Insulin Resistance: Part Two

A Leading Cause of Disease

In the previous blog we looked at the normal physiology of blood sugar management. This included the function of insulin and its effects on cells, especially in the liver and the muscle. Insulin resistance is the defining feature of Type 2 diabetes mellitus (T2DM) – a disease that is rapidly increasing in our society. In fact, T2DM was once called adult-onset diabetes because it was only seen in adults. Unfortunately, this can now be deemed a nomenclature, as poor diet, inactivity, and subsequent obesity in children has led to people as young as 10 years old being diagnosed with this disease (1). Gestational diabetes as well as polycystic ovarian syndrome are also conditions of insulin resistance, or glucose intolerance (2). Not only is insulin resistance a cornerstone of diabetes, but also of cardiovascular disease – the number one killer in the Western world (3). With the worldwide prevalence of insulin resistance ranging from 15.5-46.5%, this is a problem that needs to be resolved (4). But what is insulin resistance? Let’s break it down.

Insulin Resistance: A Breakdown

Insulin’s job is to communicate or bind to the insulin receptor on cells. Once this occurs, it allows sugar to move from the blood into cells. When cells are insulin resistant, they literally resist binding to or communicating with insulin (5). Let’s go back to our lock and key analogy, where insulin is a key unlocking a door, the insulin receptor. In an insulin resistant state, the lock on the door is gummed up and blocked, and so the key doesn’t work to open the door. The sugar cannot move into the cells and it stays in the blood, leading to high blood sugar or hyperglycaemia. This is illustrated in Diagram One. Insulin resistance is the first stage of T2DM development (5).

Diagram One: Insulin resistance prevents insulin binding to the receptor and sugar cannot move into the cell. Instead, sugar builds up in the blood.

To explain what happens next, we will build on this analogy. Insulin knocks on the door to announce the arrival of blood sugar and chaperone it into the cell. However, music is playing loudly and the cell cannot hear insulin knocking. As sugar is still high in the blood, the pancreas continues to release insulin, and the extra insulin continues to knock louder and louder on the door. Finally, with so much insulin at the door, the cell hears the knocks over the music and opens the door for insulin to chaperone the sugar in. But the insulin required to carry out the function is much higher than normal, and leads to high insulin in the blood or hyperinsulinaemia. This process is shown in Diagram Two.

Diagram Two: Insulin receptor dysfunction keeps blood sugar high. In response insulin levels continue to rise. High insulin eventually activates receptor and glucose can move into cell.

The worse the insulin resistance, or the louder the music, the more insulin is required to allow blood glucose to gain entry. When the disease is more advanced, this can lead to pancreatic burnout as the pancreas has been working overtime to meet the abnormally high insulin demands. For some people, they develop insulin-dependent type 2 diabetes, where they need to rely on exogenous insulin (like Type 1 diabetics) to manage their blood sugar (6). In fact, by the time T2DM is diagnosed 40-50% of beta-cell function (the cells that produce insulin) is lost (6). This illustrates how important it is for insulin resistance to be addressed prior to a diagnosis of T2DM. However, insulin resistance is not just an issue of T2DM. Type 1 diabetics can also be insulin resistant. While it doesn’t contribute to the development of the disease, it is a crucial factor in disease management.

The Liver: The Glucose Factory

Insulin resistance does not allow dietary carbohydrate to be metabolised properly – it stays in the blood because its chaperone isn’t able to do its job. However, there is a second and very important part to this story. We learned in Part One of this series that insulin plays a pivotal role in down-regulating or inhibiting the production of glucose in the liver (gluconeogenesis). Gluconeogenesis only occurs when there are low levels of blood sugar, which in an insulin sensitive person would always be paired with low insulin.

Low insulin normally means low blood sugar.

Insulin resistance in the liver prevents insulin from binding or communicating with the insulin receptors. The only way the liver knows insulin is present is if this receptor-insulin binding occurs. The liver assumes there is no insulin in the blood and, therefore, also that blood sugar is low. Low insulin and low blood sugar are THE drivers of gluconeogenesis (your body’s production of glucose), which leads to raised blood sugar (7).

Therefore, not only does insulin resistance cause high blood sugar by not allowing carbohydrate from food to leave the blood after a meal, it also leads to more sugar being released from the liver. This means that someone can eat a ketogenic (a low or no carbohydrate) diet and experience high blood sugar if they are insulin resistant. They are not eating carbohydrate, but because insulin cannot communicate with their liver, the liver produces high amounts of glucose.

Also, the action of the primary anti-diabetic pharmaceutical medication, Metformin, involves significantly reducing gluconeogenesis in the liver (8). This prevents consequences of insulin resistance, thereby lowering and helping to manage blood glucose levels.

Diagram Three: Insulin resistance in the liver leads to the production of glucose, which is released into the blood. This contributes to high blood glucose levels, high insulin levels, and ultimately beta-cell dysfunction in the pancreas.

Hopefully now you have a better understanding of what insulin resistance is and how it leads to high blood sugar. Next time, we’ll look at the causes of insulin resistance. I am 100% sure the science will shock you! Buckle up!

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Written by Jessica Zabow
Accredited Practicing Nutritionist (BHSc)
& Yoga Teacher (RYT500)

References: 

1.     Rao, G., & Jensen. E.T. (2020). Type 2 diabetes in youth. Global pediatric health, 7(1), 1-9. https://doi.org/10.1177/2333794X20981343

2. Manoharan, V., & Wong, V.W. (2020). Impact of comorbid polycystic ovarian syndrome and gestational diabetes mellitus on pregnancy outcomes: A retrospective cohort study. BMC Pregnancy and Childbirth, 20(1), 1-7.
https://doi.org/10.1186/s12884-020-03175-5

3.     Zhang, H.J., Tan, X., & Wang, N.J. (2021). National trends in insulin resistance and beta-cell dysfunction among adults with prediabetes: NHANES 2001-2016. Chronic Diseases and Translational Medicine, 7(2), 125-134. https://doi.org/10.1016/j.cdtm.2020.11.003

4.     Fahed, M., Jaoudeh, M.G.A., Merhi, S., Bou Mosleh, J.M., Ghadieh, R., Al Hayek, S., & El Hayek Fares, J.E. (2020). Evaluation of risk factors for insulin resistance: A cross sectional study among employees at a private university in Lebanon. BMC Endocrine Disorders, 20(1), 1-14. https://doi.org/10.1186/s12902-020-00558-9

5.     Rahman, S., Hossain, K.S., Das, S., Kundu, S., Adegoke, E.O., Rahman, A., … Pang, M.G. (2021). Role of insulin in health and disease: An update. International Journal of Molecular Sciences, 22(12), 1-19. https://doi.org/10.3390/ijms22126403

6.     Wysham, C., & Shubrook, J. (2020). Beta-cell failure in type 2 diabetes: Mechanisms, markers, and clinical implications. Postgraduate Medicine, 132(2), 678-686. https://doi.org/10.1080/00325481.2020.1771047

7.     Hatting, M., Tavares, C.D.J., Rines, A.K., & Puigserver, P. (2018). Insulin regulation of gluconeogenesis. Annals of the New York Academy of Sciences, 1411(1), 21-35. https://doi.org/10.1111/nyas.13435

8. LaMoia, T.E., & Shulman, G.I. (2021). Cellular and molecular mechanisms of metformin action. Endocrine Reviews, 42(1), 77-96. https://doi.org/10.1210/endrev/bnaa023