat and hence become fattier. Which means insulin (and metformin and other sensitizers ) removes this protection for the liver, making it fattier faster, yet protecting cells from accelerated internal glycation and ROS production, that would take place in the hyperglycemic state. Since insulin itself promotes insulin resistance, the solution for DB T2 is to switch to a diet that does not promote high blood glucose, or a lower carb diet that was practised for T2 up to around 1970. Medicine that promotes discharge of excess sugar in the urine can of course be better than insulin, but seemingly the organs that excrete it cannot do it safely long term, making the dietary approach the remaining choice.
    A low carb diet will inhibit or reduce progress of T2, but not reverse it. To reverse T2, extreme low calorie diet (Prof Roy Taylor, Newcastle, UK) or intermittent water fasting works, and once the waist measure is normalized it indicates no metabolic syndrome remains, hence T2 gone. (A return to high carb diet can quickly return T2, so a diet that does not promote high blood sugar is necessary)
    The extreme low calorie diet is a painful experience as hunger will persist during maybe 8 weeks, while hunger usually ceases on or before day 3 in fasting.
    Google IDM Jason Fung to see his very interesting blogs! He is a kidney specialist.

Nadeem J. Qureshi